Journal: J Am Heart Assoc

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Abstract

Predictive Score of Adverse Events After Carotid Endarterectomy: The NSQIP Registry Carotid Endarterectomy Scale.

Dasenbrock HH, Smith TR, Gormley WB, Castlen JP, ... Aziz-Sultan MA, Du R

Background The goal of this study was to create a comprehensive, integer-weighted predictive scale of adverse events after carotid endarterectomy (CEA), which may augment risk stratification and patient counseling. Methods and Results The targeted carotid files from the prospective NSQIP (National Surgical Quality Improvement Program) registry (2011-2013) comprised the derivation population. Multivariable logistic regression evaluated predictors of a 30-day adverse event (stroke, myocardial infarction, or death), the effect estimates of which were used to build a weighted predictive scale that was validated using the 2014 to 2015 NSQIP registry release. A total of 10 766 and 8002 patients were included in the derivation and the validation populations, in whom 4.0% and 3.7% developed an adverse event, respectively. The NSQIP registry CEA scale included 14 variables; the highest points were allocated for insulin-dependent diabetes mellitus, high-risk cardiac physiological characteristics, admission source other than home, an emergent operation, American Society of Anesthesiologists\' classification IV to V, modified Rankin Scale score ≥2, and presentation with a stroke. NSQIP registry CEA score was predictive of an adverse event (concordance=0.67), stroke or death (concordance=0.69), mortality (concordance=0.76), an extended hospitalization (concordance=0.73), and a nonroutine discharge (concordance=0.83) in the validation population, as well as among symptomatic and asymptomatic subgroups (<0.001). In the validation population, patients with an NSQIP registry CEA scale score >8 and 17 had 30-day stroke or death rates >3% and 6%, the recommended thresholds for asymptomatic and symptomatic patients, respectively. Conclusions The NSQIP registry CEA scale predicts adverse outcomes after CEA and can risk stratify patients with both symptomatic and asymptomatic carotid stenosis using different thresholds for each population.



J Am Heart Assoc: 04 Nov 2019; 8:e013412
Dasenbrock HH, Smith TR, Gormley WB, Castlen JP, ... Aziz-Sultan MA, Du R
J Am Heart Assoc: 04 Nov 2019; 8:e013412 | PMID: 31662028
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ST-Segment-Elevation Myocardial Infarction (STEMI) Patients Without Standard Modifiable Cardiovascular Risk Factors-How Common Are They, and What Are Their Outcomes?

Vernon ST, Coffey S, D\'Souza M, Chow CK, ... Brieger D, Figtree GA

Background Programs targeting the standard modifiable cardiovascular risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, smoking) are critical to tackling coronary heart disease at a community level. However, myocardial infarction in SMuRF-less individuals is not uncommon. This study uses 2 sequential large, multicenter registries to examine the proportion and outcomes of SMuRF-less ST-segment-elevation myocardial infarction (STEMI) patients. Methods and Results We identified 3081 STEMI patients without a prior history of cardiovascular disease in the Australian GRACE (Global Registry of Acute Coronary Events) and CONCORDANCE (Cooperative National Registry of Acute Coronary Syndrome Care) registries, encompassing 42 hospitals, between 1999 and 2017. We examined the proportion that were SMuRF-less as well as outcomes. The primary outcome was in-hospital mortality, and the secondary outcome was major adverse cardiovascular events (death, myocardial infarction, or heart failure, during the index admission). Multivariate regression models were used to identify predictors of major adverse cardiovascular events. Of STEMI patients without a prior history of cardiovascular disease 19% also had no history of SMuRFs. This proportion increased from 14% to 23% during the study period (=0.0067). SMuRF-less individuals had a higher in-hospital mortality rate than individuals with 1 or more SMuRFs. There were no clinically significant differences in major adverse cardiovascular events at 6 months between the 2 groups. Conclusions A substantial and increasing proportion of STEMI presentations occur independently of SMuRFs. Discovery of new markers and mechanisms of disease beyond standard risk factors may facilitate novel preventative strategies. Studies to assess longer-term outcomes of SMuRF-less STEMI patients are warranted.



J Am Heart Assoc: 04 Nov 2019; 8:e013296
Vernon ST, Coffey S, D'Souza M, Chow CK, ... Brieger D, Figtree GA
J Am Heart Assoc: 04 Nov 2019; 8:e013296 | PMID: 31672080
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Abstract

Temporal Trends and Clinical Outcomes of Transcatheter Aortic Valve Replacement in Nonagenarians.

