Journal: J Am Heart Assoc

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Abstract

Statins and SARS-CoV-2 Infection: Results of a Population-Based Prospective Cohort Study of 469 749 Adults From 2 Canadian Provinces.

McAlister FA, Wang T, Wang X, Chu A, ... Lee DS, CORONA Collaboration *

Background:
Small observational studies have suggested that statin users have a lower risk of dying with COVID-19. We tested this hypothesis in a large, population-based cohort of adults in 2 of Canada\'s most populous provinces: Ontario and Alberta. Methods and Results We examined reverse transcriptase-polymerase chain reaction swab positivity rates for SARS-CoV-2 in adults using statins compared with nonusers. In patients with SARS-CoV-2 infection, we compared 30-day risk of all-cause emergency department visit, hospitalization, intensive care unit admission, or death in statin users versus nonusers, adjusting for baseline differences in demographics, clinical comorbidities, and prior health care use, as well as propensity for statin use. Between January and June 2020, 2.4% of 226 142 tested individuals aged 18 to 65 years, 2.7% of 88 387 people aged 66 to 75 years, and 4.1% of 154 950 people older than 75 years had a positive reverse transcriptase-polymerase chain reaction swab for SARS-CoV-2. Compared with 353 878 nonusers, the 115 871 statin users were more likely to test positive for SARS-CoV-2 (3.6% versus 2.8%, P<0.001), but this difference was not significant after adjustment for baseline differences and propensity for statin use in each age stratum (adjusted odds ratio 1.00 [95% CI, 0.88-1.14], 1.00 [0.91-1.09], and 1.06 [0.82-1.38], respectively). In individuals younger than 75 years with SARS-CoV-2 infection, statin users were more likely to visit an emergency department, be hospitalized, be admitted to the intensive care unit, or to die of any cause within 30 days of their positive swab result than nonusers, but none of these associations were significant after multivariable adjustment. In individuals older than 75 years with SARS-CoV-2, statin users were more likely to visit an emergency department (28.2% versus 17.9%, adjusted odds ratio 1.41 [1.23-1.61]) or be hospitalized (32.7% versus 21.9%, adjusted odds ratio 1.19 [1.05-1.36]), but were less likely to die (26.9% versus 31.3%, adjusted odds ratio 0.76 [0.67-0.86]) of any cause within 30 days of their positive swab result than nonusers.
Conclusions:
Compared with statin nonusers, patients taking statins exhibit the same risk of testing positive for SARS-CoV-2 and those younger than 75 years exhibit similar outcomes within 30 days of a positive test. Patients older than 75 years with a positive SARS-CoV-2 test and who were taking statins had more emergency department visits and hospitalizations, but exhibited lower 30-day all-cause mortality risk.




J Am Heart Assoc: 22 Oct 2021:e022330; epub ahead of print
McAlister FA, Wang T, Wang X, Chu A, ... Lee DS, CORONA Collaboration *
J Am Heart Assoc: 22 Oct 2021:e022330; epub ahead of print | PMID: 34689613
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Abstract

Comparison of the FRIEND and Wasserman-Hansen Equations in Predicting Outcomes in Heart Failure.

Myers J, de Souza E Silva CG, Arena R, Kaminsky L, ... Ashley E, Moneghetti K

Background:
Percentage of age-predicted peak oxygen uptake (VO2) achieved (ppVO2) has been widely used to stratify risk in patients with heart failure. However, there are limitations to traditional normal standards. We compared the recently derived FRIEND (Fitness Registry and the Importance of Exercise: A National Data Base) equation to the widely used Wasserman-Hansen (WH) ppVO2 equation to predict outcomes in patients with heart failure. Methods and Results A subgroup of 4055 heart failure patients from the FRIEND registry (mean age 53±15 years) was followed for a mean of 28±16 months. The FRIEND and WH equations along with measured peak VO2 expressed in mL/kg-1 per min-1 were compared for mortality and composite cardiovascular events. ppVO2 was higher for the FRIEND versus the WH equation (66±30% versus 58±25%; P<0.001). The areas under the receiver operating characteristic curves were slightly but significantly higher for the FRIEND equation for mortality (0.74 versus 0.72; P=0.03) and cardiac events (0.70 versus 0.68; P=0.008). Area under the receiver operating characteristic curve for measured peak VO2 was 0.70 (P<0.001) for mortality and 0.73 (P<0.001) for cardiovascular events. For each 1-SD higher ppVO2 for the FRIEND equation, mortality was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.69-0.97; P<0.02); for each 1-SD higher ppVO2 for the WH equation, the mortality was reduced by 17% (hazard ratio, 0.83; 95% CI, 0.71-0.97; P=0.02). The corresponding reductions in risk per 1 SD for cardiovascular events for the FRIEND and WH equations were 23 and 21%, respectively (both P<0.001).
Conclusions:
Peak VO2 expressed as percentage of an age-predicted standard strongly predicts mortality and major cardiovascular events in patients with heart failure. The FRIEND registry equation exhibited test characteristics slightly superior to the commonly used WH equation.




J Am Heart Assoc: 22 Oct 2021:e021246; epub ahead of print
Myers J, de Souza E Silva CG, Arena R, Kaminsky L, ... Ashley E, Moneghetti K
J Am Heart Assoc: 22 Oct 2021:e021246; epub ahead of print | PMID: 34689609
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Abstract

Temporal Trends and Factors Associated With the Inclusion of Patient-Reported Outcomes in Heart Failure Randomized Controlled Trials: A Systematic Review.

Eliya Y, Averbuch T, Le N, Xie F, ... Mamas MA, Van Spall HGC

Background:
Patient-reported outcomes (PROs) are important measures of treatment response in heart failure. We assessed temporal trends in and factors associated with inclusion of PROs in heart failure randomized controlled trials (RCTs). Methods and Results We searched MEDLINE, Embase, and CINAHL for studies published between January 2000 and July 2020 in journals with an impact factor ≥10. We assessed temporal trends using the Jonckheere-Terpstra test and conducted multivariable logistic regression to explore trial characteristics associated with PRO inclusion. We assessed the quality of PRO reporting using the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. Of 417 RCTs included, PROs were reported in 226 (54.2%; 95% CI, 49.3%-59.1%), with increased reporting between 2000 and 2020 (P<0.001). The odds of PRO inclusion were greater in RCTs that were published in recent years (adjusted odds ratio [aOR] per year, 1.08; 95% CI, 1.04-1.12; P<0.001), multicenter (aOR, 1.89; 95% CI, 1.03-3.46; P=0.040), medium-sized (aOR, 2.35; 95% CI, 1.26-4.40; P=0.008), coordinated in Central and South America (aOR, 5.93; 95% CI, 1.14-30.97; P=0.035), and tested health service (aOR, 3.12; 95% CI, 1.49-6.55; P=0.003), device/surgical (aOR, 6.66; 95% CI, 3.15-14.05; P<0.001), or exercise (aOR, 4.66; 95% CI, 1.81-12.00; P=0.001) interventions. RCTs reported a median of 4 (interquartile interval , 3-6) of a possible of 11 CONSORT PRO items.
Conclusions:
Just over half of all heart failure RCTs published in high impact factor journals between 2000 and 2020 included PROs, with increased inclusion of PROs over time. Trials that were large, tested pharmaceutical interventions, and coordinated in North America / Europe had lower adjusted odds of reporting PROs relative to other trials. The quality of PRO reporting was modest.




J Am Heart Assoc: 22 Oct 2021:e022353; epub ahead of print
Eliya Y, Averbuch T, Le N, Xie F, ... Mamas MA, Van Spall HGC
J Am Heart Assoc: 22 Oct 2021:e022353; epub ahead of print | PMID: 34689608
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Abstract

Ischemic Stroke in Acute Decompensated Heart Failure: From the KCHF Registry.

Iguchi M, Kato T, Yaku H, Morimoto T, ... Kuwahara K, Kimura T

Background:
Heart failure (HF) is a known risk factor for ischemic stroke, but data regarding ischemic stroke during hospitalization for acute decompensated HF (ADHF) are limited. Methods and Results We analyzed the data from a multicenter registry (Kyoto Congestive Heart Failure [KCHF] Registry) that enrolled 4056 consecutive patients with ADHF in Japan (mean age, 78 years; men, 2238 patients [55%]; acute coronary syndrome [ACS], 239 patients [5.9%]). We investigated the incidence and predictors of ischemic stroke during hospitalization for ADHF. During the hospitalization, 63 patients (1.6%) developed ischemic stroke. The median interval from admission to the onset of ischemic stroke was 7 [interquartile range: 2-14] days, and the most common underlying cause was cardioembolism (64%). Men (OR, 1.87; 95%CI, 1.11-3.24), ACS (OR, 2.31; 95%CI, 1.01-4.93), absence of prior HF hospitalization (OR, 2.21; 95%CI, 1.24-4.21), and high B-type natriuretic peptide (BNP)/N-terminal proBNP (NT-proBNP) levels (above the median) at admission (OR, 3.15; 95%CI, 1.84-5.60) were independently associated with ischemic stroke. In patients without ACS, the independent risk factors for ischemic stroke were fully consistent with those in the main analysis. Higher quartiles of BNP/NT-proBNP levels were significantly associated with higher incidence of ischemic stroke (P for trend, <0.001). Patients with ischemic stroke showed higher in-hospital mortality, longer length of hospital stay, and poorer functional status at discharge.
Conclusions:
During hospitalization for ADHF, 1.6% of the patients developed ischemic stroke. Men, ACS, absence of prior HF hospitalization, and high BNP/NT-proBNP levels at admission were independently associated with ischemic stroke.




J Am Heart Assoc: 22 Oct 2021:e022525; epub ahead of print
Iguchi M, Kato T, Yaku H, Morimoto T, ... Kuwahara K, Kimura T
J Am Heart Assoc: 22 Oct 2021:e022525; epub ahead of print | PMID: 34689603
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Abstract

Satellite Cell Expression of RAGE (Receptor for Advanced Glycation end Products) Is Important for Collateral Vessel Formation.

Hansen L, Joseph G, Valdivia A, Taylor WR

Background:
The growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type. Methods and Results Using a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild-type satellite cells increased tumor necrosis factor-α and monocyte chemoattractant protein-1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high-mobility group box 1. Furthermore, encapsulated wild-type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules.
Conclusions:
Thus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.




J Am Heart Assoc: 22 Oct 2021:e022127; epub ahead of print
Hansen L, Joseph G, Valdivia A, Taylor WR
J Am Heart Assoc: 22 Oct 2021:e022127; epub ahead of print | PMID: 34689598
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Abstract

Salt-Sensitive Hypertension, Renal Injury, and Renal Vasodysfunction Associated With Dahl Salt-Sensitive Rats Are Abolished in Consomic SS.BN1 Rats.

Potter JC, Whiles SA, Miles CB, Whiles JB, ... Picken MM, Polichnowski AJ

Background:
Abnormal renal hemodynamic responses to salt-loading are thought to contribute to salt-sensitive (SS) hypertension. However, this is based largely on studies in anesthetized animals, and little data are available in conscious SS and salt-resistant rats. Methods and Results We assessed arterial blood pressure, renal function, and renal blood flow during administration of a 0.4% NaCl and a high-salt (4.0% NaCl) diet in conscious, chronically instrumented 10- to 14-week-old Dahl SS and consomic SS rats in which chromosome 1 from the salt-resistant Brown-Norway strain was introgressed into the genome of the SS strain (SS.BN1). Three weeks of high salt intake significantly increased blood pressure (20%) and exacerbated renal injury in SS rats. In contrast, the increase in blood pressure (5%) was similarly attenuated in Brown-Norway and SS.BN1 rats, and both strains were completely protected against renal injury. In SS.BN1 rats, 1 week of high salt intake was associated with a significant decrease in renal vascular resistance (-8%) and increase in renal blood flow (15%). In contrast, renal vascular resistance failed to decrease, and renal blood flow remained unchanged in SS rats during high salt intake. Finally, urinary sodium excretion and glomerular filtration rate were similar between SS and SS.BN1 rats during 0.4% NaCl and high salt intake.
Conclusions:
Our data support the concept that renal vasodysfunction contributes to blood pressure salt sensitivity in Dahl SS rats, and that genes on rat chromosome 1 play a major role in modulating renal hemodynamic responses to salt loading and salt-induced hypertension.




J Am Heart Assoc: 22 Oct 2021:e020261; epub ahead of print
Potter JC, Whiles SA, Miles CB, Whiles JB, ... Picken MM, Polichnowski AJ
J Am Heart Assoc: 22 Oct 2021:e020261; epub ahead of print | PMID: 34689582
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Abstract

Center Variability in Medicare Claims-Based Publicly Reported Transcatheter Aortic Valve Replacement Outcome Measures.

Thompson MP, Hou H, Brescia AA, Pagani FD, ... McCullough JS, Likosky DS

Background:
Public reporting of transcatheter aortic valve replacement (TAVR) claims-based outcome measures is used to identify high- and low-performing centers. Whether claims-based TAVR outcomes can reliably be used for center-level comparisons is unknown. In this study, we sought to evaluate center variability in claims-based TAVR outcomes used in public reporting. Methods and Results The study sample included 119 554 Medicare beneficiaries undergoing TAVR between January 2014 and October 2018 based on procedure codes in 100% Medicare inpatient claims. Multivariable hierarchical logistic regression was used to estimate center-specific adjusted rates and reliability (R) of 30-day mortality, discharge not to home/self-care, 30-day stroke, and 30-day readmission. Reliability was defined as the ratio of between-hospital variation to the sum of the between- and within-hospital variation. The median (interquartile range [IQR]) center-level adjusted outcome rates were 3.1% (2.9%-3.4%) for 30-day mortality, 41.4% (31.3%-53.4%) for discharge not to home, 2.5% (2.3%-2.7%) for 30-day stroke, and 14.9% (14.4%-15.5%) for 30-day readmission. Median reliability was highest for the discharge not to home measure (R=0.95; IQR, 0.94-0.97), followed by the 30-day stroke (R=0.92; IQR, 0.87-0.94), 30-day mortality (R=0.86; IQR, 0.81-0.91), and 30-day readmission measures (R=0.42; IQR, 0.35-0.51). Across outcomes, there was an inverse relationship between center volume and measure reliability.
Conclusions:
Claims-based TAVR outcome measures for mortality, discharge not to home, and stroke were reliable measures for center-level comparisons, but readmission measures were unreliable. Stakeholders should consider these findings when evaluating claims-based measures to compare center-level TAVR performance.




J Am Heart Assoc: 22 Oct 2021:e021629; epub ahead of print
Thompson MP, Hou H, Brescia AA, Pagani FD, ... McCullough JS, Likosky DS
J Am Heart Assoc: 22 Oct 2021:e021629; epub ahead of print | PMID: 34689581
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Abstract

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Kikuno M, Ueno Y, Takekawa H, Kanemaru K, ... Urabe T, CHALLENGE ESUS/CS Collaborators *

Background:
Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer.
Conclusions:
Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.




J Am Heart Assoc: 22 Oct 2021:e021375; epub ahead of print
Kikuno M, Ueno Y, Takekawa H, Kanemaru K, ... Urabe T, CHALLENGE ESUS/CS Collaborators *
J Am Heart Assoc: 22 Oct 2021:e021375; epub ahead of print | PMID: 34689573
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Abstract

Changing Incidence and Mechanism of Pregnancy-Associated Myocardial Infarction in the State of California.

Jalnapurkar S, Xu KH, Zhang Z, Bairey Merz CN, Elkayam U, Pai RG

Background:
The objective of this study was to evaluate the temporal trends in pregnancy-associated myocardial infarction (PAMI) in the State of California and explore potential risk factors and mechanisms. Methods and Results The California State Inpatient Database was analyzed from 2003 to 2011 for patients with International Classification of Diseases, Ninth Revision (ICD-9) codes for acute myocardial infarction and pregnancy or postpartum admissions; risk factors were analyzed and compared with pregnant patients without myocardial infarction. A total of 341 patients were identified with PAMI from a total of 5 266 380 pregnancies (incidence of 6.5 per 100 000 pregnancies). Inpatient maternal mortality rate was 7%, and infant mortality rate was 3.5% among patients with PAMI. There was a nonsignificant trend toward an increase in PAMI incidence from 2003 to 2011, possibly attributable to higher incidence of spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome. PAMI, when compared with pregnant patients without myocardial infarction, was significant for older age (aged >30 years in 72% versus 37%, P<0.0005), higher preponderance of Black race (12% versus 6%, P<0.00005), lower socioeconomic status (median household income in lowest quartile 26% versus 20%, P=0.04), higher prevalence of hypertension (26% versus 7%, P<0.0005), diabetes (7% versus 1%, P<0.0005), anemia (31% versus 7%, P<0.0001), amphetamine use (1% versus 0%, P<0.00005), cocaine use (2% versus 0.2%, P<0.0001), and smoking (6% versus 1%, P=0.0001).
Conclusions:
There has been a trend toward an increase in PAMI incidence in California over the past decade, with an increasing trend in spontaneous coronary artery dissection, vasospasm, and Takotsubo syndrome as mechanisms. These findings warrant further investigation.




J Am Heart Assoc: 19 Oct 2021:e021056; epub ahead of print
Jalnapurkar S, Xu KH, Zhang Z, Bairey Merz CN, Elkayam U, Pai RG
J Am Heart Assoc: 19 Oct 2021:e021056; epub ahead of print | PMID: 34668401
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Impact:
Abstract

Association of Cardiology Billing Amounts With Health Care Utilization and Clinical Outcomes in Patients With Atrial Fibrillation.

Bhatia RS, Chu C, Kaoutskaia A, Ko DT, ... Goodman SG, Crystal E

Background:
The relationship between health care utilization and outcomes in patients with atrial fibrillation is unknown. The objective of this study was to investigate whether cardiologists\' billing amounts in a fee-for-service environment are associated with better patient-level clinical outcomes. Methods and Results A retrospective cohort study was conducted using administrative claims data of cardiologists in Ontario, Canada between April 1, 2011 and March 31, 2016. The cardiologists were stratified into quintiles based on their median billing patterns per patient over the observation period. The primary outcomes were patient-level receipt of repeat visits, cardiac diagnostic tests, and medications ≤1 year of index date. The secondary clinical outcomes were death, emergency department visits, and all-cause hospitalization 1-year post-index visit. The patient cohort comprised 182 572 patients with atrial fibrillation (median age 74 years, 58% male) from 467 cardiologists. Patients with atrial fibrillation seen by higher-billing cardiologists were 26% more likely to have an echocardiogram (adjusted odds ratio [aOR], 1.26 [95% CI, 1.10-1.43] for quintile 5 versus 2), 28% a stress test (aOR, 1.28 [1.12-1.46] for quintile 5 versus 2), 25% continuous electrocardiographic monitoring (aOR, 1.25 [1.08-1.46] for quintile 4 versus 2), and 79% more likely to get a stress echocardiogram (aOR, 1.79 [1.32-2.42] for quintile 5 versus 2). They also had a higher rate of all-cause hospitalization (aOR, 1.13 [1.07-1.20]). Mortality rates were similar across cardiologists billing quintiles (eg, aOR, 0.98 [0.87-1.11] for quintile 4 versus 2).
Conclusions:
Higher-billing cardiologists ordered more diagnostic tests per patient with atrial fibrillation but these are not associated with improvements in outcomes.




J Am Heart Assoc: 19 Oct 2021:e020708; epub ahead of print
Bhatia RS, Chu C, Kaoutskaia A, Ko DT, ... Goodman SG, Crystal E
J Am Heart Assoc: 19 Oct 2021:e020708; epub ahead of print | PMID: 34668397
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Abstract

Left Atrial Appendage Occlusion for Stroke Prevention in Nonvalvular Atrial Fibrillation.

Collado FMS, Lama von Buchwald CM, Anderson CK, Madan N, ... Jneid H, Kavinsky CJ
The majority of embolic strokes in patients with nonvalvular atrial fibrillation are caused by thrombi in the left atrial appendage. It is projected that strokes related to atrial fibrillation will markedly increase in the future unless effective mitigation strategies are implemented. Systemic anticoagulation has been known to be highly effective in reducing stroke risk in patients with atrial fibrillation. However, bleeding complications and nonadherence are barriers to effective anticoagulation therapy. Surgical and percutaneous left atrial appendage occlusion devices are nonpharmacologic strategies to mitigate the challenges of drug therapy. We present a contemporary review of left atrial appendage occlusion for stroke prevention in nonvalvular atrial fibrillation. A thorough review of the history of surgical and percutaneous left atrial appendage occlusion devices, recent trials, and US Food and Drug Administration milestones of current left atrial appendage occlusion devices are discussed.



J Am Heart Assoc: 19 Oct 2021:e022274; epub ahead of print
Collado FMS, Lama von Buchwald CM, Anderson CK, Madan N, ... Jneid H, Kavinsky CJ
J Am Heart Assoc: 19 Oct 2021:e022274; epub ahead of print | PMID: 34668395
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Abstract

Association Between Sleep Disturbances With Neurodevelopmental Problems and Decreased Health-Related Quality of Life in Children With Fontan Circulation.

Knobbe K, Partha M, Seckeler MD, Klewer S, ... Parthasarathy S, Combs D

Background:
Children with Fontan circulation are known to be at increased risk for neurodevelopmental problems and decreased health-related quality of life (HRQOL), but many factors that may contribute to this risk are unknown. Sleep disturbances may be one previously unidentified factor that contributes to this risk. Methods and Results We analyzed data from the Pediatric Heart Network Fontan cross-sectional study to evaluate associations between a parent or child report of sleep disturbance with reported neurodevelopmental concerns and HRQOL in 558 children with Fontan circulation. Parent-reported sleep disturbance was present in 11% of participants and child-reported sleep disturbance was present in 15%. Parent-reported sleep disturbance was associated with a significantly higher risk of attention problems, anxiety, depression, behavioral problems, and developmental delay (P<0.001 for all). Similarly, parent-reported disturbance was associated with decreased HRQOL on both parent and child-reported HRQOL (P<0.001 for most domains). Child-reported sleep disturbances were associated with increased odds of anxiety, depression, and attention problems as well as worse HRQOL. These associations were present even after adjustment for cardiac, demographic, and socioeconomic factors that may affect HRQOL and neurodevelopmental status.
Conclusions:
Sleep disturbances in children with Fontan circulation are associated with an increased risk of neurodevelopmental problems as well as reduced HRQOL compared with those without sleep disturbance. Better understanding of sleep disturbances is needed in children with Fontan circulation, as sleep disturbances may represent a reversible cause of neurodevelopmental problems and decreased HRQOL in this population.




J Am Heart Assoc: 19 Oct 2021:e021749; epub ahead of print
Knobbe K, Partha M, Seckeler MD, Klewer S, ... Parthasarathy S, Combs D
J Am Heart Assoc: 19 Oct 2021:e021749; epub ahead of print | PMID: 34668394
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Abstract

Secondary Precipitants of Atrial Fibrillation and Anticoagulation Therapy.

Ko D, Saleeba C, Sadiq H, Crawford S, ... Kapoor A, McManus D

Background:
Atrial fibrillation (AF) commonly occurs in the setting of acute conditions. We aimed to identify the acute conditions associated with secondary AF (AF precipitants) including pneumonia/sepsis, pneumothorax, respiratory failure, myocarditis, pericarditis, alcohol intoxication, thyrotoxicosis, cardiothoracic surgery, other surgery in patients with newly diagnosed AF and determine their association with subsequent oral anticoagulant use. Methods and Results We assembled a cohort of patients in the UMass Memorial Healthcare system with a new diagnosis of AF with and without AF precipitants. We used combinations of International Classification of Diseases, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, laboratory values, imaging reports, and physician notes including discharge summary texts to identify AF precipitants. We then manually reviewed the individual charts to validate presence of AF precipitants. The study sample consisted of 185 patients with and 172 patients without AF precipitants. Pneumonia/sepsis, myocardial infarction, respiratory failure, and cardiothoracic surgery were the most common precipitants identified. In multivariable analyses adjusting for age, sex, patient comorbidities, left atrial enlargement, left ventricular ejection fraction, and antiplatelet use, patients with AF precipitants were less likely to receive subsequent anticoagulation therapy at 30 days after the initial AF diagnosis (odds ratio, 0.31; 95% CI, 0.19-0.52). The association was persistent after excluding men with CHA2DS2-VASc score <2 and women with CHA2DS2-VASc score <3.
Conclusions:
Our study highlights lower usage of oral anticoagulant in secondary AF in contemporary clinical practice.




J Am Heart Assoc: 19 Oct 2021:e021746; epub ahead of print
Ko D, Saleeba C, Sadiq H, Crawford S, ... Kapoor A, McManus D
J Am Heart Assoc: 19 Oct 2021:e021746; epub ahead of print | PMID: 34668392
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Abstract

Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke.

Leskelä J, Toppila I, Härma MA, Palviainen T, ... Lehto M, Pussinen PJ

Background:
Translocation of lipopolysaccharide from gram-negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome-wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high-performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis-related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome-wide significant association with 741 single-nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1, KLKB1, F12, SLC34A1, YPEL4, CLP1, ZDHHC5, SERPING1, CBX5, and LIPC. The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism.
Conclusions:
The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.




J Am Heart Assoc: 19 Oct 2021:e022482; epub ahead of print
Leskelä J, Toppila I, Härma MA, Palviainen T, ... Lehto M, Pussinen PJ
J Am Heart Assoc: 19 Oct 2021:e022482; epub ahead of print | PMID: 34668383
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Abstract

Readmissions, Death and Its Associated Predictors in Heart Failure With Preserved Versus Reduced Ejection Fraction.

Tay WT, Teng TK, Simon O, Ouwerkerk W, ... Lam CSP, ASIAN‐HF Investigators

Background:
Data on rehospitalizations for heart failure (HF) in Asia are scarce. We sought to determine the burden and predictors of HF (first and recurrent) rehospitalizations and all-cause mortality in patients with HF and preserved versus reduced ejection fraction (preserved EF, ≥50%; reduced EF, <40%), in the multinational ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry. Methods and Results Patients with symptomatic (stage C) chronic HF were followed up for death and recurrent HF hospitalizations for 1 year. Predictors of HF hospitalizations or all-cause mortality were examined with Cox regression for time to first event and other methods for recurrent events analyses. Among 1666 patients with HF with preserved EF (mean age, 68±12 years; 50% women), and 4479 with HF with reduced EF (mean age, 61±13 years; 22% women), there were 642 and 2302 readmissions, with 28% and 45% attributed to HF, respectively. The 1-year composite event rate for first HF hospitalization or all-cause death was 11% and 21%, and for total HF hospitalization and all-cause death was 17.7 and 38.7 per 100 patient-years in HF with preserved EF and HF with reduced EF, respectively. In HF with preserved EF, consistent independent predictors of these clinical end points included enrollment as an inpatient, Southeast Asian location, and comorbid chronic kidney disease or atrial fibrillation. The same variables were predictive of outcomes in HF with reduced EF except atrial fibrillation, and also included Northeast Asian location, older age, elevated heart rate, decreased systolic blood pressure, diabetes, smoking, and non-usage of beta blockers.
Conclusions:
One-year HF rehospitalization and mortality rates were high among Asian patients with HF. Predictors of outcomes identified in this study could aid in risk stratification and timely interventions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01633398.




J Am Heart Assoc: 19 Oct 2021:e021414; epub ahead of print
Tay WT, Teng TK, Simon O, Ouwerkerk W, ... Lam CSP, ASIAN‐HF Investigators
J Am Heart Assoc: 19 Oct 2021:e021414; epub ahead of print | PMID: 34666509
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Impact:
Abstract

Cardiometabolic, Lifestyle, and Nutritional Factors in Relation to Varicose Veins: A Mendelian Randomization Study.

Yuan S, Bruzelius M, Damrauer SM, Larsson SC

Background:
We conducted a 2-sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single-nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25-hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome-wide significance level were used as instrumental variables. Summary-level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1-SD increase in the exposure were 1.34 (95% CI, 1.25-1.43) for height, 1.39 (95% CI, 1.27-1.52) for body mass index, 1.12 (95% CI, 1.04-1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16-1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62-0.92) per 1-SD increase in calcium levels and 0.97 (95% CI, 0.95-0.98) for zinc.
Conclusions:
This study identified several modifiable risk factors for varicose veins.




J Am Heart Assoc: 19 Oct 2021:e022286; epub ahead of print
Yuan S, Bruzelius M, Damrauer SM, Larsson SC
J Am Heart Assoc: 19 Oct 2021:e022286; epub ahead of print | PMID: 34666504
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Impact:
Abstract

Re-CHARGE-AF: Recalibration of the CHARGE-AF Model for Atrial Fibrillation Risk Prediction in Patients With Acute Stroke.

Ashburner JM, Wang X, Li X, Khurshid S, ... Lubitz SA, Anderson CD

Background:
Performance of existing atrial fibrillation (AF) risk prediction models in poststroke populations is unclear. We evaluated predictive utility of an AF risk model in patients with acute stroke and assessed performance of a fully refitted model. Methods and Results Within an academic hospital, we included patients aged 46 to 94 years discharged for acute ischemic stroke between 2003 and 2018. We estimated 5-year predicted probabilities of AF using the Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (CHARGE-AF) model, by recalibrating CHARGE-AF to the baseline risk of the sample, and by fully refitting a Cox proportional hazards model to the stroke sample (Re-CHARGE-AF) model. We compared discrimination and calibration between models and used 200 bootstrap samples for optimism-adjusted measures. Among 551 patients with acute stroke, there were 70 incident AF events over 5 years (cumulative incidence, 15.2%; 95% CI, 10.6%-19.5%). Median predicted 5-year risk from CHARGE-AF was 4.8% (quartile 1-quartile 3, 2.0-12.6) and from Re-CHARGE-AF was 16.1% (quartile 1-quartile 3, 8.0-26.2). For CHARGE-AF, discrimination was moderate (C statistic, 0.64; 95% CI, 0.57-0.70) and calibration was poor, underestimating AF risk (Greenwood-Nam D\'Agostino chi-square, P<0.001). Calibration with recalibrated baseline risk was also poor (Greenwood-Nam D\'Agostino chi-square, P<0.001). Re-CHARGE-AF improved discrimination (P=0.001) compared with CHARGE-AF (C statistic, 0.74 [95% CI, 0.68-0.79]; optimism-adjusted, 0.70 [95% CI, 0.65-0.75]) and was well calibrated (Greenwood-Nam D\'Agostino chi-square, P=0.97).
Conclusions:
Covariates from an established AF risk model enable accurate estimation of AF risk in a poststroke population after recalibration. A fully refitted model was required to account for varying baseline AF hazard and strength of associations between covariates and incident AF.




J Am Heart Assoc: 19 Oct 2021:e022363; epub ahead of print
Ashburner JM, Wang X, Li X, Khurshid S, ... Lubitz SA, Anderson CD
J Am Heart Assoc: 19 Oct 2021:e022363; epub ahead of print | PMID: 34666503
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Impact:
Abstract

Disability Among Young Adults With Congenital Heart Defects: Congenital Heart Survey to Recognize Outcomes, Needs, and Well-Being 2016-2019.

Downing KF, Oster ME, Klewer SE, Rose CE, ... Andrews JG, Farr SL

Background:
Disabilities have implications for health, well-being, and health care, yet limited information is available on the percentage of adults with congenital heart defects (CHD) living with disabilities. We evaluated the prevalence of disability and associated characteristics among the 2016-2019 CH STRONG (Congenital Heart Survey to Recognize Outcomes, Needs, and Well-Being) population-based sample of 19- to 38-year-olds with CHD from 3 US locations. Methods and Results Prevalence of disability types (hearing, vision, cognition, mobility, self-care, living independently) were compared with similarly aged adults from the general population as estimated by the American Community Survey and standardized to the CH STRONG eligible population to reduce nonresponse bias and confounding. Health-related quality of life (HRQOL) was measured via Patient-Reported Outcomes Measurement Information System Global Health Scale T-scores standardized to US 18- to 34-year-olds. Separate multivariable regression models assessed associations between disability and HRQOL. Of 1478 participants, 40% reported disabilities, with cognition most prevalent (29%). Of those reporting disability, 45% ever received disability benefits and 46% were unemployed. Prevalence of disability types were 5 to 8 times higher in adults with CHD than the general population. Those with ≥1 disability had greater odds of being female, and of having non-Hispanic Black maternal race and ethnicity, severe CHD, recent cardiac care, and noncardiac congenital anomalies. On average, adults with CHD and cognition, mobility, and self-care disabilities had impaired mental HRQOL and those with any disability type had impaired physical HRQOL.
Conclusions:
Two of 5 adults with CHD may have disabilities, which are associated with impaired HRQOL. These results may inform healthcare needs and services for this growing population.




J Am Heart Assoc: 19 Oct 2021:e022440; epub ahead of print
Downing KF, Oster ME, Klewer SE, Rose CE, ... Andrews JG, Farr SL
J Am Heart Assoc: 19 Oct 2021:e022440; epub ahead of print | PMID: 34666499
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Impact:
Abstract

Cell-Free Mitochondrial DNA as a Potential Biomarker for Astronauts\' Health.

Bisserier M, Shanmughapriya S, Rai AK, Gonzalez C, ... Hadri L, Goukassian DA

Background:
Space travel-associated stressors such as microgravity or radiation exposure have been reported in astronauts after short- and long-duration missions aboard the International Space Station. Despite risk mitigation strategies, adverse health effects remain a concern. Thus, there is a need to develop new diagnostic tools to facilitate early detection of physiological stress. Methods and Results We measured the levels of circulating cell-free mitochondrial DNA in blood plasma of 14 astronauts 10 days before launch, the day of landing, and 3 days after return. Our results revealed a significant increase of cell-free mitochondrial DNA in the plasma on the day of landing and 3 days after return with vast ~2 to 355-fold interastronaut variability. In addition, gene expression analysis of peripheral blood mononuclear cells revealed a significant increase in markers of inflammation, oxidative stress, and DNA damage.
Conclusions:
Our study suggests that cell-free mitochondrial DNA abundance might be a biomarker of stress or immune response related to microgravity, radiation, and other environmental factors during space flight.




J Am Heart Assoc: 19 Oct 2021:e022055; epub ahead of print
Bisserier M, Shanmughapriya S, Rai AK, Gonzalez C, ... Hadri L, Goukassian DA
J Am Heart Assoc: 19 Oct 2021:e022055; epub ahead of print | PMID: 34666498
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Impact:
Abstract

Supplementing Existing Societal Risk Models for Surgical Aortic Valve Replacement With Machine Learning for Improved Prediction.

Kilic A, Habib RH, Miller JK, Shahian DM, Dearani JA, Dubrawski AW

Background:
This study evaluated the role of supplementing Society of Thoracic Surgeons (STS) risk models for surgical aortic valve replacement with machine learning (ML). Methods and Results Adults undergoing isolated surgical aortic valve replacement in the STS National Database between 2007 and 2017 were included. ML models for operative mortality and major morbidity were previously developed using extreme gradient boosting. Concordance and discordance in predicted risk between ML and STS models were defined using equal-size tertile-based thresholds of risk. Calibration metrics and discriminatory capability were compared between concordant and discordant patients. A total of 243 142 patients were included. Nearly all calibration metrics were improved in cases of concordance. Similarly, concordance indices improved substantially in cases of concordance for all models with the exception of deep sternal wound infection. The greatest improvements in concordant versus discordant cases were in renal failure: ML model (concordance index, 0.660 [95% CI, 0.632-0.687] discordant versus 0.808 [95% CI, 0.794-0.822] concordant) and STS model (concordance index, 0.573 [95% CI, 0.549-0.576] discordant versus 0.797 [95% CI, 0.782-0.811] concordant) (each P<0.001). Excluding deep sternal wound infection, the concordance indices ranged from 0.549 to 0.660 for discordant cases and 0.674 to 0.808 for concordant cases.
Conclusions:
Supplementing ML models with existing STS models for surgical aortic valve replacement may have an important role in risk prediction and should be explored further. In particular, for the roughly 25% to 50% of patients demonstrating discordance in estimated risk between ML and STS, there appears to be a substantial decline in predictive performance suggesting vulnerability of the existing models in these patient subsets.




J Am Heart Assoc: 17 Oct 2021:e019697; epub ahead of print
Kilic A, Habib RH, Miller JK, Shahian DM, Dearani JA, Dubrawski AW
J Am Heart Assoc: 17 Oct 2021:e019697; epub ahead of print | PMID: 34658259
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Impact:
Abstract

Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial.

Matsuzawa Y, Kimura K, Yasuda S, Kaikita K, ... Ogawa H, AFIRE Investigators

Background:
Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high-risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non-valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub-study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non-atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all-cause death, while the safety end point was major bleeding. Net adverse events consisted of all-cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34-0.74; P<0.001), with a decrease in both efficacy (HR, 0.68; 95% CI, 0.47-0.99; P=0.044) and safety (HR, 0.37; 95% CI, 0.19-0.71; P=0.003) end points. By contrast, there were no differences between treatment outcomes for the non-atherothrombosis group.
Conclusions:
Rivaroxaban monotherapy significantly reduced net adverse events as compared with combination therapy for patients with atrial fibrillation, coronary artery disease, and prior atherothrombotic disease. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02642419.




J Am Heart Assoc: 17 Oct 2021:e020907; epub ahead of print
Matsuzawa Y, Kimura K, Yasuda S, Kaikita K, ... Ogawa H, AFIRE Investigators
J Am Heart Assoc: 17 Oct 2021:e020907; epub ahead of print | PMID: 34658247
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Impact:
Abstract

Prognostic Value of Transthoracic Doppler Echocardiography Coronary Flow Velocity Reserve in Patients With Asymmetric Hypertrophic Cardiomyopathy.

Tesic M, Beleslin B, Giga V, Jovanovic I, ... Ostojic M, Djordjevic Dikic A

Background:
Microvascular dysfunction might be a major determinant of clinical deterioration and outcome in patients with hypertrophic cardiomyopathy (HCM). However, long-term prognostic value of transthoracic Doppler echocardiography (TDE) coronary flow velocity reserve (CFVR) on clinical outcome is uncertain in HCM patients. Therefore, the aim of our study was to assess long-term prognostic value of CFVR on clinical outcome in HCM population. Methods and Results We prospectively included 150 HCM patients (82 women; mean age 48±15 years). Patients\' clinical characteristics, echocardiographic and CFVR findings (both for left anterior descending [LAD] and posterior descending artery [PD]), were assessed in all patients. The primary outcome was a composite of: HCM related death, heart failure requiring hospitalization, sustained ventricular tachycardia and ischemic stroke. Patients were stratified into 2 subgroups depending on CFVR LAD value: Group 1 (CFVR LAD>2, [n=87]) and Group 2 (CFVR LAD≤2, [n=63]). During a median follow-up of 88 months, 41/150 (27.3%) patients had adverse cardiac events. In Group 1, there were 8/87 (9.2%), whereas in Group 2 there were 33/63 (52.4%, P<0.001 vs. Group 1) adverse cardiac events. By Kaplan-Meier analysis, patients with preserved CFVR LAD had significantly higher cumulative event-free survival rate compared to patients with impaired CFVR LAD (96.4% and 90.9% versus 66.9% and 40.0%, at 5 and 8 years, respectively: log-rank 37.2, P<0.001). Multivariable analysis identified only CFVR LAD≤2 as an independent predictor for adverse cardiac outcome (HR 6.54; 95% CI 2.83-16.30, P<0.001), while CFVR PD was not significantly associated with outcome.
Conclusions:
In patients with HCM, impaired CFVR LAD (≤2) is a strong, independent predictor of adverse cardiac outcome. When the aim of testing is HCM risk stratification and CFVR LAD data are available, the evaluation of CFVR PD is redundant.




J Am Heart Assoc: 11 Oct 2021:e021936; epub ahead of print
Tesic M, Beleslin B, Giga V, Jovanovic I, ... Ostojic M, Djordjevic Dikic A
J Am Heart Assoc: 11 Oct 2021:e021936; epub ahead of print | PMID: 34634920
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Impact:
Abstract

Syndrome of Reversible Cardiogenic Shock and Left Ventricular Ballooning in Obstructive Hypertrophic Cardiomyopathy.

Sherrid MV, Swistel DG, Olivotto I, Pieroni M, ... Maron BJ, Kim B

Background:
Cardiogenic shock from most causes has unfavorable prognosis. Hypertrophic cardiomyopathy (HCM) can uncommonly present with apical ballooning and shock in association with sudden development of severe and unrelenting left ventricular (LV) outflow obstruction. Typical HCM phenotypic features of mild septal thickening, outflow gradients, and distinctive mitral abnormalities differentiate these patients from others with Takotsubo syndrome, who have normal mitral valves and no outflow obstruction. Methods and Results We analyzed 8 patients from our 4 HCM centers with obstructive HCM and abrupt presentation of cardiogenic shock with LV ballooning, and 6 cases reported in literature. Of 14 patients, 10 (71%) were women, aged 66±9 years, presenting with acute symptoms: LV ballooning; depressed ejection fraction (25±5%); refractory systemic hypotension; marked LV outflow tract obstruction (peak gradient, 94±28 mm Hg); and elevated troponin, but absence of atherosclerotic coronary disease. Shock was managed with intravenous administration of phenylephrine (n=6), norepinephrine (n=6), β-blocker (n=7), and vasopressin (n=1). Mechanical circulatory support was required in 8, including intra-aortic balloon pump (n=4), venoarterial extracorporeal membrane oxygenation (n=3), and Impella and Tandem Heart in 1 each. In refractory shock, urgent relief of obstruction by myectomy was performed in 5, and alcohol ablation in 1. All patients survived their critical illness, with full recovery of systolic function.
Conclusions:
When cardiogenic shock and LV ballooning occur in obstructive HCM, they are marked by distinctive anatomic and physiologic features. Relief of obstruction with targeted pharmacotherapy, mechanical circulatory support, and myectomy, when necessary for refractory shock, may lead to survival and normalization of systolic function.