Mentias A, Saad M, Desai MY, Horwitz PA, ... London B, Vaughan Sarrazin MS

Background Contemporary outcomes of transcatheter aortic valve replacement (TAVR) in nonagenarians are unknown. Methods and Results We identified 13 544 nonagenarians (aged 90-100 years) who underwent TAVR between 2012 and 2016 using Medicare claims. Generalized estimating equations were used to study the change in short-term outcomes among nonagenarians over time. We compared outcomes between nonagenarians and non-nonagenarians undergoing TAVR in 2016. A mixed-effect multivariable logistic regression was performed to determine predictors of 30-day mortality in nonagenarians in 2016. A center was defined as aif it performed ≥100 TAVR procedures per year. After adjusting for changes in patients\' characteristics, risk-adjusted 30-day mortality declined in nonagenarians from 9.8% in 2012 to 4.4% in 2016 (<0.001), whereas mortality for patients <90 years decreased from 6.4% to 3.5%. In 2016, 35 712 TAVR procedures were performed, of which 12.7% were in nonagenarians. Overall, in-hospital mortality in 2016 was higher in nonagenarians compared with younger patients (2.4% versus 1.7%, <0.05) but did not differ in analysis limited to high-volume centers (2.2% versus 1.7%; odds ratio: 1.33; 95% CI, 0.97-1.81; =0.07). Important predictors of 30-day mortality in nonagenarians included in-hospital stroke (adjusted odds ratio [aOR]: 8.67; 95% CI, 5.03-15.00), acute kidney injury (aOR: 4.11; 95% CI, 2.90-5.83), blood transfusion (aOR: 2.66; 95% CI, 1.81-3.90), respiratory complications (aOR: 2.96; 95% CI, 1.52-5.76), heart failure (aOR: 1.86; 95% CI, 1.04-3.34), coagulopathy (aOR: 1.59; 95% CI, 1.12-2.26; <0.05 for all). Conclusions Short-term outcomes after TAVR have improved in nonagenarians. Several procedural complications were associated with increased 30-day mortality among nonagenarians.



J Am Heart Assoc: 04 Nov 2019; 8:e013685
Mentias A, Saad M, Desai MY, Horwitz PA, ... London B, Vaughan Sarrazin MS
J Am Heart Assoc: 04 Nov 2019; 8:e013685 | PMID: 31668118
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Clinical Predictors and Prognostic Impact of Recovery of Wall Motion Abnormalities in Takotsubo Syndrome: Results From the International Takotsubo Registry.

Jurisic S, Gili S, Cammann VL, Kato K, ... Ghadri JR, Templin C

Background Left ventricular (LV) recovery in takotsubo syndrome (TTS) occurs over a wide-ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut-off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In-hospital outcomes and 1-year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1-year outcome compared with patients with early recovery (=0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1-year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.



J Am Heart Assoc: 04 Nov 2019; 8:e011194
Jurisic S, Gili S, Cammann VL, Kato K, ... Ghadri JR, Templin C
J Am Heart Assoc: 04 Nov 2019; 8:e011194 | PMID: 31672100
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Abstract

Impact of Sex on Clinical Course and Survival in the Contemporary Treatment Era for Hypertrophic Cardiomyopathy.

Rowin EJ, Maron MS, Wells S, Patel PP, Koethe BC, Maron BJ

Background The relation of sex to clinical presentation and course in hypertrophic cardiomyopathy (HCM) remains incompletely resolved. We assessed differences in clinical outcomes between men and women within our large HCM cohort. Methods and Results Of 2123 consecutive patients, a minority (38%) were women who were diagnosed with HCM at older ages or referred for subspecialty evaluation later than men (50±19 versus 44±16 and 55±18 versus 49±16; <0.001). Women more commonly developed advanced New York Heart Association class III/IV symptoms (53% versus 35% in men; <0.001), predominantly secondary to outflow obstruction. While end-stage heart failure with systolic dysfunction (ejection fraction <50%) was similar in men (5% versus 4% in women; =0.33), women were 3-fold more likely to develop heart failure with preserved systolic function (7.5% versus 2.6%; =0.002). Sudden death events terminated by defibrillator therapy were similar in women (0.9%/year) versus men (1.0%/year; hazard ratio, 0.92; 95% CI, 0.6-1.5; =0.73). HCM mortality was uncommon, with identical rates in both sexes (0.3%/year; hazard ratio, 1.5; 95% CI, 0.7-3.4;, =0.25). Age-adjusted all-cause mortality also did not differ between women and men (1.7% versus 1.3%/year; hazard ratio, 1.32; 95% CI, 0.92-1.91; =0.13). Conclusions Survival was not less favorable in women with HCM. Contemporary treatments including surgical myectomy to reverse heart failure and defibrillators to prevent sudden death, were effective in both sexes contributing to low mortality. However, despite more frequent outflow obstruction, women with HCM are underrecognized and referred to centers later than men, often with more advanced heart failure. Greater awareness of HCM in women should lead to earlier diagnosis and treatment, with implications for improved quality of life.