J Am Heart Assoc: 11 Oct 2021:e021141; epub ahead of print
Sherrid MV, Swistel DG, Olivotto I, Pieroni M, ... Maron BJ, Kim B
J Am Heart Assoc: 11 Oct 2021:e021141; epub ahead of print | PMID: 34634917
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Impact:
Abstract

Falling Through the Cracks: The Current Gap in the Health Care Transition of Patients With Kawasaki Disease: A Scientific Statement From the American Heart Association.

Dahdah N, Kung SC, Friedman KG, Marelli A, ... and the Council on Arteriosclerosis, Thrombosis and Vascular Biology

Background:
Health care transition (HCT) is a period of high vulnerability for patients with chronic childhood diseases, particularly when patients shift from a pediatric to an adult care setting. An increasing number of patients with Kawasaki disease (KD) who develop medium and large coronary artery aneurysms (classified by the American Heart Association according to maximal internal coronary artery diameter Z-scores ≥5 and ≥10, respectively) are becoming adults and thus undergoing an HCT. However, a poor transition to an adult provider represents a risk of loss to follow-up, which can result in increasing morbidity and mortality. Methods and Results This scientific statement provides a summary of available literature and expert opinion pertaining to KD and HCT of children as they reach adulthood. The statement reviews the existing life-long risks for patients with KD, explains current guidelines for long-term care of patients with KD, and offers guidance on assessment and preparation of patients with KD for HCT. The key element to a successful HCT, enabling successful transition outcomes, is having a structured intervention that incorporates the components of planning, transfer, and integration into adult care. This structured intervention can be accomplished by using the Six Core Elements approach that is recommended by the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians.
Conclusions:
Formal HCT programs for patients with KD who develop aneurysms should be established to ensure a smooth transition with uninterrupted medical care as these youths become adults.




J Am Heart Assoc: 10 Oct 2021:e023310; epub ahead of print
Dahdah N, Kung SC, Friedman KG, Marelli A, ... and the Council on Arteriosclerosis, Thrombosis and Vascular Biology
J Am Heart Assoc: 10 Oct 2021:e023310; epub ahead of print | PMID: 34632822
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Impact:
Abstract

Sex Differences in Cardiovascular Research: A Scientometric Analysis.

Millenaar D, Dillmann M, Fehlmann T, Flohr A, ... Keller A, Mahfoud F

Background:
We sought to investigate sex-specific differences in authorship of cardiovascular research over the past decade. Methods and Results All 387 463 cardiovascular publications between 2010 and 2019 were retrieved from Web of Science. Articles increased from 19 960 to 29 604 articles per year (P>0.001). The number of articles written by female first authors increased by 76.3% (6434-11 343 articles) and by 35.0% for male first authors (13 526-18 261) (P<0.001). The first author was more likely to be a female author in articles with female last authors. The median impact factor (IF) for articles by female first authors was lower (2.46 [interquartile range, 7 1.11-4.03] versus 2.51 [interquartile range, 1.17-4.10]; P<0.001). Female authorship articles reached the highest IF in North America (average IF, 3.7), with the lowest in Africa (average IF, 1.8).
Conclusions:
Publications in cardiovascular research have increased over the past decade, particularly by female authors. Female researchers are cited less often compared with their male peers. The IF remains lower for articles by female researchers.




J Am Heart Assoc: 10 Oct 2021:e021522; epub ahead of print
Millenaar D, Dillmann M, Fehlmann T, Flohr A, ... Keller A, Mahfoud F
J Am Heart Assoc: 10 Oct 2021:e021522; epub ahead of print | PMID: 34632817
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Impact:
Abstract

Outcomes of Venoarterial Extracorporeal Membrane Oxygenation for Cardiac Arrest in Adult Patients in the United States.

Gill G, Patel JK, Casali D, Rowe G, ... Chikwe J, Parikh PB

Background:
Factors associated with poor prognosis following receipt of extracorporeal membrane oxygenation (ECMO) in adults with cardiac arrest remain unclear. We aimed to identify predictors of mortality in adults with cardiac arrest receiving ECMO in a nationally representative sample. Methods and Results The US Healthcare Cost and Utilization Project\'s National Inpatient Sample was used to identify 782 adults hospitalized with cardiac arrest who received ECMO between 2006 and 2014. The primary outcome of interest was all-cause in-hospital mortality. Factors associated with mortality were analyzed using multivariable logistic regression. The overall in-hospital mortality rate was 60.4% (n=472). Patients who died were older and more often men, of non-White race, and with lower household income than those surviving to discharge. In the risk-adjusted analysis, independent predictors of mortality included older age, male sex, lower annual income, absence of ventricular arrhythmia, absence of percutaneous coronary intervention, and presence of therapeutic hypothermia.
Conclusions:
Demographic and therapeutic factors are independently associated with mortality in patients with cardiac arrest receiving ECMO. Identification of which patients with cardiac arrest may receive the utmost benefit from ECMO may aid with decision-making regarding its implementation. Larger-scale studies are warranted to assess the appropriate candidates for ECMO in cardiac arrest.




J Am Heart Assoc: 10 Oct 2021:e021406; epub ahead of print
Gill G, Patel JK, Casali D, Rowe G, ... Chikwe J, Parikh PB
J Am Heart Assoc: 10 Oct 2021:e021406; epub ahead of print | PMID: 34632807
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Impact:
Abstract

Highly Selective PPARα (Peroxisome Proliferator-Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular-Microstructural Imaging.

Iwata H, Osborn EA, Ughi GJ, Murakami K, ... Aikawa M, Jaffer FA

Background:
New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator-activated receptor α) agonist, suppresses coronary stent-induced arterial inflammation and neointimal hyperplasia.
Methods and results:
Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2-4 per animal; 44 stents total). On day 7, intracoronary molecular-structural near-infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent-induced inflammatory protease activity (near-infrared fluorescence target-to-background ratio: pemafibrate, median [25th-75th percentile]: 2.8 [2.5-3.3] versus control, 4.1 [3.3-4.3], P=0.02). At day 28, animals underwent repeat near-infrared fluorescence-optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7-54.1] mm3 versus control, 54.2 [41.2-81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-α (tumor necrosis factor-α) and MMP-9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)-myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.




J Am Heart Assoc: 10 Oct 2021:e020834; epub ahead of print
Iwata H, Osborn EA, Ughi GJ, Murakami K, ... Aikawa M, Jaffer FA
J Am Heart Assoc: 10 Oct 2021:e020834; epub ahead of print | PMID: 34632804
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Impact:
Abstract

Sex Differences in the Utilization and Outcomes of Cardiac Valve Replacement Surgery for Infective Endocarditis: Insights From the National Inpatient Sample.

Bansal A, Cremer PC, Jaber WA, Rampersad P, Menon V

Background:
The data on the differential impact of sex on the utilization and outcomes of valve replacement surgery for infective endocarditis are limited to single-center and small sample size patient population. Methods and Results We utilized the National Inpatient Sample database to identify patients with a discharge diagnosis of infective endocarditis from 2004 to 2015 to assess differences in the characteristics and clinical outcomes of patients hospitalized with infective endocarditis stratified by sex. We also evaluated trends in utilization of cardiac valve replacement and individual valve replacement surgeries in women versus men over a 12-year period, and compared in-hospital mortality after surgical treatment in women versus men. A total of 81 942 patients were hospitalized with a primary diagnosis of infective endocarditis from January 2004 to September 2015, of whom 44.31% were women. Women were less likely to undergo overall cardiac valve replacement (6.92% versus 12.12%), aortic valve replacement (3.32% versus 8.46%), mitral valve replacement (4.60% versus 5.57%), and combined aortic and mitral valve replacement (0.85% versus 1.81%) but had similar in-hospital mortality rates. From 2004 to 2015, the overall rates of cardiac valve replacement increased from 11.76% to 13.96% in men and 6.34% to 9.26% in women and in-hospital mortality declined in both men and women. Among the patients undergoing valve replacement surgery, in-hospital mortality was higher in women (9.94% versus 6.99%, P<0.001).
Conclusions:
Despite increased utilization of valve surgery for infective endocarditis in both men and women and improving trends in mortality, we showed that there exists a treatment bias with underutilization of valve surgeries for infective endocarditis in women and demonstrated that in-hospital mortality was higher in women undergoing valve surgery in comparison to men.




J Am Heart Assoc: 10 Oct 2021:e020095; epub ahead of print
Bansal A, Cremer PC, Jaber WA, Rampersad P, Menon V
J Am Heart Assoc: 10 Oct 2021:e020095; epub ahead of print | PMID: 34632795
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Impact:
Abstract

Long-Term (7-Year) Clinical Implications of Newly Unveiled Asymptomatic Abnormal Ankle-Brachial Index in Patients With Coronary Artery Disease.

Lee JY, Lee SJ, Lee SW, Kim TO, ... Lee CW, Park SW

Background:
The long-term impact of newly discovered, asymptomatic abnormal ankle-brachial index (ABI) in patients with significant coronary artery disease is limited. Methods and Results Between January 2006 and December 2009, ABI was evaluated in 2424 consecutive patients with no history of claudication or peripheral artery disease who had significant coronary artery disease. We previously reported a 3-year result; therefore, the follow-up period was extended. The primary end point was a composite of all-cause death, myocardial infarction (MI), and stroke over 7 years. Of the 2424 patients with significant coronary artery disease, 385 had an abnormal ABI (ABI ≤0.9 or ≥1.4). During the follow-up period, the rate of the primary outcome was significantly higher in the abnormal ABI group than in the normal ABI group (P<0.001). The abnormal ABI group had a significantly higher risk of composite of all-cause death/MI/stroke than the normal ABI group, after adjustment with multivariable Cox proportional hazards regression analysis (hazard ratio [HR], 2.07; 95% CI, 1.67-2.57; P<0.001) and propensity score-matched analysis (HR, 1.97; 95% CI, 1.49-2.60; P<0.001). In addition, an abnormal ABI was associated with a higher risk of all-cause death, MI, and stroke, but not repeat revascularization.
Conclusions:
Among patients with significant coronary artery disease, asymptomatic abnormal ABI was associated with sustained and increased incidence of composite of all-cause death/MI/stroke, all-cause death, MI, and stroke during extended follow-up over 7 years.




J Am Heart Assoc: 10 Oct 2021:e021587; epub ahead of print
Lee JY, Lee SJ, Lee SW, Kim TO, ... Lee CW, Park SW
J Am Heart Assoc: 10 Oct 2021:e021587; epub ahead of print | PMID: 34632785
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Impact:
Abstract

Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia-Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model.

Ren R, Lu Q, Sherchan P, Fang Y, ... Zhang J, Tang J

Background:
Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia-induced blood-brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia-induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2\',4\'-trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3-methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin-1/transforming growth factor-β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB-related proteins, ZO-1 and Claudin-5.
Conclusions:
AHR may serve as a potential therapeutic target to attenuate hyperglycemia-induced hematoma expansion and to preserve the BBB in patients with ICH.




J Am Heart Assoc: 07 Oct 2021:e022701; epub ahead of print
Ren R, Lu Q, Sherchan P, Fang Y, ... Zhang J, Tang J
J Am Heart Assoc: 07 Oct 2021:e022701; epub ahead of print | PMID: 34622690
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Impact:
Abstract

Impact of Center Volume on Outcomes in Myocardial Infarction Complicated by Cardiogenic Shock: A CULPRIT-SHOCK Substudy.

Schrage B, Zeymer U, Montalescot G, Windecker S, ... Thiele H, Clemmensen P

Background:
Little is known about the impact of center volume on outcomes in acute myocardial infarction complicated by cardiogenic shock. The aim of this study was to investigate the association between center volume, treatment strategies, and subsequent outcome in patients with acute myocardial infarction complicated by cardiogenic shock. Methods and Results In this subanalysis of the randomized CULPRIT-SHOCK (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) trial, study sites were categorized based on the annual volume of acute myocardial infarction complicated by cardiogenic shock into low-/intermediate-/high-volume centers (<50; 50-100; and >100 cases/y). Subjects from the study/compulsory registry with available volume data were included. Baseline/procedural characteristics, overall treatment, and 1-year all-cause mortality were compared across categories. n=1032 patients were included in this study (537 treated at low-volume, 240 at intermediate-volume, and 255 at high-volume centers). Baseline risk profile of patients across the volume categories was similar, although high-volume centers included a larger number of older patients. Low-/intermediate-volume centers had more resuscitated patients (57.5%/58.8% versus 42.2%; P<0.01), and more patients on mechanical ventilation in comparison to high-volume centers. There were no differences in reperfusion success despite considerable differences in adjunctive pharmacological/device therapies. There was no difference in 1-year all-cause mortality across volume categories (51.1% versus 56.5% versus 54.4%; P=0.34).
Conclusions:
In this study of patients with acute myocardial infarction complicated by cardiogenic shock, considerable differences in adjunctive medical and mechanical support therapies were observed. However, we could not detect an impact of center volume on reperfusion success or mortality.




J Am Heart Assoc: 07 Oct 2021:e021150; epub ahead of print
Schrage B, Zeymer U, Montalescot G, Windecker S, ... Thiele H, Clemmensen P
J Am Heart Assoc: 07 Oct 2021:e021150; epub ahead of print | PMID: 34622680
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Impact:
Abstract

Inpatient Versus Outpatient Acute Venous Thromboembolism Management: Trends and Postacute Healthcare Utilization From 2011 to 2018.

Lutsey PL, Walker RF, MacLehose RF, Norby FL, ... Alonso A, Zakai NA

Background:
Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases (ICD) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]).
Conclusions:
Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.




J Am Heart Assoc: 07 Oct 2021:e020428; epub ahead of print
Lutsey PL, Walker RF, MacLehose RF, Norby FL, ... Alonso A, Zakai NA
J Am Heart Assoc: 07 Oct 2021:e020428; epub ahead of print | PMID: 34622678
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Impact:
Abstract

Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis.

Uchiyama S, Toyoda K, Omae K, Saita R, ... Yasuda S, Yamaguchi T

Background:
Long-term benefit of dual antiplatelet therapy (DAPT) over single antiplatelet therapy (SAPT) for the prevention of recurrent stroke has not been established in patients with intracranial arterial stenosis. We compared the efficacy and safety of DAPT with cilostazol and clopidogrel or aspirin to those of SAPT with clopidogrel or aspirin in patients with intracranial arterial stenosis, who were recruited to the Cilostazol Stroke Prevention Study for Antiplatelet Combination trial, a randomized controlled trial in high-risk Japanese patients with ischemic stroke. Methods and Results We compared the vascular and hemorrhagic events between DAPT and SAPT in patients with ischemic stroke and symptomatic or asymptomatic intracranial arterial stenosis of at least 50% in a major intracranial artery. Patients were placed in two groups: 275 were assigned to receive DAPT and 272 patients SAPT. The risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95); and composite of stroke, myocardial infarction, and vascular death (HR, 0.48; 95% CI, 0.26-0.91) were lower in DAPT than SAPT, whereas the risk of severe or life-threatening bleeding (HR, 0.72; 95% CI, 0.12-4.30) did not differ between the 2 treatment groups.
Conclusions:
DAPT using cilostazol was superior to SAPT with clopidogrel or aspirin for the prevention of recurrent stroke and vascular events without increasing bleeding risk among patients with intracranial arterial stenosis after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370.




J Am Heart Assoc: 07 Oct 2021:e022575; epub ahead of print
Uchiyama S, Toyoda K, Omae K, Saita R, ... Yasuda S, Yamaguchi T
J Am Heart Assoc: 07 Oct 2021:e022575; epub ahead of print | PMID: 34622679
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Impact:
Abstract

Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning.

Diwan D, Vellimana AK, Aum DJ, Clarke J, ... Gidday JM, Zipfel GJ

Background:
Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1-/- mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1-Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post-SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1-dependent fashion.
Conclusions:
The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning-based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.




J Am Heart Assoc: 07 Oct 2021:e021113; epub ahead of print
Diwan D, Vellimana AK, Aum DJ, Clarke J, ... Gidday JM, Zipfel GJ
J Am Heart Assoc: 07 Oct 2021:e021113; epub ahead of print | PMID: 34622677
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Impact:
Abstract

Health Care Policy and Congenital Heart Disease: 2020 Focus on Our 2030 Future.

Chowdhury D, Johnson JN, Baker-Smith CM, Jaquiss RDB, ... Saidi A, Shaffer K
The congenital heart care community faces a myriad of public health issues that act as barriers toward optimum patient outcomes. In this article, we attempt to define advocacy and policy initiatives meant to spotlight and potentially address these challenges. Issues are organized into the following 3 key facets of our community: patient population, health care delivery, and workforce. We discuss the social determinants of health and health care disparities that affect patients in the community that require the attention of policy makers. Furthermore, we highlight the many needs of the growing adults with congenital heart disease and those with comorbidities, highlighting concerns regarding the inequities in access to cardiac care and the need for multidisciplinary care. We also recognize the problems of transparency in outcomes reporting and the promising application of telehealth. Finally, we highlight the training of providers, measures of productivity, diversity in the workforce, and the importance of patient-family centered organizations in advocating for patients. Although all of these issues remain relevant to many subspecialties in medicine, this article attempts to illustrate the unique needs of this population and highlight ways in which to work together to address important opportunities for change in the cardiac care community and beyond. This article provides a framework for policy and advocacy efforts for the next decade.



J Am Heart Assoc: 07 Oct 2021:e020605; epub ahead of print
Chowdhury D, Johnson JN, Baker-Smith CM, Jaquiss RDB, ... Saidi A, Shaffer K
J Am Heart Assoc: 07 Oct 2021:e020605; epub ahead of print | PMID: 34622676
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Impact:
Abstract

Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis.

Pucci A, Aimo A, Musetti V, Barison A, ... Rapezzi C, Emdin M

Background:
The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods and Results We included all patients diagnosed with amyloid light-chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68-81). Lambda-positive AL was found in 14 of 19 AL cases (38%) and kappa-positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%-30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%-23%; range, 5%-60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (r=0.661, P=0.001). The combined amyloid and fibrosis extent correlated with high-sensitivity troponin T (P=0.035) and N-terminal pro-B-type natriuretic peptide (P=0.002) serum levels.
Conclusions:
Extracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.




J Am Heart Assoc: 07 Oct 2021:e020358; epub ahead of print
Pucci A, Aimo A, Musetti V, Barison A, ... Rapezzi C, Emdin M
J Am Heart Assoc: 07 Oct 2021:e020358; epub ahead of print | PMID: 34622675
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Impact:
Abstract

Impact of Peripheral Microvascular Endothelial Dysfunction on White Matter Hyperintensity.

Toya T, Sara JD, Scharf EL, Ahmad A, ... Lerman LO, Lerman A

Background:
White matter hyperintensity (WMH), characterized by hyperintensities on T2-weighted fluid-attenuated inversion recovery brain magnetic resonance imaging, has been linked to an increased risk of ischemic stroke (IS). Endothelial dysfunction is an indicator of vascular dysfunction, predicting the risk of IS. This study aimed to investigate the association between endothelial dysfunction and regional WMH, and its impact on future risk of IS. Methods and Results We enrolled 219 patients (mean age, 53.1±14.1 years; 34.7% men) who underwent peripheral endothelial function assessment using reactive hyperemia peripheral arterial tonometry and brain magnetic resonance imaging without any history of IS. Volumetric WMH segmentation was automatically extrapolated using a validated automated digital tool. Total and juxtacortical WMH volume/intracranial volume (%) increased with aging and became more prominent in patients aged >50 years (n=131) than those aged ≤50 years (n=88) (total WMH: ≤50 years, Pearson r=0.24, P=0.03; >50 years, Pearson r=0.62, P<0.0001; juxtacortical WMH: ≤50 years, Pearson r=0.09, P=0.40; >50 years, Pearson r=0.55, P<0.0001). Reactive hyperemia peripheral arterial tonometry index was negatively associated with total and juxtacortical WMH volume/intracranial volume (%) in patients aged >50 years after adjustment for other covariates (reactive hyperemia peripheral arterial tonometry index, standardized β coefficient -0.17, P=0.04). Juxtacortical WMH volume/intracranial volume (%) was associated with an increased risk of IS during median follow-up of 6.5 years (hazard ratio, 1.47; 95% CI, 1.05-1.92; P=0.03).
Conclusions:
Peripheral endothelial dysfunction is associated with an increased volume of juxtacortical WMH in patients aged >50 years, which is a potential marker to predict future risk of IS.




J Am Heart Assoc: 07 Oct 2021:e021066; epub ahead of print
Toya T, Sara JD, Scharf EL, Ahmad A, ... Lerman LO, Lerman A
J Am Heart Assoc: 07 Oct 2021:e021066; epub ahead of print | PMID: 34622674
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Impact:
Abstract

Induction of Heme Oxygenase-1 Is Linked to the Severity of Disease in Human Abdominal Aortic Aneurysm.

Hofmann A, Müglich M, Wolk S, Khorzom Y, ... Poitz DM, Reeps C

Background:
Rupture of abdominal aortic aneurysm (rAAA) is associated with high case fatality rates, and risk of rupture increases with the AAA diameter. Heme oxygenase-1 (gene HMOX1, protein HO-1) is a stress-induced protein and induction has protective effects in the vessel wall. HMOX1-/- mice are more susceptible to angiotensin II-induced AAA formation, but the regulation in human nonruptured and ruptured AAA is only poorly understood. Our hypothesis proposed that HO-1 is reduced in AAA and lowering is inversely associated with the AAA diameter. Methods and Results AAA walls from patients undergoing elective open repair (eAAA) or surgery because of rupture (rAAA) were analyzed for aortic HMOX1/HO-1 expression by quantitative real-time polymerase chain reaction and Western blot. Aortas from patients with aortic occlusive disease served as controls. HMOX1/HO-1 expression was 1.1- to 7.6-fold upregulated in eAAA and rAAA. HO-1 expression was 3-fold higher in eAAA specimen with a diameter >84.4 mm, whereas HO-1 was not different in rAAA. Other variables that are known for associations with AAA and HO-1 induction were tested. In eAAA, HO-1 expression was negatively correlated with aortic collagen content and oxidative stress parameters H2O2 release, oxidized proteins, and thiobarbituric acid reactive substances. Serum HO-1 concentrations were analyzed in patients with eAAA, and maximum values were found in an aortic diameter of 55 to 70 mm with no further increase >70 mm, compared with <55 mm.
Conclusions:
Aortic HO-1 expression was increased in eAAA and rAAA. HO-1 increased with the severity of disease but was additionally connected to less oxidative stress and vasoprotective mechanisms.




J Am Heart Assoc: 07 Oct 2021:e022747; epub ahead of print
Hofmann A, Müglich M, Wolk S, Khorzom Y, ... Poitz DM, Reeps C
J Am Heart Assoc: 07 Oct 2021:e022747; epub ahead of print | PMID: 34622673
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Impact:
Abstract

The Emerging Role of Irisin in Cardiovascular Diseases.

Fu J, Li F, Tang Y, Cai L, ... Yang Y, Yang J
Irisin, a novel hormone like polypeptide, is cleaved and secreted by an unknown protease from a membrane-spanning protein, FNDC5 (fibronectin type III domain-containing protein 5). The current knowledge on the biological functions of irisin includes browning white adipose tissue, regulating insulin use, and anti-inflammatory and antioxidative properties. Dysfunction of irisin has shown to be involved in cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and myocardial ischemia-reperfusion injury. Moreover, irisin gene variants are also associated with cardiovascular diseases. In this review, we discuss the current knowledge on irisin-mediated regulatory mechanisms and their roles in the pathogenesis of cardiovascular diseases.



J Am Heart Assoc: 07 Oct 2021:e022453; epub ahead of print
Fu J, Li F, Tang Y, Cai L, ... Yang Y, Yang J
J Am Heart Assoc: 07 Oct 2021:e022453; epub ahead of print | PMID: 34622672
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Impact:
Abstract

Bilirubin Nanoparticles Protect Against Cardiac Ischemia/Reperfusion Injury in Mice.

Ai W, Bae S, Ke Q, Su S, ... Jon S, Kang PM

Background:
Ischemia/reperfusion (I/R) injury causes overproduction of reactive oxygen species, which are the major culprits of oxidative stress that leads to inflammation, apoptosis, myocardial damage, and dysfunction. Bilirubin acts as a potent endogenous antioxidant that is capable of scavenging various reactive oxygen species. We have previously generated bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol-conjugated bilirubin. In this study, we examined the therapeutic effects of BRNPs on myocardial I/R injury in mice. Methods and Results In vivo imaging using fluorophore encapsulated BRNPs showed BRNPs preferentially targeted to the site of I/R injury in the heart. Cardiac I/R surgery was performed by first ligating the left anterior descending coronary artery. After 45 minutes, reperfusion was achieved by releasing the ligation. BRNPs were administered intraperitoneally at 5 minutes before and 24 hours after reperfusion. Mice that received BRNPs showed significant improvements in their cardiac output, assessed by echocardiogram and pressure volume loop measurements, compared with the ones that received vehicle treatment. BRNPs treatment also significantly reduced the myocardial infarct size in mice that underwent cardiac I/R, compared with the vehicle-treatment group. In addition, BRNPs effectively suppressed reactive oxygen species and proinflammatory factor levels, as well as the amount of cardiac apoptosis.
Conclusions:
Taken together, BRNPs could exert their therapeutic effects on cardiac I/R injury through attenuation of oxidative stress, apoptosis, and inflammation, providing a novel therapeutic modality for myocardial I/R injury.




J Am Heart Assoc: 07 Oct 2021:e021212; epub ahead of print
Ai W, Bae S, Ke Q, Su S, ... Jon S, Kang PM
J Am Heart Assoc: 07 Oct 2021:e021212; epub ahead of print | PMID: 34622671
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Impact:
Abstract

Association of Global Coagulation Profiles With Cardiovascular Risk Factors and Atherosclerosis: A Sex Disaggregated Analysis From the BioHEART-CT Study.

Kott KA, Morel-Kopp MC, Vernon ST, Takagi Y, ... Ward C, Figtree GA

Background:
Although the association between dysregulated coagulation and atherosclerosis is well recognized, individual assays have been of minimal value in understanding disease susceptibility. Here we investigated the association of global coagulation profiles with coronary artery disease with consideration of sex differences. Methods and Results The study included patients from the BioHEART-CT (The BioHEART Study: Assessing Patients With Suspected Cardiovascular Disease for New Disease Markers and Risk Factors) biobank who had computed tomography coronary angiograms scored for coronary artery calcium score (CACS) and Gensini score. The cohort included 206 adult patients who were referred for clinically indicated computed tomography coronary angiography and had a median of 2 major cardiac risk factors; 50% were women and the average age was 62.6 years (±9.9 years). The overall hemostatic potential (OHP) and calibrated automated thrombography generation assays were performed on platelet-poor plasma. CACS and Gensini score in men were significantly correlated in bivariate analysis with measures from the OHP assay, and regression models predicting disease severity by CACS or Gensini score were improved by adding the OHP assay variables in men but not in women. The calibrated automated thrombography generation assay demonstrated a more hypercoagulable profile in women than in men. The OHP assay showed hypercoagulable profiles in women with hyperlipidemia and men with obesity.
Conclusions:
The OHP assay identified hypercoagulable profiles associated with different risk factors for each sex and was associated with CACS and Gensini score severity in men, emphasizing the associations between increased fibrin generation and reduced fibrinolysis with cardiac risk factors and early atherosclerosis. Registration Information www.anzctr.org.au. Identifier: ACTRN12618001322224.




J Am Heart Assoc: 07 Oct 2021:e020604; epub ahead of print
Kott KA, Morel-Kopp MC, Vernon ST, Takagi Y, ... Ward C, Figtree GA
J Am Heart Assoc: 07 Oct 2021:e020604; epub ahead of print | PMID: 34622670
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Impact:
Abstract

Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization.

Piccolo R, Bonaa KH, Efthimiou O, Varenne O, ... Valgimigli M, Coronary Stent Trialists’ (CST) Collaboration

Background:
New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). Methods and Results The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P-interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68-0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83-1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70-0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65-0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76-0.97).
Conclusions:
As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42017060520.




J Am Heart Assoc: 07 Oct 2021:e018828; epub ahead of print
Piccolo R, Bonaa KH, Efthimiou O, Varenne O, ... Valgimigli M, Coronary Stent Trialists’ (CST) Collaboration
J Am Heart Assoc: 07 Oct 2021:e018828; epub ahead of print | PMID: 34622669
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Impact:
Abstract

Cardiovascular Diseases That Have Emerged From the Darkness.

Maron BJ, Maron MS, Maurer MS, Rowin EJ, Maron BA, Galiè N
It is important for both the patient and physician communities to have timely access to information recognizing rapid progress in the diagnosis and treatment of familiar but relatively uncommon cardiovascular diseases. Patients with 3 cardiovascular diseases (ie, hypertrophic cardiomyopathy, pulmonary arterial hypertension, and transthyretin (TTR) cardiac amyloidosis (ATTR)]), once considered rare without effective management options and associated with malignant prognosis, have now benefited substantially from the development of a variety of innovative therapeutic strategies. In addition, in each case, enhanced diagnostic testing has expanded the patient population and allowed for more widespread administration of contemporary treatments. In hypertrophic cardiomyopathy, introduction of implantable defibrillators to prevent sudden death as well as high-benefit:low-risk septal reduction therapies to reverse heart failure have substantially reduced morbidity and disease-related mortality (to 0.5% per year). For pulmonary arterial hypertension, a disease once characterized by a particularly grim prognosis, prospective randomized drug trials with aggressive single (or combined) pharmacotherapy have measurably improved survival and quality of life for many patients. In cardiac amyloidosis, development of disease-specific drugs can for the first time reduce morbidity and mortality, prominently with breakthrough ATTR-protein-stabilizing tafamidis. In conclusion, in less common and visible cardiovascular diseases, it is crucial to recognize substantial progress and achievement, given that penetration of such information into clinical practice and the patient community can be inconsistent. Diseases such as hypertrophic cardiomyopathy, pulmonary arterial hypertension, and ATTR cardiac amyloidosis, once linked to a uniformly adverse prognosis, are now associated with the opportunity for patients to experience satisfactory quality of life and extended longevity.



J Am Heart Assoc: 07 Oct 2021:e021095; epub ahead of print
Maron BJ, Maron MS, Maurer MS, Rowin EJ, Maron BA, Galiè N
J Am Heart Assoc: 07 Oct 2021:e021095; epub ahead of print | PMID: 34622668
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Impact:
Abstract

Association of Preoperative Diuretic Use With Early Acute Kidney Injury in Infants With Biventricular Hearts Following Cardiac Surgery.

Rathgeber SL, Chakrabarti A, Kapravelou E, Hemphill N, ... Skippen P, Harris KC

Background:
Diuretics are used to manage congestive heart failure in infants with congenital heart disease. Adult data indicate that preoperative diuretic use increases the risk of cardiac surgery associated acute kidney injury (CS-AKI). We have sought to understand if preoperative diuretics in infants increases the risk of CS-AKI. Methods and Results This is a single-center retrospective study of infants (1-12 months) who had CS requiring cardiopulmonary bypass between 2013 and 2018. The diagnosis and severity of CS-AKI was defined according to the Kidney Disease Improving Global Outcomes guidelines. Three hundred patients were included (mean 6 months, SD 2.4, range 1.2-12.9 months). A total of 149 (49.7%) patients were diagnosed with CS-AKI (stage 1: 80 [54%], stage 2: 57 [38%], stage 3: 12 [8%]). Logistic regression analysis showed preoperative diuretics were not associated with CS-AKI (odds ratio [OR], 0.79; 95% CI, 0.43-1.44; P=0.45). A diagnosis of tetralogy of Fallot was an independent risk factor for CS-AKI (OR, 3.49; 95% CI, 1.33-9.1, P=0.01). A diagnosis of tetralogy of Fallot (OR, 3.6; 95% CI, 1.28-10.22; P=0.02) and longer cardiopulmonary bypass (OR, 1.01; 95% CI, 1.0-1.02; P=0.04) time are risk factors for moderate to severe CS-AKI.
Conclusions:
Preoperative diuretic use does not contribute to the risk of CS-AKI in infants early after surgery. A diagnosis of tetralogy of Fallot was the only risk factor for CS-AKI identified using multivariate analysis in our cohort. Furthermore, a diagnosis of tetralogy of Fallot and longer cardiopulmonary bypass time are risk factors for moderate to severe CS-AKI.




J Am Heart Assoc: 07 Oct 2021:e020519; epub ahead of print
Rathgeber SL, Chakrabarti A, Kapravelou E, Hemphill N, ... Skippen P, Harris KC
J Am Heart Assoc: 07 Oct 2021:e020519; epub ahead of print | PMID: 34622667
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Impact:
Abstract

Cysteine-Rich Angiogenic Inducer 61 Improves Prognostic Accuracy of GRACE (Global Registry of Acute Coronary Events) 2.0 Risk Score in Patients With Acute Coronary Syndromes.

Klingenberg R, Aghlmandi S, Räber L, Akhmedov A, ... Lüscher TF, Matter CM

Background:
It remains unclear whether the novel biomarker cysteine-rich angiogenic inducer 61 (CCN1) adds incremental prognostic value to the GRACE 2.0 (Global Registry of Acute Coronary Events) risk score and biomarkers high-sensitivity Troponin T, hsCRP (high-sensitivity C-reactive protein), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in patients with acute coronary syndromes. Methods and Results Patients referred for coronary angiography with a primary diagnosis of acute coronary syndromes were enrolled in the Special Program University Medicine - Acute Coronary Syndromes and Inflammation cohort. The primary/secondary end points were 30-day/1-year all-cause mortality and the composite of all-cause mortality or myocardial infarction as used in the GRACE risk score. Associations between biomarkers and outcome were assessed using log-transformed biomarker values and the GRACE risk score (versions 1.0 and 2.0). The incremental value of CCN1 beyond a reference model was assessed using Harrell\'s C-statistics calculated from a Cox proportional-hazard model. The P value of the C-statistics was derived from a likelihood ratio test. Among 2168 patients recruited, 1732 could be analyzed. CCN1 was the strongest single predictor of all-cause mortality at 30 days (hazard ratio [HR], 1.77 [1.31, 2.40]) and 1 year (HR, 1.81 [1.47, 2.22]). Adding CCN1 alone to the GRACE 2.0 risk score improved C-statistics for prognostic accuracy of all-cause mortality at 30 days (0.87-0.88) and 1 year (0.81-0.82) and when combined with high-sensitivity Troponin T, hsCRP, NT-proBNP for 30 days (0.87-0.91), and for 1-year follow-up (0.81-0.84). CCN1 also increased the prognostic value for the composite of all-cause mortality or myocardial infarction.
Conclusions:
CCN1 predicts adverse outcomes in patients with acute coronary syndromes adding incremental information to the GRACE risk score, suggesting distinct underlying molecular mechanisms. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01000701.




J Am Heart Assoc: 07 Oct 2021:e020488; epub ahead of print
Klingenberg R, Aghlmandi S, Räber L, Akhmedov A, ... Lüscher TF, Matter CM
J Am Heart Assoc: 07 Oct 2021:e020488; epub ahead of print | PMID: 34622666
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Impact:
Abstract

Efficacy and Safety of Vorapaxar by Intensity of Background Lipid-Lowering Therapy in Patients With Peripheral Artery Disease: Insights From the TRA2P-TIMI 50 Trial.

Gilchrist IC, Morrow DA, Creager MA, Olin JW, ... Goodrich EL, Bonaca MP

Background:
Patients with peripheral artery disease are at increased risk of both major adverse cardiovascular events (MACEs) and limb events. The pathobiology of limb events is likely multifactorial. Observational studies suggest a benefit of statin therapy for reducing the risk of limb ischemic events while randomized trials demonstrate a benefit with more potent antithrombotic therapies, particularly those targeting thrombin. Whether the effects of these therapeutic pathways are independent and complementary is not known. Methods and Results The TRA 2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50) trial demonstrated that vorapaxar significantly reduced MACEs and limb events. The purpose of the current analysis was to evaluate the association of statin use and intensity and the occurrence of MACEs and limb events in 5845 patients with symptomatic peripheral artery disease randomized in TRA 2°P-TIMI 50 and then to understand whether statin use modified the benefits of vorapaxar for MACEs or limb ischemic events. We found that statin therapy was associated with significantly lower risk of MACEs (hazard ratio [HR], 0.77; 95% CI, 0.66-0.89; P<0.001) and limb ischemic events (HR, 0.73; 95% CI, 0.60-0.89; P=0.002). The benefit of vorapaxar for reducing MACEs and limb events was consistent regardless of background statin (P-interaction=0.715 and 0.073, respectively). Event rates were lowest in patients receiving the combination of statin therapy and vorapaxar.
Conclusions:
In conclusion, statin use and intensity is associated with significantly lower rates of MACEs and limb ischemic events. Thrombin inhibition with vorapaxar is effective regardless of background statin therapy. These results suggest that targeting both lipid and thrombotic risk in peripheral artery disease is necessary in order to optimize outcomes.




J Am Heart Assoc: 07 Oct 2021:e021412; epub ahead of print
Gilchrist IC, Morrow DA, Creager MA, Olin JW, ... Goodrich EL, Bonaca MP
J Am Heart Assoc: 07 Oct 2021:e021412; epub ahead of print | PMID: 34622665
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Impact:
Abstract

Impact of Diastolic Interventricular Septal Flattening on Clinical Outcome in Patients With Severe Tricuspid Regurgitation.

Omori T, Maeda M, Kagawa S, Uno G, ... Siegel RJ, Shiota T

Background:
Little is known about the impact of diastolic interventricular septal flattening on the clinical outcome in patients with severe tricuspid regurgitation. This study sought to evaluate the association of diastolic interventricular septal flattening with clinical outcome in patients with severe tricuspid regurgitation. Methods and Results We retrospectively studied 407 patients who underwent 2-dimensional transthoracic echocardiography and were diagnosed with severe tricuspid regurgitation between January 2014 and December 2015. Cardiovascular events were defined as cardiovascular death or admission for heart failure. The magnitude of interventricular septal flattening was calculated by the eccentricity index (EI) of the left ventricle, and hemodynamic parameters were obtained from transthoracic echocardiography. During follow-up (median, 200 days; interquartile range, 35-1059), 117 of the patients experienced cardiovascular events. By multivariate analysis including potential covariates, EI at end-diastole and left ventricular ejection fraction were independent predictors of cardiovascular events (hazard ratio, 5.33 [1.63-17.41]; hazard ratio, 0.98 [0.97-0.99], respectively). An EI of 1.2 at end-diastole was the optimal cutoff value for identifying poor hemodynamic status defined as cardiac index ≤2.2 L/min per m2 and right atrial pressure 15 mm Hg, both on transthoracic echocardiography. Patients with D-shaped left ventricle defined as EI ≥1.2 at end-diastole showed worse outcomes than those without (adjusted hazard ratio, 1.80 [1.18-2.74]).
Conclusions:
Increasing EI at end-diastole was strongly associated with worse outcomes in patients with severe tricuspid regurgitation. Furthermore, the presence of D-shaped left ventricle defined as EI ≥1.2 at end-diastole provides prognostic value for cardiovascular events.




J Am Heart Assoc: 07 Oct 2021:e021363; epub ahead of print
Omori T, Maeda M, Kagawa S, Uno G, ... Siegel RJ, Shiota T
J Am Heart Assoc: 07 Oct 2021:e021363; epub ahead of print | PMID: 34622664
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Impact:
Abstract

Triglyceride Levels and Residual Risk of Atherosclerotic Cardiovascular Disease Events and Death in Adults Receiving Statin Therapy for Primary or Secondary Prevention: Insights From the KP REACH Study.

Ambrosy AP, Yang J, Sung SH, Allen AR, ... Granowitz C, Go AS

Background:
Patients with risk factors or established atherosclerotic cardiovascular disease remain at high-risk for ischemic events. Triglyceride levels may play a causal role. Methods and Results We performed a retrospective study of adults aged ≥45 years receiving statin therapy, with a low-density lipoprotein cholesterol of 41 to 100 mg/dL, and ≥1 risk factor or established atherosclerotic cardiovascular disease between 2010 and 2017. Outcomes included death, all-cause hospitalization, and major adverse cardiovascular events (myocardial infarction, stroke, or peripheral artery disease). The study sample included 373 389 primary prevention patients and 97 832 secondary prevention patients. The primary prevention cohort had a mean age of 65±10 years, with 51% women and 44% people of color, whereas the secondary prevention cohort had a mean age of 71±11 years, with 37% women and 32% people of color. Median triglyceride levels for the primary and secondary prevention cohorts were 122 mg/dL (interquartile range, 88-172 mg/dL) and 116 mg/dL (interquartile range, 84-164 mg/dL), respectively. In multivariable analyses, primary prevention patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (hazard ratio [HR], 0.91; 95% CI, 0.89-0.94) and higher risk of major adverse cardiovascular events (HR, 1.14; 95% CI, 1.05-1.24). In the secondary prevention cohort, patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (HR, 0.95; 95% CI, 0.92-0.97) and higher risk of all-cause hospitalization (HR, 1.03; 95% CI, 1.01-1.05) and major adverse cardiovascular events (HR, 1.04; 95% CI, 1.05-1.24).
Conclusions:
In a contemporary cohort receiving statin therapy, elevated triglyceride levels were associated with a greater risk of atherosclerotic cardiovascular disease events and lower risk of death.




J Am Heart Assoc: 07 Oct 2021:e020377; epub ahead of print
Ambrosy AP, Yang J, Sung SH, Allen AR, ... Granowitz C, Go AS
J Am Heart Assoc: 07 Oct 2021:e020377; epub ahead of print | PMID: 34622663
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Impact:
Abstract

Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease-Associated Pulmonary Hypertension.

Daly CM, Griffiths M, Simpson CE, Yang J, ... Yung D, Everett AD

Background:
Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH. Methods and Results Serum endostatin was measured in cross-sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH-CHD, N=185). Outcomes, assessed by regression and Kaplan-Meier analysis, included hemodynamics, change in endostatin over time, and transplant-free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH-CHD. In APAH-CHD, endostatin was associated with a shorter 6-minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant-free survival. Addition of endostatin to an NT-proBNP (N-terminal pro-B-type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells.
Conclusions:
Endostatin is associated with disease severity, disease improvement, and worse survival in APAH-CHD. Endostatin with NT-proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH-CHD.




J Am Heart Assoc: 07 Oct 2021:e021409; epub ahead of print
Daly CM, Griffiths M, Simpson CE, Yang J, ... Yung D, Everett AD
J Am Heart Assoc: 07 Oct 2021:e021409; epub ahead of print | PMID: 34622662
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Impact:
Abstract

Regional Disparity of Reperfusion Therapy for Acute Ischemic Stroke in Japan: A Retrospective Analysis of Nationwide Claims Data from 2010 to 2015.

Maeda M, Fukuda H, Matsuo R, Ago T, Kitazono T, Kamouchi M

Background:
We aimed to determine whether a regional disparity exists in usage of reperfusion therapy (intravenous recombinant tissue plasminogen activator [IV rt-PA] and endovascular thrombectomy [EVT]) and post-reperfusion 30-day mortality in patients with acute ischemic stroke, and which regional factors are associated with their usage. Methods and Results We retrospectively investigated 69 948 patients (mean age±SD, 74.9±12.0 years; women, 41.4%) with acute ischemic stroke treated with reperfusion therapy between April 2010 and March 2016 in Japan using nationwide claims data. Regional disparity was evaluated using Gini coefficients for age- and sex-adjusted usage of reperfusion therapy and 30-day post-reperfusion in-hospital death ratio in 47 administrative regions. The association between regional factors and reperfusion therapy usage was evaluated with fixed-effects regression models. During the study period, Gini coefficients showed low inequality (0.11-0.15) for use of IV rt-PA monotherapy and IV rt-PA and/or EVT and extreme inequality (0.49) for EVT usage in 2010, which became moderate inequality (0.25) by 2015. The densities of stroke centers and endovascular specialists, as well as market concentration, were associated with increased usage of reperfusion therapy whereas the proportion of rural residents and delayed ambulance transport were negatively associated with usage. Inequality in the standardized death ratio after EVT was extreme (0.86) in 2010 but became moderate (0.29) by 2015; inequality was low to moderate (0.17-0.23) for IV rt-PA monotherapy and IV rt-PA and/or EVT.
Conclusions:
Scrutinizing existing data sources revealed regional disparity in reperfusion therapy for acute ischemic stroke and its associated regional factors in Japan.




J Am Heart Assoc: 07 Oct 2021:e021853; epub ahead of print
Maeda M, Fukuda H, Matsuo R, Ago T, Kitazono T, Kamouchi M
J Am Heart Assoc: 07 Oct 2021:e021853; epub ahead of print | PMID: 34622661
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Impact:
Abstract

Effect of Religious Fasting in Ramadan on Blood Pressure: Results From LORANS (London Ramadan Study) and a Meta-Analysis.

Al-Jafar R, Zografou Themeli M, Zaman S, Akbar S, ... Tsilidis KK, Dehghan A

Background:
Ramadan fasting is practiced by hundreds of millions every year. This ritual practice changes diet and lifestyle dramatically; thus, the effect of Ramadan fasting on blood pressure must be determined. Methods and Results LORANS (London Ramadan Study) is an observational study, systematic review, and meta-analysis. In LORANS, we measured systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 85 participants before and right after Ramadan. In the systematic review, studies were retrieved from PubMed, Embase, and Scopus from inception to March 3, 2020. We meta-analyzed the effect from these studies and unpublished data from LORANS. We included observational studies that measured SBP and/or DBP before Ramadan and during the last 2 weeks of Ramadan or the first 2 weeks of the month after. Data appraisal and extraction were conducted by at least 2 reviewers in parallel. We pooled SBP and DBP using a random-effects model. The systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42019159477). In LORANS, 85 participants were recruited; mean age was 45.6±15.9 years, and 52.9% (n=45) of participants were men. SBP and DBP after Ramadan fasting were lower by 7.29 mm Hg (-4.74 to -9.84) and 3.42 mm Hg (-1.73 to -5.09), even after adjustment for potential confounders. We identified 2778 studies of which 33 with 3213 participants were included. SBP and DBP after/before Ramadan were lower by 3.19 mm Hg (-4.43 to -1.96, I2=48%) and 2.26 mm Hg (-3.19 to -1.34, I2=66%), respectively. In subgroup analyses, lower blood pressures were observed in the groups who are healthy or have hypertension or diabetes but not in patients with chronic kidney disease.
Conclusions:
Our study suggests beneficial effects of Ramadan fasting on blood pressure independent of changes in weight, total body water, and fat mass and supports recommendations for some governmental guidelines that describe Ramadan fasting as a safe religious practice with respect to blood pressure.




J Am Heart Assoc: 07 Oct 2021:e021560; epub ahead of print
Al-Jafar R, Zografou Themeli M, Zaman S, Akbar S, ... Tsilidis KK, Dehghan A
J Am Heart Assoc: 07 Oct 2021:e021560; epub ahead of print | PMID: 34619991
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Impact:
Abstract

Assessment of an ECG-Based System for Localizing Ventricular Arrhythmias in Patients With Structural Heart Disease.

Zhou S, AbdelWahab A, Sapp JL, Sung E, ... Trayanova NA, Chrispin J

Background:
We have previously developed an intraprocedural automatic arrhythmia-origin localization (AAOL) system to identify idiopathic ventricular arrhythmia origins in real time using a 3-lead ECG. The objective was to assess the localization accuracy of ventricular tachycardia (VT) exit and premature ventricular contraction (PVC) origin sites in patients with structural heart disease using the AAOL system. Methods and Results In retrospective and prospective case series studies, a total of 42 patients who underwent VT/PVC ablation in the setting of structural heart disease were recruited at 2 different centers. The AAOL system combines 120-ms QRS integrals of 3 leads (III, V2, V6) with pace mapping to predict VT exit/PVC origin site and projects that site onto the patient-specific electroanatomic mapping surface. VT exit/PVC origin sites were clinically identified by activation mapping and/or pace mapping. The localization error of the VT exit/PVC origin site was assessed by the distance between the clinically identified site and the estimated site. In the retrospective study of 19 patients with structural heart disease, the AAOL system achieved a mean localization accuracy of 6.5±2.6 mm for 25 induced VTs. In the prospective study with 23 patients, mean localization accuracy was 5.9±2.6 mm for 26 VT exit and PVC origin sites. There was no difference in mean localization error in epicardial sites compared with endocardial sites using the AAOL system (6.0 versus 5.8 mm, P=0.895).
Conclusions:
The AAOL system achieved accurate localization of VT exit/PVC origin sites in patients with structural heart disease; its performance is superior to current systems, and thus, it promises to have potential clinical utility.




J Am Heart Assoc: 05 Oct 2021:e022217; epub ahead of print
Zhou S, AbdelWahab A, Sapp JL, Sung E, ... Trayanova NA, Chrispin J
J Am Heart Assoc: 05 Oct 2021:e022217; epub ahead of print | PMID: 34612085
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Impact:
Abstract

Two-Thumb Technique Is Superior to Two-Finger Technique in Cardiopulmonary Resuscitation of Simulated Out-of-Hospital Cardiac Arrest in Infants.

Cioccari G, Sica da Rocha T, Piva JP

Background:
To compare the 2-finger and 2-thumb chest compression techniques on infant manikins in an out-of-hospital setting regarding efficiency of compressions, ventilation, and rescuer pain and fatigue. Methods and Results In a randomized crossover design, 78 medical students performed 2 minutes of cardiopulmonary resuscitation with mouth-to-nose ventilation at a 30:2 rate on a Resusci Baby QCPR infant manikin (Laerdal, Stavanger, Norway), using a barrier device and the 2-finger and 2-thumb compression techniques. Frequency and depth of chest compressions, proper hand position, complete chest recoil at each compression, hands-off time, tidal volume, and number of ventilations were evaluated through manikin-embedded SkillReporting software. After the interventions, standard Likert questionnaires and analog scales for pain and fatigue were applied. The variables were compared by a paired t-test or Wilcoxon test as suitable. Seventy-eight students participated in the study and performed 156 complete interventions. The 2-thumb technique resulted in a greater depth of chest compressions (42 versus 39.7 mm; P<0.01), and a higher percentage of chest compressions with adequate depth (89.5% versus 77%; P<0.01). There were no differences in ventilatory parameters or hands-off time between techniques. Pain and fatigue scores were higher for the 2-finger technique (5.2 versus 1.8 and 3.8 versus 2.6, respectively; P<0.01).
Conclusions:
In a simulation of out-of-hospital, single-rescuer infant cardiopulmonary resuscitation, the 2-thumb technique achieves better quality of chest compressions without interfering with ventilation and causes less rescuer pain and fatigue.




J Am Heart Assoc: 05 Oct 2021:e018050; epub ahead of print
Cioccari G, Sica da Rocha T, Piva JP
J Am Heart Assoc: 05 Oct 2021:e018050; epub ahead of print | PMID: 34612083
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Impact:
Abstract

Period Prevalence of Rheumatic Heart Disease and the Need for a Centralized Patient Registry in American Samoa, 2016 to 2018.

Woodruff RC, Eliapo-Unutoa I, Chiou H, Gayapa M, ... Van Beneden CA, Ritchey M

Background:
Rheumatic heart disease (RHD) is a severe, chronic complication of acute rheumatic fever, triggered by group A streptococcal pharyngitis. Centralized patient registries are recommended for RHD prevention and control, but none exists in American Samoa. Using existing RHD tracking systems, we estimated RHD period prevalence and the proportion of people with RHD documented in the electronic health record. Methods and Results RHD cases were identified from a centralized electronic health record system, which retrieved clinical encounters with RHD International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, clinical problem lists referencing RHD, and antibiotic prophylaxis administration records; 3 RHD patient tracking spreadsheets; and an all-cause mortality database. RHD cases had ≥1 clinical encounter with RHD ICD-10-CM codes, a diagnostic echocardiogram, or RHD as a cause of death, or were included in RHD patient tracking spreadsheets. Period prevalence per 1000 population among children aged <18 years and adults aged ≥18 years from 2016 to 2018 and the proportion of people with RHD with ≥1 clinical encounter with an RHD ICD-10-CM code were estimated. From 2016 to 2018, RHD was documented in 327 people (57.2%: children aged <18 years). Overall RHD period prevalence was 6.3 cases per 1000 and varied by age (10.0 pediatric cases and 4.3 adult cases per 1000). Only 67% of people with RHD had ≥1 clinical encounter with an RHD ICD-10-CM code.
Conclusions:
RHD remains a serious public health problem in American Samoa, and the existing electronic health record does not include all cases. A centralized patient registry could improve tracking people with RHD to ensure they receive necessary care.




J Am Heart Assoc: 05 Oct 2021:e020424; epub ahead of print
Woodruff RC, Eliapo-Unutoa I, Chiou H, Gayapa M, ... Van Beneden CA, Ritchey M
J Am Heart Assoc: 05 Oct 2021:e020424; epub ahead of print | PMID: 34612073
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Impact:
Abstract

Myocardial Infarction Is Associated With Increased Stroke Severity, In-Hospital Mortality, and Complications: Insights From China Stroke Center Alliance Registries.

Duan H, Li Z, Gu HQ, Zhou Q, ... Wang Y, Mo D

Background:
Prior studies have shown an increased risk of ischemic stroke (IS) after myocardial infarction (MI); however, there are limited studies concerning the characteristics, in-hospital mortality, and complications of patients with IS with a medical history of MI. We hypothesized that patients with IS with a medical history of MI may experience more severe strokes and have a higher risk of in-hospital mortality and complications than patients with IS without a medical history of MI. Methods and Results Consecutive in-hospital data were extracted from the China Stroke Center Alliance database from August 2015 to July 2019. Patient characteristics, hospital tests, in-hospital mortality, and complications were analyzed and compared in patients with IS with or without a history of MI. Of 893 429 patients with IS, we identified 81 646 (9.1%) patients with a history of MI (MI group). Compared with patients with IS without MI, MI group patients were older, had a lower prevalence of current smoking, had a higher prevalence of a relative medical history, and took more medications before admission. Compared with the group with IS without MI, the MI group had a higher National Institute of Health Stroke Scale score after onset (4.0 versus 3.0; Hodges-Lehmann estimator, 22.5) and a higher proportion of severe strokes (National Institute of Health Stroke Scale score ≥15) (7.1% versus 4.4%; absolute standardized difference=11.6%). In the fully adjusted models, the risk of in-hospital mortality was higher in the MI group (odds ratio [OR], 1.74; 95% CI, 1.57-1.92; P<0.0001). MI group patients also had a higher risk of complications, including urinary tract infection (OR, 1.28; 95% CI, 1.2-1.36; P<0.0001), gastrointestinal bleeding (OR, 1.29; 95% CI, 1.19-1.39; P<0.0001), pneumonia (OR, 1.24; 95% CI, 1.21-1.28; P<0.0001), depression (OR, 1.33; 95% CI, 1.24-1.42; P<0.0001), seizure (OR, 1.35; 95% CI, 1.22-1.49; P<0.0001), atrial fibrillation (OR, 1.78; 95% CI, 1.71-1.86; P<0.0001), and cardiac or respiratory arrest (OR, 1.98; 95% CI, 1.78-2.2; P<0.0001).
Conclusions:
Patients with IS with a medical history of MI have an increased risk of severe stroke, in-hospital mortality, and complications. Studies exploring the underlying mechanisms are needed to improve and tailor stroke treatment strategies.




J Am Heart Assoc: 05 Oct 2021:e021602; epub ahead of print
Duan H, Li Z, Gu HQ, Zhou Q, ... Wang Y, Mo D
J Am Heart Assoc: 05 Oct 2021:e021602; epub ahead of print | PMID: 34612071
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Impact:
Abstract

Sacubitril/Valsartan Initiation Among Veterans Who Are Renin-Angiotensin-Aldosterone System Inhibitor Naïve With Heart Failure and Reduced Ejection Fraction.

Mohanty AF, Levitan EB, King JB, Dodson JA, ... Fang JC, Bress AP

Background:
Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, received US Food and Drug Administration approval in 2015 for heart failure with reduced ejection fraction (HFrEF). Our objective was to describe the sacubitril/valsartan initiation rate, associated characteristics, and 6-month follow-up dosing among veterans with HFrEF who are renin-angiotensin-aldosterone system inhibitor (RAASi) naïve. Methods and Results Retrospective cohort study of veterans with HFrEF who are RAASi naïve defined as left ventricular ejection fraction (LVEF) ≤40%; ≥1 in/outpatient heart failure visit, first RAASi (sacubitril/valsartan, angiotensin-converting enzyme inhibitor [ACEI]), or angiotensin-II receptor blocker [ARB]) fill from July 2015 to June 2019. Characteristics associated with sacubitril/valsartan initiation were identified using Poisson regression models. From July 2015 to June 2019, we identified 3458 sacubitril/valsartan and 29 367 ACEI or ARB initiators among veterans with HFrEF who are RAASi naïve. Sacubitril/valsartan initiation increased from 0% to 26.5%. Sacubitril/valsartan (versus ACEI or ARB) initiators were less likely to have histories of stroke, myocardial infarction, or hypertension and more likely to be older and have diabetes mellitus and lower LVEF. At 6-month follow-up, the prevalence of ≥50% target daily dose for sacubitril/valsartan, ACEI, and ARB initiators was 23.5%, 43.2%, and 47.1%, respectively.
Conclusions:
Sacubitril/valsartan initiation for HFrEF in the Veterans Administration increased in the 4 years immediately following Food and Drug Administration approval. Sacubitril/valsartan (versus ACEI or ARB) initiators had fewer baseline cardiovascular comorbidities and the lowest proportion on ≥50% target daily dose at 6-month follow-up. Identifying the reasons for lower follow-up dosing of sacubitril/valsartan could support guideline recommendations and quality improvement strategies for patients with HFrEF.




J Am Heart Assoc: 05 Oct 2021:e020474; epub ahead of print
Mohanty AF, Levitan EB, King JB, Dodson JA, ... Fang JC, Bress AP
J Am Heart Assoc: 05 Oct 2021:e020474; epub ahead of print | PMID: 34612065
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Impact:
Abstract

Long-Term Exposure to Air Pollution, Road Traffic Noise, and Heart Failure Incidence: The Danish Nurse Cohort.

Lim YH, Jørgensen JT, So R, Cole-Hunter T, ... Maric M, Andersen ZJ

Background:
We examined the association of long-term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3-year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO2 and road traffic noise since 1970 were estimated at participants\' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01-1.36), 1.10 (95% CI, 0.99-1.22), and 1.12 (95% CI, 0.99-1.26) per increase of 5.1 µg/m3 in particulate matter with a diameter <2.5 µm, 8.6 µg/m3 in NO2, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (Peffect modification<0.05).
Conclusions:
We found that long-term exposures to air pollution and road traffic noise were independently associated with HF.




J Am Heart Assoc: 05 Oct 2021:e021436; epub ahead of print
Lim YH, Jørgensen JT, So R, Cole-Hunter T, ... Maric M, Andersen ZJ
J Am Heart Assoc: 05 Oct 2021:e021436; epub ahead of print | PMID: 34612059
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Impact:
Abstract

Circulating miR-19b-3p as a Novel Prognostic Biomarker for Acute Heart Failure.

Su Y, Sun Y, Tang Y, Li H, ... Ong SB, Xu D

Background:
Circulating microRNAs are emerging biomarkers for heart failure (HF). Our study aimed to assess the prognostic value of microRNA signature that is differentially expressed in patients with acute HF. Methods and Results Our study comprised a screening cohort of 15 patients with AHF and 5 controls, a PCR-discovery cohort of 50 patients with AHF and 26 controls and a validation cohort of 564 patients with AHF from registered study DRAGON-HF (Diagnostic, Risk Stratification and Prognostic Value of Novel Biomarkers in Patients With Heart Failure). Through screening by RNA-sequencing and verification by reverse-transcription quantitative polymerase chain reaction, 9 differentially expressed microRNAs were verified (miR-939-5p, miR-1908-5p, miR-7706, miR-101-3p, miR-144-3p, miR-4732-3p, miR-3615, miR-484 and miR-19b-3p). Among them, miR-19b-3p was identified as the microRNA signature with the highest fold-change of 8.4 and the strongest prognostic potential (area under curve with 95% CI, 0.791, 0.654-0.927). To further validate its prognostic value, in the validation cohort, the baseline level of miR-19b-3p was measured. During a follow-up period of 19.1 (17.7, 20.7) months, primary end point comprising of all-cause mortality or readmission due to HF occurred in 48.9% patients, while patients in the highest quartile of miR-19b-3p level presented the worst survival (Log-rank P<0.001). Multivariate Cox model showed that the level of miR-19b-3p could independently predict the occurrence of primary end point (adjusted hazard ratio,1.39; 95% CI, 1.18-1.64). In addition, miR-19b-3p positively correlated with soluble suppression of tumorigenicity 2 and echocardiographic indexes of left ventricular hypertrophy.
Conclusions:
Circulating miR-19b-3p could be a valuable prognostic biomarker for AHF. In addition, a high level of circulating miR-19b-3p might indicate ventricular hypertrophy in AHF subjects. Registration URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03727828.




J Am Heart Assoc: 05 Oct 2021:e022304; epub ahead of print
Su Y, Sun Y, Tang Y, Li H, ... Ong SB, Xu D
J Am Heart Assoc: 05 Oct 2021:e022304; epub ahead of print | PMID: 34612058
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Impact:
Abstract

Prognostic Importance of Pulmonary Arterial Capacitance in Acute Decompensated Heart Failure With Preserved Ejection Fraction.

Nakagawa A, Yasumura Y, Yoshida C, Okumura T, ... Sakata Y, Osaka CardioVascular Conference (OCVC)‐Heart Failure investigators

Background:
Although the prognostic importance of pulmonary arterial capacitance (PAC; stroke volume/pulmonary arterial pulse pressure) has been elucidated in heart failure with reduced ejection fraction, whether its significance in patients suffering from heart failure with preserved ejection fraction is not known. We aimed to examine the association of PAC with outcomes in inpatients with heart failure with preserved ejection fraction. Methods and Results We prospectively studied 705 patients (median age, 83 years; 55% women) registered in PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction). We investigated the association of echocardiographic PAC at discharge with the primary end point of all-cause death or heart failure rehospitalization with a mean follow-up of 384 days. We further tested the acceptability of the prognostic significance of PAC in a subgroup of patients (167/705 patients; median age, 81 years; 53% women) in whom PAC was assessed by right heart catheterization. The median echocardiographic PAC was 2.52 mL/mm Hg, with a quartile range of 1.78 to 3.32 mL/mm Hg. Univariable and multivariable Cox regression testing revealed that echocardiographic PAC was associated with the primary end point (unadjusted hazard ratio, 0.82; 95% CI, 0.72-0.92; P=0.001; adjusted hazard ratio, 0.86; 95% CI, 0.74-0.99; P=0.035, respectively). Univariable Cox regression testing revealed that PAC assessed by right heart catheterization (median calculated PAC, 2.82 mL/mm Hg) was also associated with the primary end point (unadjusted HR, 0.70; 95% CI, 0.52-0.91; P=0.005).
Conclusions:
A prospective cohort study revealed that impaired PAC diagnosed with both echocardiography and right heart catheterization was associated with adverse outcomes in inpatients with heart failure with preserved ejection fraction. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.




J Am Heart Assoc: 05 Oct 2021:e023043; epub ahead of print
Nakagawa A, Yasumura Y, Yoshida C, Okumura T, ... Sakata Y, Osaka CardioVascular Conference (OCVC)‐Heart Failure investigators
J Am Heart Assoc: 05 Oct 2021:e023043; epub ahead of print | PMID: 34612057
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Impact:
Abstract

Dose of Cardiac Rehabilitation to Reduce Mortality and Morbidity: A Population-Based Study.

Medina-Inojosa JR, Grace SL, Supervia M, Stokin G, ... Thomas R, Lopez-Jimenez F

Background:
There is wide variability in cardiac rehabilitation (CR) dose (ie, number of sessions) delivered, and no evidence-based recommendations regarding what dose to prescribe. We aimed to test what CR dose impacts major adverse cardiovascular events (MACEs). Methods and Results This is an historical cohort study of all patients who had coronary artery disease and who initiated supervised CR between 2002 and 2012 from a single major CR center. CR dose was defined as number of visits including exercise and patient education. Follow-up was performed using record linkage from the Rochester Epidemiology Project. MACEs included acute myocardial infarction, unstable angina, ventricular arrhythmias, stroke, revascularization, or all-cause mortality. Dose was analyzed in several ways, including tertiles, categories, and as a continuous variable. Cox models were adjusted for factors associated with dose and MACE. The cohort consisted of 2345 patients, who attended a mean of 12.5±11.1 of 36 prescribed sessions. After a mean follow-up of 6 years, 695 (29.65%) patients had a MACE, including 231 who died. CR dose was inversely associated with MACE (hazard ratio, 0.66 [95% CI]; 0.55-0.91) in those completing ≥20 sessions, when compared with those not exposed to formal exercise sessions (≤1 session; log-rank P=0.007). We did not find evidence of nonlinearity (P≥0.050), suggesting no minimal threshold nor ceiling. Each additional session was associated with a lower rate of MACE (fully adjusted hazard ratio, 0.98 [95% CI, 0.97-0.99]). Greater session frequency was also associated with lower MACE risk (fully adjusted hazard ratio, 0.74 [95% CI, 0.58-0.94]).
Conclusions:
CR reduces MACEs, but the benefit appears to be linear, with greater risk reduction with higher doses, and no upper threshold.




J Am Heart Assoc: 05 Oct 2021:e021356; epub ahead of print
Medina-Inojosa JR, Grace SL, Supervia M, Stokin G, ... Thomas R, Lopez-Jimenez F
J Am Heart Assoc: 05 Oct 2021:e021356; epub ahead of print | PMID: 34612055
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Impact:
Abstract

Vascular Stiffening Mediated by Rho-Associated Coiled-Coil Containing Kinase Isoforms.

Li Y, Tai HC, Sladojevic N, Kim HH, Liao JK

Background:
The pathogenesis of vascular stiffening and hypertension is marked by non-compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho-associated coiled-coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. Methods and Results Hemizygous Rock mice (Rock1+/- and Rock2+/-) were used to determine the role of ROCK1 and ROCK2 in age-related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild-type mice compared with that of Rock1+/- and Rock2+/- mice. As a model for age-related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L-Nω-nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12-week-old male Rock1+/- and Rock2+/- mice. Similar to advancing age, angiotensin II/L-Nω-nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2+/-, and to a lesser extent, Rock1+/- mice. The reduction of aortic stiffening in Rock2+/- mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor-β1 or angiotensin II was greatly attenuated in Rock2-/- mouse embryonic fibroblasts.
Conclusions:
These findings indicate that ROCK1 and ROCK2 mediate both age-related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age-related vascular stiffening.




J Am Heart Assoc: 05 Oct 2021:e022568; epub ahead of print
Li Y, Tai HC, Sladojevic N, Kim HH, Liao JK
J Am Heart Assoc: 05 Oct 2021:e022568; epub ahead of print | PMID: 34612053
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Impact:
Abstract

Subintimal Versus Intraluminal Approach for Femoropopliteal Chronic Total Occlusions Treated With Intravascular Ultrasound Guidance.

Tomoi Y, Takahara M, Kuramitsu S, Soga Y, ... Ando K, IVORY Study Investigators

Background:
The subintimal approach (SA) is widely used in endovascular therapy for femoropopliteal chronic total occlusion lesions. However, when compared with the intraluminal approach (IA), the safety and efficacy of SA in real-world practice are not well characterized. Furthermore, there is a paucity of data on the clinical impact of subintimal and intraluminal wire passage (SWP and IWP, respectively) assessed by intravascular ultrasound. Methods and Results From the IVORY (Intravascular Ultrasound-Supported Endovascular Therapy in Superficial Femoral Artery) registry, this study included 500 patients undergoing endovascular therapy for femoropopliteal chronic total occlusion lesions (SA, n=67; IA, n=433; and SWP, n=186; IWP, n=314). The primary end point was the cumulative 1-year incidence of restenosis. The rate of perioperative complications was also assessed. Propensity score matching analysis was performed to adjust for the intergroup differences. After propensity score matching, the final study population consisted of 59 pairs (SA, n=59; IA, n=348) and 170 pairs (SWP, n=170; IWP, n=293), respectively. Cumulative 1-year incidence of restenosis was comparable between the SA and IA groups (41.0% versus 43.4%, P=0.40). No significant difference in 1-year restenosis rate between the SWP and IWP groups was observed (48.2% versus 40.8%, P=0.40), although the SWP group tended to be a higher rate of perioperative complications than the IWP group (8.2% versus 4.1%, P=0.07).
Conclusions:
At 1 year, both SA and IA showed acceptable results for femoropopliteal chronic total occlusion lesions. Cumulative 1-year incidence of restenosis was not significantly different between SWP and IWP, whereas perioperative complications occurred more frequently in SWP than in IWP. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000020472.




J Am Heart Assoc: 05 Oct 2021:e021903; epub ahead of print
Tomoi Y, Takahara M, Kuramitsu S, Soga Y, ... Ando K, IVORY Study Investigators
J Am Heart Assoc: 05 Oct 2021:e021903; epub ahead of print | PMID: 34612052
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Impact:
Abstract

Validation of the 4-Item PRECISE-DAPT Score: A SWEDEHEART Study.

Wester A, Mohammad MA, Olivecrona G, Holmqvist J, Yndigegn T, Koul S

Background:
The Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score has been shown to predict out-of-hospital major bleeding after myocardial infarction treated with percutaneous coronary intervention and dual antiplatelet therapy (DAPT). However, large validation studies have been scarce and the discriminative ability for patients with a preexisting bleeding risk factor (elderly, underweight, women, anemia, kidney dysfunction, or cancer) in a real-world setting is unknown. Methods and Results Patients undergoing percutaneous coronary intervention for myocardial infarction between 2008 and 2017 were included from the SWEDEHEART (Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry (n=66 295). The predictive value of the PRECISE-DAPT score for rehospitalization with major bleeding during dual antiplatelet therapy was evaluated using receiver operating characteristic analyses. A high PRECISE-DAPT score (≥25; n=13 894) was associated with increased risk of major bleeding (3.9% versus 1.8%; hazard ratio [HR], 2.2; 95% CI, 2.0-2.5; P<0.001) compared with a non-high score (<25; n=52 401). The score demonstrated a c-statistic of 0.64 (95% CI, 0.63-0.66). The discriminative ability of the score to further stratify bleeding risk in patients with preexisting bleeding risk factors was poor, especially in patients who are elderly (c-statistic=0.57; 95% CI, 0.55-0.60) or underweight (c-statistic=0.56; 95% CI, 0.51-0.61), for whom a non-high PRECISE-DAPT score was associated with similar bleeding risk as a high PRECISE-DAPT score in the general myocardial infarction population.
Conclusions:
In this nationwide population-based study, the PRECISE-DAPT score performed moderately in the general myocardial infarction population and poorly in patients with preexisting bleeding risk factors, where its usefulness seems limited.




J Am Heart Assoc: 05 Oct 2021:e020974; epub ahead of print
Wester A, Mohammad MA, Olivecrona G, Holmqvist J, Yndigegn T, Koul S
J Am Heart Assoc: 05 Oct 2021:e020974; epub ahead of print | PMID: 34612051
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Impact:
Abstract

Clinical Characteristics, Management Strategies, and Outcomes of Non-ST-Segment-Elevation Myocardial Infarction Patients With and Without Prior Coronary Artery Bypass Grafting.

Shoaib A, Rashid M, Berry C, Curzen N, ... Kinnaird T, Mamas MA

Background:
There are limited data on the management strategies, temporal trends and clinical outcomes of patients who present with non-ST-segment-elevation myocardial infarction and have a prior history of CABG. Methods and Results We identified 287 658 patients with non-ST-segment-elevation myocardial infarction between 2010 and 2017 in the United Kingdom Myocardial Infarction National Audit Project database. Clinical and outcome data were analyzed by dividing into 2 groups by prior history of coronary artery bypass grafting (CABG): group 1, no prior CABG (n=262 362); and group 2, prior CABG (n=25 296). Patients in group 2 were older, had higher GRACE (Global Registry of Acute Coronary Events) risk scores and burden of comorbid illnesses. More patients underwent coronary angiography (69% versus 63%) and revascularization (53% versus 40%) in group 1 compared with group 2. Adjusted odds of receiving inpatient coronary angiogram (odds ratio [OR], 0.91; 95% CI, 0.88-0.95; P<0.001) and revascularization (OR, 0.73; 95% CI, 0.70-0.76; P<0.001) were lower in group 2 compared with group 1. Following multivariable logistic regression analyses, the OR of in-hospital major adverse cardiovascular events (composite of inpatient death and reinfarction; OR, 0.97; 95% CI, 0.90-1.04; P=0.44), all-cause mortality (OR, 0.96; 95% CI, 0.88-1.04; P=0.31), reinfarction (OR, 1.02; 95% CI, 0.89-1.17; P=0.78), and major bleeding (OR, 1.01; 95% CI, 0.90-1.11; P=0.98) were similar across groups. Lower adjusted risk of inpatient mortality (OR, 0.67; 95% CI, 0.46-0.98; P=0.04) but similar risk of bleeding (OR,1.07; CI, 0.79-1.44; P=0.68) and reinfarction (OR, 1.13; 95% CI, 0.81-1.57; P=0.47) were observed in group 2 patients who underwent percutaneous coronary intervention compared with those managed medically.
Conclusions:
In this national cohort, patients with non-ST-segment-elevation myocardial infarction with prior CABG had a higher risk profile, but similar risk-adjusted in-hospital adverse outcomes compared with patients without prior CABG. Patients with prior CABG who received percutaneous coronary intervention had lower in-hospital mortality compared with those who received medical management.




J Am Heart Assoc: 05 Oct 2021:e018823; epub ahead of print
Shoaib A, Rashid M, Berry C, Curzen N, ... Kinnaird T, Mamas MA
J Am Heart Assoc: 05 Oct 2021:e018823; epub ahead of print | PMID: 34612049
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Impact:
Abstract

Tracking Blood Pressure Control Performance and Process Metrics in 25 US Health Systems: The PCORnet Blood Pressure Control Laboratory.

Cooper-DeHoff RM, Fontil V, Carton T, Chamberlain AM, ... Wozniak G, Pletcher MJ

Background:
The National Patient-Centered Clinical Research Network Blood Pressure Control Laboratory Surveillance System was established to identify opportunities for blood pressure (BP) control improvement and to provide a mechanism for tracking improvement longitudinally. Methods and Results We conducted a serial cross-sectional study with queries against standardized electronic health record data in the National Patient-Centered Clinical Research Network (PCORnet) common data model returned by 25 participating US health systems. Queries produced BP control metrics for adults with well-documented hypertension and a recent encounter at the health system for a series of 1-year measurement periods for each quarter of available data from January 2017 to March 2020. Aggregate weighted results are presented overall and by race and ethnicity. The most recent measurement period includes data from 1 737 995 patients, and 11 956 509 patient-years were included in the trend analysis. Overall, 15% were Black, 52% women, and 28% had diabetes. BP control (<140/90 mm Hg) was observed in 62% (range, 44%-74%) but varied by race and ethnicity, with the lowest BP control among Black patients at 57% (odds ratio, 0.79; 95% CI, 0.66-0.94). A new class of antihypertensive medication (medication intensification) was prescribed in just 12% (range, 0.6%-25%) of patient visits where BP was uncontrolled. However, when medication intensification occurred, there was a large decrease in systolic BP (≈15 mm Hg; range, 5-18 mm Hg).
Conclusions:
Major opportunities exist for improving BP control and reducing disparities, especially through consistent medication intensification when BP is uncontrolled. These data demonstrate substantial room for improvement and opportunities to close health equity gaps.




J Am Heart Assoc: 05 Oct 2021:e022224; epub ahead of print
Cooper-DeHoff RM, Fontil V, Carton T, Chamberlain AM, ... Wozniak G, Pletcher MJ
J Am Heart Assoc: 05 Oct 2021:e022224; epub ahead of print | PMID: 34612048
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Impact:
Abstract

Favorable Atrial Remodeling After Percutaneous Pulmonary Valve Implantation and Its Association With Changes in Exercise Capacity and Right Ventricular Function.

Latus H, Born D, Shehu N, Stern H, ... Eicken A, Tutarel O

Background:
Right atrial (RA) dilatation and impaired right ventricular (RV) filling are common in patients with RV outflow tract dysfunction. We aimed to study potential correlations between atrial function with clinically relevant hemodynamic parameters and to assess the predictive impact of atrial performance on the recovery of exercise capacity and RV pump function after percutaneous pulmonary valve implantation (PPVI). Methods and Results Altogether, 105 patients with right ventricular outflow tract dysfunction (median age at PPVI, 19.2 years; range, 6.2-53.4 years) who underwent cardiac magnetic resonance imaging before and 6 months after PPVI were included. RA and left atrial maximal and minimal volumes as well as atrial passive and active emptying function were assessed from axial cine slices. RA emptying function was inversely related to invasive RV end-diastolic pressure, and RA passive emptying correlated significantly with peak oxygen uptake. After PPVI, a significant decrease in RA minimum volume was observed, whereas RA passive emptying function improved, and RA active emptying function decreased significantly. Patients with predominant right ventricular outflow tract stenosis showed more favorable changes in RA active and left atrial passive emptying than those with primary volume overload. None of the RA and left atrial emptying parameters was predictive for recovery of peak oxygen uptake or RV ejection fraction.
Conclusions:
In patients with right ventricular outflow tract dysfunction, impaired RA emptying assessed by cardiac magnetic resonance imaging was associated with increased RV filling pressures and lower exercise capacity. PPVI leads to a reduction in RA size and improved passive RA emptying function. However, RA function was not associated with improved exercise performance and RV pump function.




J Am Heart Assoc: 05 Oct 2021:e021416; epub ahead of print
Latus H, Born D, Shehu N, Stern H, ... Eicken A, Tutarel O
J Am Heart Assoc: 05 Oct 2021:e021416; epub ahead of print | PMID: 34612047
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Impact:
Abstract

Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cornwell WK, Baggish AL, Bhatta YKD, Brosnan MJ, ... and Secondary Prevention Committee of the Council on Clinical Cardiology; and Council on Arteriosclerosis, Thrombosis and Vascular Biology
An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.



J Am Heart Assoc: 04 Oct 2021; 10:e023225
Cornwell WK, Baggish AL, Bhatta YKD, Brosnan MJ, ... and Secondary Prevention Committee of the Council on Clinical Cardiology; and Council on Arteriosclerosis, Thrombosis and Vascular Biology
J Am Heart Assoc: 04 Oct 2021; 10:e023225 | PMID: 34496612
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Impact:
Abstract

Sex Disparities in Organ Donation: Finding an Equitable Donor Pool.

Yee E, Hosseini SM, Duarte B, Knapp SM, ... Sweitzer NK, Breathett K

Background:
The majority of living organ donors are women, but few are deceased organ donors, which increases risks associated with sex mismatched organs. We sought to identify reasons for sex disparities in organ donation and strategies for equity. Methods and Results Using Amazon\'s Mechanical Turk, we examined US adults\' perceptions regarding donation in a mixed-methods survey study. Results were compared by sex with Fisher\'s exact test and T-tests for quantitative results and qualitative descriptive analyses for write-in responses. Among 667 participants (55% women), the majority of men (64.8%) and women (63.4%) self-identified as registered donors. Women\'s willingness to donate their own organs to family members (P=0.03) or strangers (P=0.03) was significantly higher than men. Donors from both sexes were guided by: desire to help, personal experience, and believing organs would be useless to deceased donors. Non-donors from both sexes were guided by: no reason, medical mistrust, contemplating donation. When considering whether to donate organs of a deceased family member, women were equally guided by a family member\'s wishes and believing the family member had no further use for organs. Men had similar themes but valued the family member\'s wishes more. Among non-donors, both sexes would consider donation if more information was provided.
Conclusions:
In a national survey, both sexes had similar reasons for becoming and not becoming an organ donor. However, compared with men, women were more willing to donate their organs to family members and strangers. Improving education and communicating wishes regarding organ donation with direct relatives may increase sex equity in deceased organ donation.




J Am Heart Assoc: 04 Oct 2021; 10:e020820
Yee E, Hosseini SM, Duarte B, Knapp SM, ... Sweitzer NK, Breathett K
J Am Heart Assoc: 04 Oct 2021; 10:e020820 | PMID: 34558313
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Impact:
Abstract

Effect of Posting on Social Media on Systolic Blood Pressure and Management of Hypertension: A Randomized Controlled Trial.

Mancheno C, Asch DA, Klinger EV, Goldshear JL, ... Yang L, Merchant RM

Background:
Online platforms are used to manage aspects of our lives including health outside clinical settings. Little is known about the effectiveness of using online platforms to manage hypertension. We assessed effects of tweeting/retweeting cardiovascular health content by individuals with poorly controlled hypertension on systolic blood pressure (SBP) and patient activation. Methods and Results We conducted this 2-arm randomized controlled trial. Eligibility included diagnosis of hypertension; SBP >140 mm Hg; and an existing Twitter account or willingness to create one to follow study Twitter account. Intervention arm was asked to tweet/retweet health content 2×/week using a specific hashtag for study duration (6 months). The main measures include primary outcome change in SBP; secondary outcome point change in Patient Activation Measure (PAM). We remotely recruited and enrolled 611 participants, mean age 52 (SD, 11.7). Mean baseline SBP for the intervention group was 155.8 and for control was 155.6. At 6 months, mean SBP for intervention group was 137.6 and for control was 135.7. Mean change in SBP from baseline to 6 months for the intervention group was -18.5 and for control was -19.8 (P=0.48). Mean PAM at baseline for the intervention group was 70.3 for control was 72.7. At 6 months, mean PAM scores were 71.1 (intervention) and 75.6 (control). Mean change in PAM score for the intervention group was 0.0 and for control was 3.3 (P=0.12).
Conclusions:
Recruiting and engaging patients and collecting outcome measures remotely are feasible using Twitter. Encouraging patients with poorly controlled hypertension to tweet or retweet health content on Twitter did not improve SBP or PAM score at 6 months. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02622256.




J Am Heart Assoc: 04 Oct 2021; 10:e020596
Mancheno C, Asch DA, Klinger EV, Goldshear JL, ... Yang L, Merchant RM
J Am Heart Assoc: 04 Oct 2021; 10:e020596 | PMID: 34558301
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Impact:
Abstract

Surgery Is Underused in Elderly Patients With Left-Sided Infective Endocarditis: A Nationwide Registry Study.

Ragnarsson S, Salto-Alejandre S, Ström A, Olaison L, Rasmussen M

Background:
Infective endocarditis is associated with higher mortality in elderly patients, but the role of surgery in this group has not been fully evaluated. The aim of this study was to assess outcomes of left-sided infective endocarditis in elderly patients and to determine the influence of surgery on mortality in the elderly. Methods and Results A nationwide retrospective study was performed of 2186 patients with left-sided infective endocarditis recorded in the SRIE (Swedish Registry of Infective Endocarditis), divided into patients aged <65 years (n=864), 65 to 79 years (n=806), and ≥80 years (n=516). Survival analysis was performed using the Swedish National Population Registry, and propensity score matching was applied to assess the effect of surgery on survival among patients of all ages. The rate of surgery decreased with increasing age, from 46% in the <65 group to 6% in the ≥80 group. In-hospital mortality was 3 times higher in the ≥80 group compared with the <65 group (23% versus 7%) and almost twice that of the 65 to 79 group (12%). In propensity-matched groups, the mortality rate was significantly lower between the ages of 55 and 82 years in patients who underwent surgery compared with patients who did not undergo surgery. Surgery was also associated with better long-term survival in matched patients who were ≥75 years (hazard ratio, 0.36; 95% CI, 0.24-0.54 [P<0.001]).
Conclusions:
The proportion of elderly patients with infective endocarditis who underwent surgery was low compared with that of younger patients. Surgery was associated with lower mortality irrespective of age. In matched elderly patients, long-term mortality was higher in patients who did not undergo surgery, suggesting that surgery is underused in elderly patients.




J Am Heart Assoc: 04 Oct 2021; 10:e020221
Ragnarsson S, Salto-Alejandre S, Ström A, Olaison L, Rasmussen M
J Am Heart Assoc: 04 Oct 2021; 10:e020221 | PMID: 34558291
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Impact:
Abstract

Association of Rosacea With Cardiovascular Disease: A Retrospective Cohort Study.

Choi D, Choi S, Choi S, Park SM, Yoon HS

Background:
There is emerging evidence that rosacea, a chronic cutaneous inflammatory disease, is associated with various systemic diseases. However, its association with cardiovascular disease (CVD) remains controversial. We aimed to investigate whether patients with rosacea are at increased risk of developing CVD. Methods and Results This retrospective cohort study from the Korean National Health Insurance Service-Health Screening Cohort included patients with newly diagnosed rosacea (n=2681) and age-, sex-, and index year-matched reference populations without rosacea (n=26 810) between 2003 and 2014. The primary outcome was subsequent CVD including coronary heart disease and stroke. Multivariable Cox regression analyses were used to evaluate adjusted hazard ratios for subsequent CVD adjusted for major risk factors of CVD. Compared with the reference population (13 410 women; mean [SD] age, 57.7 [9.2] years), patients with rosacea (1341 women; mean [SD] age, 57.7 [9.2] years) displayed an increased risk for CVD (adjusted hazard ratios, 1.20; 95% CI, 1.03-1.40) and coronary heart disease (adjusted hazard ratios, 1.29; 95% CI, 1.05-1.60). The risk for stroke was not significantly elevated (adjusted hazard ratios, 1.12; 95% CI, 0.91-1.37).
Conclusions:
This study suggests that patients with rosacea are more likely to develop subsequent CVD. Proper education for patients with rosacea to manage other modifiable risk factors of CVD along with rosacea is needed.




J Am Heart Assoc: 04 Oct 2021; 10:e020671
Choi D, Choi S, Choi S, Park SM, Yoon HS
J Am Heart Assoc: 04 Oct 2021; 10:e020671 | PMID: 34558290
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Impact:
Abstract

Outcomes of Elderly Patients Undergoing Left Atrial Appendage Closure.

Sanjoy SS, Choi YH, Sparrow RT, Jneid H, ... Mamas MA, Bagur R

Background:
Elderly patients have a higher burden of comorbidities that influence clinical outcomes. We aimed to compare in-hospital outcomes in patients ≥80 years old to younger patients, and to determine the factors associated with increased risk of major adverse events (MAE) after left atrial appendage closure. Methods and Results The National Inpatient Sample was used to identify discharges after left atrial appendage closure between October 2015 and December 2018. The primary outcome was in-hospital MAE defined as the composite of postprocedural bleeding, vascular and cardiac complications, acute kidney injury, stroke, and death. A total of 6779 hospitalizations were identified, of which, 2371 (35%) were ≥80 years old and 4408 (65%) were <80 years old. Patients ≥80 years old experienced a higher rate of MAE compared with those aged <80 years old (6.0% versus 4.6%, P=0.01), and this difference was driven by a numerically higher rate of cardiac complications (2.4% versus 1.8%, P=0.09) and death (0.3% versus 0.1%, P=0.05) among individuals ≥80 years old. In patients ≥80 years old, higher odds of in-hospital MAE were observed in women (1.61-fold), and those with preprocedural congestive heart failure (≈2-fold), diabetes (≈1.5-fold), renal disease (≈2.6-fold), anemia (≈2.7-fold), and dementia (≈5-fold). In patients <80 years old, a higher risk of in-hospital MAE was encountered among women (≈1.4-fold) and those with diabetes (≈1.3-fold), renal disease (≈2.6-fold), anemia (≈2-fold), and dyslipidemia (≈1.2-fold).
Conclusions:
Patients ≥80 years old had higher rates of in-hospital MAE compared with patients aged <80 years old. Female sex and the presence of heart failure, diabetes, renal disease, and anemia were factors associated with in-hospital MAE among both groups.




J Am Heart Assoc: 04 Oct 2021; 10:e021973
Sanjoy SS, Choi YH, Sparrow RT, Jneid H, ... Mamas MA, Bagur R
J Am Heart Assoc: 04 Oct 2021; 10:e021973 | PMID: 34558289
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Impact:
Abstract

QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System.

Mantri N, Lu M, Zaroff JG, Risch N, ... Jorgenson E, Iribarren C

Background:
Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07).
Conclusions:
Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.




J Am Heart Assoc: 04 Oct 2021; 10:e018513
Mantri N, Lu M, Zaroff JG, Risch N, ... Jorgenson E, Iribarren C
J Am Heart Assoc: 04 Oct 2021; 10:e018513 | PMID: 34581201
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Impact:
Abstract

Conceptual Framework for Personal Recovery in Patients With Acute Myocardial Infarction.

Dreyer RP, Pavlo AJ, Horne A, Dunn R, ... Slade M, Davidson L

Background:
Although there has been movement in cardiology to advance patient-centered approaches to postacute myocardial infarction (AMI) care, work remains to be done in aligning patient preferences with clinical care. Our objective was to characterize patients\' experience of AMI and treatment to develop a new conceptual framework of patient-centered recovery in cardiology. Methods and Results We conducted in-depth interviews with people who previously experienced an AMI (2016-2019). The interview focused on participants\' experiences of their recovery, which were audio-recorded, transcribed verbatim, and analyzed using a phenomenological framework. The overarching theme described by the 42 participants was feeling like a \"different person\" after the AMI. This shift manifested itself in both losses and gains, each of which posed new challenges to everyday life. The experience appeared to be an active process requiring people to take responsibility for their health. In terms of loss, participants describe how the AMI threatened their sense of safety and security and led to social isolation, fragility, uncertainty about the future, and difficulty expressing emotions accompanied this new fear. A conceptual framework describing the relationship between AMI, identity change, and functioning was developed.
Conclusions:
Participants experienced the AMI as an unexpected disruption in their lives that had far-reaching effects on their daily functioning, and were resolved in numerous ways. The conceptual framework may assist in providing a theoretical basis for future interventions in cardiology that not only engage and retain patients in care but also improve long-term adherence to secondary prevention and other aspects of self-care.




J Am Heart Assoc: 04 Oct 2021; 10:e022354
Dreyer RP, Pavlo AJ, Horne A, Dunn R, ... Slade M, Davidson L
J Am Heart Assoc: 04 Oct 2021; 10:e022354 | PMID: 34581198
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Impact:
Abstract

Incidence and Outcomes of Infective Endocarditis After Transcatheter or Surgical Aortic Valve Replacement.

Lanz J, Reardon MJ, Pilgrim T, Stortecky S, ... Huang J, Windecker S

Background:
Data comparing the frequency and outcomes of infective endocarditis (IE) after transcatheter (TAVR) to surgical aortic valve replacement (SAVR) are scarce. The objective of this study is to compare the incidence and outcomes of IE after TAVR using a supra-annular, self-expanding platform (CoreValve and Evolut) to SAVR. Methods and Results Data of 3 randomized clinical trials comparing TAVR to SAVR and a prospective continued TAVR access study were pooled. IE was defined on the basis of the modified Duke criteria. The cumulative incidence of IE was determined by modeling the cause-specific hazard. Estimates of all-cause mortality were calculated by means of the Kaplan-Meier method. Outcomes are reported for the valve-implant cohort. During a mean follow-up time of 2.17±1.51 years, 12 (0.5%) of 2249 patients undergoing TAVR and 21 (1.1%) of 1828 patients undergoing SAVR developed IE. Patients with IE more frequently had diabetes mellitus than those without (57.6% versus 34.2%; P=0.005). The cumulative incidence of IE was 1.01% (95% CI, 0.47%-1.96%) after TAVR and 1.58% (95% CI, 0.97%-2.46%) after SAVR (P=0.047) at 5 years. Among patients with IE, the rate of all-cause mortality was 27.3% (95% CI, 1.0%-53.6%) in the TAVR and 51.8% (95% CI, 28.2%-75.3%) in the SAVR group at 1 year (log-rank P=0.15).
Conclusions:
Pooled prospectively collected data comparing TAVR with a supra-annular, self-expanding device to SAVR showed a low cumulative risk of IE irrespective of treatment modality, although the risk was lower in the TAVR implant group. Once IE occurred, mortality was high. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01240902, NCT01586910, NCT02701283.




J Am Heart Assoc: 04 Oct 2021; 10:e020368
Lanz J, Reardon MJ, Pilgrim T, Stortecky S, ... Huang J, Windecker S
J Am Heart Assoc: 04 Oct 2021; 10:e020368 | PMID: 34581194
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Impact:
Abstract

Infective Endocarditis Hospitalizations and Outcomes in Patients With End-Stage Kidney Disease: A Nationwide Data-Linkage Study.

Gallacher PJ, McAllister DA, Mills NL, Cruden NL, Shah ASV, Dhaun N

Background:
We investigated the clinical features, microbiology, and short- and long-term outcomes of incident infective endocarditis (IE) hospitalizations in patients with end-stage kidney disease (ESKD) requiring dialysis or with a kidney transplant over 25 years in Scotland. Methods and Results In this retrospective, population-based cohort study linking national hospitalization and mortality data, we identified patients with a history of ESKD and hospitalized with IE in Scotland between January 1, 1990 and December 31, 2014. From January 1, 2008, individual IE hospitalizations were additionally linked to national microbiology data. Multivariable logistic regression, adjusting for patient demographics and comorbidities, evaluated the association between ESKD and all-cause death at 1 and 3 years. Of 7638 incident IE hospitalizations between 1990 and 2014, 2.8% (216/7638) occurred in 210 patients with ESKD and 97.2% (7422/7638) occurred in 7303 patients without ESKD. Positive findings from blood cultures were identified in 42% (950/2267) of incident IE hospitalizations from 2008. Staphylococcus aureus was isolated in 25.9% (21/81) and 12.8% (280/2186) of patients with and without ESKD, respectively (P=0.002). ESKD was associated with an increased odds of death at 1 (44.9% versus 31.4%; adjusted odds ratio [aOR], 2.47, 95% CI, 1.85-3.30;, P<0.001) and 3 years (63.9% versus 42.8%; aOR, 3.77; 95% CI, 2.79-5.12; P<0.001).
Conclusions:
IE is associated with a poor prognosis in patients with ESKD, especially in the longer term. Compared with patients without ESKD, patients with ESKD were twice as likely to die within 1 year, and 3 times as likely to die within 3 years of IE hospitalization.




J Am Heart Assoc: 04 Oct 2021; 10:e022002
Gallacher PJ, McAllister DA, Mills NL, Cruden NL, Shah ASV, Dhaun N
J Am Heart Assoc: 04 Oct 2021; 10:e022002 | PMID: 34581192
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Impact:
Abstract

Identification of Frailty Using a Claims-Based Frailty Index in the CoreValve Studies: Findings from the EXTEND-FRAILTY Study.

Strom JB, Xu J, Orkaby AR, Shen C, ... Gerszten RE, Yeh RW

Background:
In aortic valve disease, the relationship between claims-based frailty indices (CFIs) and validated measures of frailty constructed from in-person assessments is unclear but may be relevant for retrospective ascertainment of frailty status when otherwise unmeasured. Methods and Results We linked adults aged ≥65 years in the US CoreValve Studies (linkage rate, 67%; mean age, 82.7±6.2 years, 43.1% women), to Medicare inpatient claims, 2011 to 2015. The Johns Hopkins CFI, validated on the basis of the Fried index, was generated for each study participant, and the association between CFI tertile and trial outcomes was evaluated as part of the EXTEND-FRAILTY substudy. Among 2357 participants (64.9% frail), higher CFI tertile was associated with greater impairments in nutrition, disability, cognition, and self-rated health. The primary outcome of all-cause mortality at 1 year occurred in 19.3%, 23.1%, and 31.3% of those in tertiles 1 to 3, respectively (tertile 2 versus 1: hazard ratio, 1.22; 95% CI, 0.98-1.51; P=0.07; tertile 3 versus 1: hazard ratio, 1.73; 95% CI, 1.41-2.12; P<0.001). Secondary outcomes (bleeding, major adverse cardiovascular and cerebrovascular events, and hospitalization) were more frequent with increasing CFI tertile and persisted despite adjustment for age, sex, New York Heart Association class, and Society of Thoracic Surgeons risk score.
Conclusions:
In linked Medicare and CoreValve study data, a CFI based on the Fried index consistently identified individuals with worse impairments in frailty, disability, cognitive dysfunction, and nutrition and a higher risk of death, hospitalization, bleeding, and major adverse cardiovascular and cerebrovascular events, independent of age and risk category. While not a surrogate for validated metrics of frailty using in-person assessments, use of this CFI to ascertain frailty status among patients with aortic valve disease may be valid and prognostically relevant information when otherwise not measured.




J Am Heart Assoc: 04 Oct 2021; 10:e022150
Strom JB, Xu J, Orkaby AR, Shen C, ... Gerszten RE, Yeh RW
J Am Heart Assoc: 04 Oct 2021; 10:e022150 | PMID: 34585597
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Impact:
Abstract

Three-Dimensional Global Left Ventricular Myocardial Strain Reduced in All Directions in Subclinical Diabetic Cardiomyopathy: A Systematic Review and Meta-Analysis.

Ghoreyshi-Hefzabad SM, Jeyaprakash P, Gupta A, Vo HQ, Pathan F, Negishi K

Background:
Three-dimensional (3D) speckle tracking echocardiography can identify subclinical diabetic cardiomyopathy without geometric assumption and loss of speckle from out-of-plane motions. There is, however, significant heterogeneity among the previous reports. We performed a systematic review and meta-analysis to compare 3D strain values between adults with asymptomatic, subclinical diabetes mellitus (ie, patients with diabetes mellitus without known clinical manifestations of cardiac disease) and healthy controls. Methods and Results After systematic review of 5 databases, 12 valid studies (544 patients with diabetes mellitus and 489 controls) were eligible for meta-analysis. Pooled means and mean difference (MD) using a random-effects model for 3D global longitudinal, circumferential, radial, and area strain were calculated. Patients with diabetes mellitus had an overall 2.31 percentage points lower 3D global longitudinal strain than healthy subjects (16.6%, 95% CI, 15.7-17.6 versus 19.0; 95% CI, 18.2-19.7; MD, -2.31, 95% CI, -2.72 to -2.03). Similarly, 3D global circumferential strain (18.9%; 95% CI, 17.5-20.3 versus 20.5; 95% CI, 18.9-22.1; MD, -1.50; 95% CI, -2.09 to -0.91); 3D global radial strain (44.6%; 95% CI, 40.2-49.1 versus 48.2; 95% CI, 44.7-51.8; MD, -3.47; 95% CI, -4.98 to -1.97), and 3D global area strain (30.5%; 95% CI, 29.2-31.8 versus 32.4; 95% CI, 30.5-34.3; MD, -1.76; 95% CI, -2.74 to -0.78) were also lower in patients with diabetes mellitus. Significant heterogeneity was noted between studies for all strain directions (inconsistency factor [I2], 37%-78%). Meta-regression in subgroup analysis of studies using the most popular vendor found higher prevalence of hypertension as a significant contributor to worse 3D global longitudinal strain. Higher hemoglobulin A1c was the most significant contributor to worse 3D global circumferential strain in patients with diabetes mellitus.
Conclusions:
Three-dimensional myocardial strain was reduced in all directions in asymptomatic diabetic patients. Hypertension and hemoglobin A1c were associated with worse 3D global longitudinal strain and 3D global circumferential strain, respectively. Registration URL: https://www.crd.york.ac.uk/prospero; unique identifier: CRD42020197825.




J Am Heart Assoc: 04 Oct 2021; 10:e020811
Ghoreyshi-Hefzabad SM, Jeyaprakash P, Gupta A, Vo HQ, Pathan F, Negishi K
J Am Heart Assoc: 04 Oct 2021; 10:e020811 | PMID: 34585594
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Impact:
Abstract

Comparison of Transvalvular Aortic Mean Gradients Obtained by Intraprocedural Echocardiography and Invasive Measurement in Balloon and Self-Expanding Transcatheter Valves.

Abbas AE, Mando R, Kadri A, Khalili H, ... Pibarot P, Mack M

Background:
Concerns about discordance between echocardiographic and invasive mean gradients after transcatheter aortic valve replacement (TAVR) with balloon-expandable valves (BEVs) versus self-expanding valves (SEVs) exist. Methods and Results In a multicenter study, direct-invasive and echocardiography-derived transvalvular mean gradients obtained before and after TAVR were compared as well as post-TAVR and discharge echocardiographic mean gradients in BEVs versus SEVs in 808 patients. Pre-TAVR, there was good correlation (R=0.614; P<0.0001) between direct-invasive and echocardiography-derived mean gradients and weak correlation (R=0.138; P<0.0001) post-TAVR. Compared with post-TAVR echocardiographic mean gradients, both valves exhibit lower invasive and higher discharge echocardiographic mean gradients. Despite similar invasive mean gradients, a small BEV exhibits higher post-TAVR and discharge echocardiographic mean gradients than a large BEV, whereas small and large SEVs exhibit similar post-TAVR and discharge mean gradients. An ejection fraction <50% (P=0.028) and higher Society of Thoracic Surgeons predicted risk of mortality score (P=0.007), but not invasive or echocardiographic mean gradient ≥10 mm Hg (P=0.378 and P=0.341, respectively), nor discharge echocardiographic mean gradient ≥20 mm Hg (P=0.393), were associated with increased 2-year mortality.
Conclusions:
Invasively measured and echocardiography-derived transvalvular mean gradients correlate well in aortic stenosis but weakly post-TAVR. Post-TAVR, echocardiography overestimates transvalvular mean gradients compared with invasive measurements, and poor correlation suggests these modalities cannot be used interchangeably. Moreover, echocardiographic mean gradients are higher on discharge than post-TAVR in all valves. Despite similar invasive mean gradients, a small BEV exhibits higher post-TAVR and discharge echocardiographic mean gradients than a large BEV, whereas small and large SEVs exhibit similar post-TAVR and discharge mean gradients. Immediately post-TAVR, elevated echocardiographic-derived mean gradients should be assessed with caution and compared with direct-invasive mean gradients. A low ejection fraction and higher Society of Thoracic Surgeons score, but not elevated mean gradients, are associated with increased 2-year mortality.




J Am Heart Assoc: 04 Oct 2021; 10:e021014
Abbas AE, Mando R, Kadri A, Khalili H, ... Pibarot P, Mack M
J Am Heart Assoc: 04 Oct 2021; 10:e021014 | PMID: 34585593
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Impact:
Abstract

Risk-Attributable Burden of Ischemic Heart Disease in 137 Low- and Middle-Income Countries From 2000 to 2019.

Wang C, Sun Y, Jiang D, Wang C, Liu S

Background:
Ischemic heart disease (IHD) imposes the greatest disease burden globally, especially in low- and middle-income countries (LMICs). We aim to examine the population-attributable fraction and risk-attributable death and disability-adjusted life years (DALYs) for IHD in 137 low- and middle-income countries. Methods and Results Using comparative risk assessment framework from the 2019 Global Burden of Disease study, the population-attributable fraction and IHD burden (death and DALYs) attributable to risk factors in low-income countries, lower-middle-income countries (LMCs), and upper-middle-income countries were assessed from 2000 to 2019. In 2019, the population-attributable fraction (%) of IHD deaths in relation to all modifiable risk factors combined was highest in lower-middle-income countries (94.2; 95% uncertainty interval, 91.9-96.2), followed by upper-middle-income countries (93.5; 90.4-95.8) and low-income countries (92.5; 90.0-94.7). There was a >13-fold difference between Peru and Uzbekistan in age-standardized rates (per 100 000) of attributable death (44.3 versus 660.4) and DALYs (786.7 versus 10506.1). Dietary risks accounted for the largest proportion of IHD\'s behavioral burden in low- and middle-income countries, primarily attributable to diets low in whole grains. High systolic blood pressure and high low-density lipoprotein cholesterol remained the 2 leading causes of DALYs, with the former topping the list in 116 countries, while the latter led in 21 of the 137 countries. Compared with 2000 to 2010, the increases in risk-attributable deaths and DALYs among upper-middle income countries were slower from 2010 to 2019, while the trends in low-income countries and lower-middle income countries were opposite.
Conclusions:
IHD\'s attributable burden remains high in low- and middle-income countries. Considerable heterogeneity was observed among different income-classified regions and countries.




J Am Heart Assoc: 04 Oct 2021; 10:e021024
Wang C, Sun Y, Jiang D, Wang C, Liu S
J Am Heart Assoc: 04 Oct 2021; 10:e021024 | PMID: 34585592
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Impact:
Abstract

Importance of Risk Assessment in Timing of Invasive Coronary Evaluation and Treatment of Patients With Non-ST-Segment-Elevation Acute Coronary Syndrome: Insights From the VERDICT Trial.

Butt JH, Kofoed KF, Kelbæk H, Hansen PR, ... Engstrøm T, Køber L

Background:
The optimal timing of invasive examination and treatment of high-risk patients with non-ST-segment-elevation acute coronary syndrome has not been established. We investigated the efficacy of early invasive coronary angiography compared with standard-care invasive coronary angiography on the risk of all-cause mortality according to the GRACE (Global Registry of Acute Coronary Events) risk score in a predefined subgroup analysis of the VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) trial. Methods and Results Patients with clinical suspicion of non-ST-segment-elevation acute coronary syndrome with ECG changes indicating new ischemia and/or elevated troponin, in whom invasive coronary angiography was clinically indicated and deemed logistically feasible within 12 hours, were eligible for inclusion. Patients were randomized 1:1 to an early (≤12 hours) or standard (48-72 hours) invasive strategy. The primary outcome of the present study was all-cause mortality. Of 2147 patients randomized in the VERDICT trial, 2092 patients had an available GRACE risk score. Of these, 1021 (48.8%) patients had a GRACE score >140. During a median follow-up of 4.1 years, 192 (18.8%) and 54 (5.0%) patients died in the high and low GRACE score groups, respectively. The risk of death with the early invasive strategy was increased in patients with a GRACE score ≤140 (hazard ratio [HR], 2.04 [95% CI, 1.16-3.59]), whereas there was a trend toward a decreased risk of death with the early invasive strategy in patients with a GRACE score >140 (HR, 0.83 [95% CI, 0.63-1.10]) (Pinteraction=0.006).
Conclusions:
In patients with non-ST-segment-elevation acute coronary syndrome, we found a significant interaction between timing of invasive coronary angiography and GRACE score on the risk of death. Randomized clinical trials are warranted to establish the efficacy and safety among high-risk and low-risk patients with non-ST-segment-elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02061891.




J Am Heart Assoc: 04 Oct 2021; 10:e022333
Butt JH, Kofoed KF, Kelbæk H, Hansen PR, ... Engstrøm T, Køber L
J Am Heart Assoc: 04 Oct 2021; 10:e022333 | PMID: 34585591
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Impact:
Abstract

Coronary Artery Calcification and Plaque Characteristics in People Living With HIV: A Systematic Review and Meta-Analysis.

Soares C, Samara A, Yuyun MF, Echouffo-Tcheugui JB, ... Wu WC, Erqou S

Background:
Studies have reported that people living with HIV have higher burden of subclinical cardiovascular disease, but the data are not adequately synthesized. We performed meta-analyses of studies of coronary artery calcium and coronary plaque in people living with HIV. Methods and Results We performed systematic search in electronic databases, and data were abstracted in standardized forms. Study-specific estimates were pooled using meta-analysis. 43 reports representing 27 unique studies and involving 10 867 participants (6699 HIV positive, 4168 HIV negative, mean age 52 years, 86% men, 32% Black) were included. The HIV-positive participants were younger (mean age 49 versus 57 years) and had lower Framingham Risk Score (mean score 6 versus 18) compared with the HIV-negative participants. The pooled estimate of percentage with coronary artery calcium >0 was 45% (95% CI, 43%-47%) for HIV-positive participants, and 52% (50%-53%) for HIV-negative participants. This difference was no longer significant after adjusting for difference in Framingham Risk Score between the 2 groups. The odds ratio of coronary artery calcium progression for HIV-positive versus -negative participants was 1.64 (95% CI, 0.91-2.37). The pooled estimate for prevalence of noncalcified plaque was 49% (95% CI, 47%-52%) versus 20% (95% CI, 17%-23%) for HIV-positive versus HIV-negative participants, respectively. Odds ratio for noncalcified plaque for HIV-positive versus -negative participants was 1.23 (95% CI, 1.08-1.38). There was significant heterogeneity that was only partially explained by available study-level characteristics.
Conclusions:
People living with HIV have higher prevalence of noncalcified coronary plaques and similar prevalence of coronary artery calcium, compared with HIV-negative individuals. Future studies on coronary artery calcium and plaque progression can further elucidate subclinical atherosclerosis in people living with HIV.




J Am Heart Assoc: 04 Oct 2021; 10:e019291
Soares C, Samara A, Yuyun MF, Echouffo-Tcheugui JB, ... Wu WC, Erqou S
J Am Heart Assoc: 04 Oct 2021; 10:e019291 | PMID: 34585590
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Impact:
Abstract

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

Diakos NA, Taleb I, Kyriakopoulos CP, Shah KS, ... Stellos K, Drakos SG

Background:
Recent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD-mediated cardiac improvement to guide patient selection, treatment, and monitoring. Methods and Results Ninety-three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-6, IL-7, IL-13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription-3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01-0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00-0.43), independently predict cardiac improvement, creating a 2-cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001).
Conclusions:
Baseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2-cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD-mediated cardiac improvement and device weaning.




J Am Heart Assoc: 30 Sep 2021:e020238; epub ahead of print
Diakos NA, Taleb I, Kyriakopoulos CP, Shah KS, ... Stellos K, Drakos SG
J Am Heart Assoc: 30 Sep 2021:e020238; epub ahead of print | PMID: 34595931
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Impact:
Abstract

Ketone Ester D-β-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice.

Thai PN, Miller CV, King MT, Schaefer S, ... Bers DM, Dedkova EN

Background:
Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D-β-hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. Methods and Results Type 2 diabetic (db/db) and their corresponding wild-type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl-CoA:3-oxoacid-CoA transferase and restored decreased expression of mitochondrial β-hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP-mediated oxygen consumption in cardiac mitochondria from both wild-type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule-associated protein 1 light chain 3-mediated autophagosome formation.
Conclusions:
Moderate elevation in circulating D-β-hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.




J Am Heart Assoc: 28 Sep 2021:e020729; epub ahead of print
Thai PN, Miller CV, King MT, Schaefer S, ... Bers DM, Dedkova EN
J Am Heart Assoc: 28 Sep 2021:e020729; epub ahead of print | PMID: 34583524
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Impact:
Abstract

Enhanced Heart Failure in Redox-Dead Cys17Ser PKARIα Knock-In Mice.

Islam MMT, Tarnowski D, Zhang M, Trum M, ... Sag CM, Wagner S

Background:
PKARIα (protein kinase A type I-α regulatory subunit) is redox-active independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIα activation may be of relevance to cardiac excitation-contraction coupling. Methods and Results We used a redox-dead transgenic mouse model with homozygous knock-in replacement of redox-sensitive cysteine 17 with serine within the regulatory subunits of PKARIα (KI). Reactive oxygen species were acutely evoked by exposure of isolated cardiac myocytes to AngII (angiotensin II, 1 µmol/L). The long-term relevance of oxidized PKARIα was investigated in KI mice and their wild-type (WT) littermates following transverse aortic constriction (TAC). AngII increased reactive oxygen species in both groups but with RIα dimer formation in WT only. AngII induced translocation of PKARI to the cell membrane and resulted in protein kinase A-dependent stimulation of ICa (L-type Ca current) in WT with no effect in KI myocytes. Consequently, Ca transients were reduced in KI myocytes as compared with WT cells following acute AngII exposure. Transverse aortic constriction-related reactive oxygen species formation resulted in RIα oxidation in WT but not in KI mice. Within 6 weeks after TAC, KI mice showed an enhanced deterioration of contractile function and impaired survival compared with WT. In accordance, compared with WT, ventricular myocytes from failing KI mice displayed significantly reduced Ca transient amplitudes and lack of ICa stimulation. Conversely, direct pharmacological stimulation of ICa using Bay K8644 rescued Ca transients in AngII-treated KI myocytes and contractile function in failing KI mice in vivo.
Conclusions:
Oxidative activation of PKARIα with subsequent stimulation of ICa preserves cardiac function in the setting of acute and chronic oxidative stress.




J Am Heart Assoc: 28 Sep 2021:e021985; epub ahead of print
Islam MMT, Tarnowski D, Zhang M, Trum M, ... Sag CM, Wagner S
J Am Heart Assoc: 28 Sep 2021:e021985; epub ahead of print | PMID: 34583520
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Abstract

Temporal Changes in Mortality After Transcatheter and Surgical Aortic Valve Replacement: Retrospective Analysis of US Medicare Patients (2012-2019).

Lauck SB, Baron SJ, Irish W, Borregaard B, ... Webb JG, Wijeysundera HC

Background:
The treatment of aortic stenosis is evolving rapidly. Pace of change in the care of patients undergoing transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) differs. We sought to determine differences in temporal changes in 30-day mortality, 30-day readmission, and length of stay after TAVR and SAVR. Methods and Results We conducted a retrospective cohort study of patients treated in the United States between 2012 and 2019 using data from the Medicare Data Set Analytic File 100% Fee for Service database. We included consecutive patients enrolled in Medicare Parts A and B and aged ≥65 years who had SAVR or transfemoral TAVR. We defined 3 study cohorts, including all SAVR, isolated SAVR (without concomitant procedures), and elective isolated SAVR and TAVR. The primary end point was 30-day mortality; secondary end points were 30-day readmission and length of stay. Statistical models controlled for patient demographics, frailty measured by the Hospital Frailty Risk Score, and comorbidities measured by the Elixhauser Comorbidity Index (ECI). Cox proportional hazard models were developed with TAVR versus SAVR as the main covariates with a 2-way interaction term with index year. We repeated these analyses restricted to full aortic valve replacement hospitals offering both SAVR and TAVR. The main study cohort included 245 269 patients with SAVR and 188 580 patients with TAVR, with mean±SD ages 74.3±6.0 years and 80.7±6.9 years, respectively, and 36.5% and 46.2% female patients, respectively. Patients with TAVR had higher ECI scores (6.4±3.6 versus 4.4±3) and were more frail (55.4% versus 33.5%). Total aortic valve replacement volumes increased 61% during the 7-year span; TAVR volumes surpassed SAVR in 2017. The magnitude of mortality benefit associated with TAVR increased until 2016 in the main cohort (2012: hazard ratio [HR], 0.76 [95% CI, 0.67-0.86]; 2016: HR, 0.39 [95% CI, 0.36-0.43]); although TAVR continued to have lower mortality rates from 2017 to 2019, the magnitude of benefit over SAVR was attenuated. A similar pattern was seen with readmission, with a lower risk of readmission from 2012 to 2016 for patients with TAVR (2012: HR, 0.68 [95% CI, 0.63-0.73]; 2016: HR, 0.43 [95% CI, 0.41-0.45]) followed by a lesser difference from 2017 to 2019. Year over year, TAVR was associated with increasingly shorter lengths of stay compared with SAVR (2012: HR, 1.91 [95% CI, 1.84-1.98]; 2019: HR, 5.34 [95% CI, 5.22-5.45]). These results were consistent in full aortic valve replacement hospitals.
Conclusions:
The rate of improvement in TAVR outpaced SAVR until 2016, with the recent presence of U-shaped phenomena suggesting a narrowing gap between outcomes. Future longitudinal research is needed to determine the long-term implications of lowering risk profiles across treatment options to guide case selection and clinical care.




J Am Heart Assoc: 27 Sep 2021:e021748; epub ahead of print
Lauck SB, Baron SJ, Irish W, Borregaard B, ... Webb JG, Wijeysundera HC
J Am Heart Assoc: 27 Sep 2021:e021748; epub ahead of print | PMID: 34581191
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Abstract

High-Resolution Mapping and Ablation of Atrial Tachycardias Involving the Lateral Left Atrium.

Miyazaki S, Hasegawa K, Yamao K, Mukai M, ... Iesaka Y, Tada H

Background:
The lateral left atrium (LA) is often associated with atrial tachycardia (AT) because of its complex anatomy. We sought to characterize ATs associated with the lateral LA, including the posterolateral mitral isthmus (MI) and left atrial ridge. Methods and Results Twenty-eight lateral LA-associated ATs were mapped with high-resolution mapping systems and entrainment pacing. The vein of Marshall was mapped with a 1.8-Fr mapping catheter when possible. ATs were associated with the posterolateral MI in 18 ATs (14 perimitral, 3 small reentry, and 1 focal AT). All patients had undergone MI area ablation, and all ATs were successfully eliminated. During 27.0 (interquartile range, 10.5-40.0) months of follow-up, all were free from any atrial tachyarrhythmias, with 3 patients on antiarrhythmics. Of 10 ATs involving the ridge or Marshall bundle, 3 were ridge related, 3 were Marshall bundle related based on vein of Marshall mapping, and 1 was a persistent left superior vena cava related AT. All 7 patients had undergone MI linear ablation. The critical isthmus was in the LA-ridge junction or the LA-Marshall bundle junction. Bidirectional conduction block between the LA and ridge or Marshall bundle was created. Two patients had the critical isthmus in the other area. The remaining patient had micro-reentry in the ridge. All 10 ATs were terminated during ablation at the critical isthmus. During 12.0 (5.2-31.7) months of follow-up, all were free from any atrial tachyarrhythmias, with 7 patients on antiarrhythmics.
Conclusions:
Most ATs occurred after MI area ablation. An high resolution mapping-guided approach is highly effective for identifying the mechanism.




J Am Heart Assoc: 27 Sep 2021:e022384; epub ahead of print
Miyazaki S, Hasegawa K, Yamao K, Mukai M, ... Iesaka Y, Tada H
J Am Heart Assoc: 27 Sep 2021:e022384; epub ahead of print | PMID: 34581187
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Abstract

Insights From the Ventricular Fibrillation Waveform Into the Mechanism of Survival Benefit From Bystander Cardiopulmonary Resuscitation.

Bessen B, Coult J, Blackwood J, Hsu CH, ... Rea T, Kwok H

Background:
The mechanism by which bystander cardiopulmonary resuscitation (CPR) improves survival following out-of-hospital cardiac arrest is unclear. We hypothesized that ventricular fibrillation (VF) waveform measures, as surrogates of myocardial physiology, mediate the relationship between bystander CPR and survival. Methods and Results We performed a retrospective cohort study of adult, bystander-witnessed patients with out-of-hospital cardiac arrest with an initial rhythm of VF who were treated by a metropolitan emergency medical services system from 2005 to 2018. Patient, resuscitation, and outcome variables were extracted from emergency medical services and hospital records. A total of 3 VF waveform measures (amplitude spectrum area, peak frequency, and median peak amplitude) were computed from a 3-second ECG segment before the initial shock. Multivariable logistic regression estimated the association between bystander CPR and survival to hospital discharge adjusted for Utstein elements. Causal mediation analysis quantified the proportion of survival benefit that was mediated by each VF waveform measure. Of 1069 patients, survival to hospital discharge was significantly higher among the 814 patients who received bystander CPR than those who did not (0.52 versus 0.43, respectively; P<0.01). The multivariable-adjusted odds ratio for bystander CPR and survival was 1.6 (95% CI, 1.2, 2.1), and each VF waveform measure attenuated this association. Depending on the specific waveform measure, the proportion of mediation varied: 53% for amplitude spectrum area, 31% for peak frequency, and 29% for median peak amplitude.
Conclusions:
Bystander CPR correlated with more robust initial VF waveform measures, which in turn mediated up to one-half of the survival benefit associated with bystander CPR. These results provide insight into the biological mechanism of bystander CPR in VF out-of-hospital cardiac arrest.




J Am Heart Assoc: 24 Sep 2021:e020825; epub ahead of print
Bessen B, Coult J, Blackwood J, Hsu CH, ... Rea T, Kwok H
J Am Heart Assoc: 24 Sep 2021:e020825; epub ahead of print | PMID: 34569292
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Abstract

Comprehensive Physiological Modeling Provides Novel Insights Into Heart Failure With Preserved Ejection Fraction Physiology.

Kaye DM, Wolsk E, Nanayakkara S, Mariani J, ... Sunagawa K, Burkhoff D

Background:
Although a rapid rise in left atrial pressure during exertion is considered pathognomonic of heart failure with preserved ejection fraction (HFpEF), the fundamental circulatory determinants of this response are not clear, impacting upon the development of more effective therapies. We aimed to comprehensively describe the circulatory mechanics of patients with HFpEF at rest and during exercise in comparison with controls. Methods and Results We performed simultaneous right-heart catheterization and echocardiography at rest and during exercise in 22 healthy control volunteers and 60 patients with confirmed HFpEF. Using detailed individual patient-level hemodynamic and left ventricular ejection fraction data we performed computer simulations to evaluate the circulatory parameters including the estimated stressed blood volumethat contribute to the resting and exercise pulmonary capillary pressure. At rest and during exercise, left ventricular stiffness (V30, the end-diastolic pressure-volume relationship at a filling pressure of 30 mm Hg), left ventricular elastance, and arterial elastance were all significantly greater in HFpEF than in controls. Stressed blood volume was significantly greater in HFpEF (26.9±5.4 versus 20.2±4.7 mL/kg, P<0.001), becoming even more pronounced during exercise (40.9±3.7 versus 27.5±7.0 mL per 70 kg, P<0.001). During exercise, the magnitude of the change in stressed blood volume (r=0.67, P<0.001) and left ventricular stiffness (r=-0.44, P<0.001) were key determinants of the rise in pulmonary capillary wedge pressure. Further detailed modeling studies showed that the hemodynamic response to exercise results from a complex non-linear interaction between circulatory parameters.
Conclusions:
The circulatory determinants of HFpEF physiology are complex. We identified stressed blood volume at rest and during exercise is a novel, key factor, therebyrepresenting an important potential therapeutic target.




J Am Heart Assoc: 24 Sep 2021:e021584; epub ahead of print
Kaye DM, Wolsk E, Nanayakkara S, Mariani J, ... Sunagawa K, Burkhoff D
J Am Heart Assoc: 24 Sep 2021:e021584; epub ahead of print | PMID: 34569288
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Abstract

Combination of Antioxidant Enzyme Overexpression and N-Acetylcysteine Treatment Enhances the Survival of Bone Marrow Mesenchymal Stromal Cells in Ischemic Limb in Mice With Type 2 Diabetes.

Zhu Q, Hao H, Xu H, Fichman Y, ... Zhou S, Liu Z

Background:
Therapy with mesenchymal stem cells remains a promising but challenging approach to critical limb ischemia in diabetes because of the dismal cell survival. Methods and Results Critical limb ischemia in type 2 diabetes mouse model was used to explore the impact of diabetic limb ischemia on the survival of bone marrow mesenchymal stromal cells (bMSCs). Inhibition of intracellular reactive oxygen species was achieved with concomitant overexpression of superoxide dismutase (SOD)-1 and glutathione peroxidase-1 in the transplanted bMSCs, and extracellular reactive oxygen species was attenuated using SOD-3 overexpression and N-acetylcysteine treatment. In vivo optical fluorescence imaging and laser Doppler perfusion imaging were used to track cell retention and determine blood flow in diabetic ischemic limb, respectively. Survival of the transplanted bMSCs was significantly decreased in diabetic ischemic limb compared with the control. In vitro study indicated that advanced glycation end products, not high glucose, significantly decreased the proliferation of bMSCs and increased their apoptosis associated with increased reactive oxygen species production and selective reduction of SOD-1 and SOD-3. In vivo study demonstrated that concomitant overexpression of SOD-1, SOD-3, and glutathione peroxidase-1, or host treatment with N-acetylcysteine, significantly enhanced in vivo survival of transplanted bMSCs, and improved critical limb ischemia in diabetic mice. Combination of triple antioxidant enzyme overexpression in bMSCs with host N-acetylcysteine treatment further improved bMSC survival with enhanced circulatory and functional recovery from diabetic critical limb ischemia.
Conclusions:
Simultaneous suppression of reactive oxygen species from transplanted bMSCs and host tissue could additively enhance bMSC survival in diabetic ischemic limb with increased therapeutic efficacy in diabetes.




J Am Heart Assoc: 24 Sep 2021:e023491; epub ahead of print
Zhu Q, Hao H, Xu H, Fichman Y, ... Zhou S, Liu Z
J Am Heart Assoc: 24 Sep 2021:e023491; epub ahead of print | PMID: 34569277
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