J Am Heart Assoc: 04 Nov 2019; 8:e012041
Rowin EJ, Maron MS, Wells S, Patel PP, Koethe BC, Maron BJ
J Am Heart Assoc: 04 Nov 2019; 8:e012041 | PMID: 31663408
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Association Between Neighborhood Walkability and Predicted 10-Year Cardiovascular Disease Risk: The CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Cohort.

Howell NA, Tu JV, Moineddin R, Chu A, Booth GL

Background Individuals living in unwalkable neighborhoods appear to be less physically active and more likely to develop obesity, diabetes mellitus, and hypertension. It is unclear whether neighborhood walkability is a risk factor for future cardiovascular disease. Methods and Results We studied residents living in major urban centers in Ontario, Canada on January 1, 2008, using linked electronic medical record and administrative health data from the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) cohort. Walkability was assessed using a validated index based on population and residential density, street connectivity, and the number of walkable destinations in each neighborhood, divided into quintiles (Q). The primary outcome was a predicted 10-year cardiovascular disease risk of ≥7.5% (recommended threshold for statin use) assessed by the American College of Cardiology/American Heart Association Pooled Cohort Equation. Adjusted associations were estimated using logistic regression models. Secondary outcomes included measured systolic blood pressure, total and high-density lipoprotein cholesterol levels, prior diabetes mellitus diagnosis, and current smoking status. In total, 44 448 individuals were included in our analyses. Fully adjusted analyses found a nonlinear relationship between walkability and predicted 10-year cardiovascular disease risk (least [Q1] versus most [Q5] walkable neighborhood: odds ratio =1.09, 95% CI: 0.98, 1.22), with the greatest difference between Q3 and Q5 (odds ratio=1.33, 95% CI: 1.23, 1.45). Dose-response associations were observed for systolic blood pressure, high-density lipoprotein cholesterol, and diabetes mellitus risk, while an inverse association was observed with smoking status. Conclusions In our setting, adults living in less walkable neighborhoods had a higher predicted 10-year cardiovascular disease risk than those living in highly walkable areas.



J Am Heart Assoc: 04 Nov 2019; 8:e013146
Howell NA, Tu JV, Moineddin R, Chu A, Booth GL
J Am Heart Assoc: 04 Nov 2019; 8:e013146 | PMID: 31665997
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Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

West JD, Galindo CL, Kim K, Shin JJ, ... Markham LW, Carrier EJ

Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.



J Am Heart Assoc: 04 Nov 2019; 8:e011902
West JD, Galindo CL, Kim K, Shin JJ, ... Markham LW, Carrier EJ
J Am Heart Assoc: 04 Nov 2019; 8:e011902 | PMID: 31662020
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Understanding Readmissions in Medicare Beneficiaries During the 90-Day Follow-Up Period of an Acute Myocardial Infarction Admission.

Culler SD, Kugelmass AD, Cohen DJ, Reynolds MR, ... Schlosser ML, Simon AW

Background Medicare has a voluntary episodic payment model for Medicare beneficiaries that bundles payment for the index acute myocardial infarction (AMI) hospitalization and all post-discharge services for a 90-day follow-up period. The purpose of this study is to report on the types and frequency of readmissions and identify demographic and clinical factors associated with readmission of Medicare beneficiaries that survived their AMI hospitalization. Methods and Results This retrospective study used the Inpatient Standard Analytical File for 2014. There were 143 286 Medicare beneficiaries with AMI who were discharged alive from 3619 hospitals. All readmissions occurring in any hospital within 90 days of the index AMI discharge date were identified. Of 143 286 Medicare beneficiaries discharged alive from their index AMI hospitalization, 28% (40 145) experienced at least 1 readmission within 90 days and 8% (11 477) had >1 readmission. Readmission rates were higher among Medicare beneficiaries who did not undergo a percutaneous coronary intervention in their index AMI admission (34%) compared with those that underwent a percutaneous coronary intervention (20.2%). Using all Medicare beneficiary\'s index AMI, 27 comorbid conditions were significantly associated with the likelihood of a Medicare beneficiary having a readmission during the follow-up period. The strongest clinical characteristics associated with readmissions were dialysis dependence, type 1 diabetes mellitus, and heart failure. Conclusions This study provides benchmark information on the types of hospital readmissions Medicare beneficiaries experience during a 90-day AMI bundle. This paper also suggests that interventions are needed to alleviate the need for readmissions in high-risk populations, such as, those managed medically and those at risk of heart failure.



J Am Heart Assoc: 04 Nov 2019; 8:e013513
Culler SD, Kugelmass AD, Cohen DJ, Reynolds MR, ... Schlosser ML, Simon AW
J Am Heart Assoc: 04 Nov 2019; 8:e013513 | PMID: 31663436
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Metabolic Remodeling in the Pressure-Loaded Right Ventricle: Shifts in Glucose and Fatty Acid Metabolism-A Systematic Review and Meta-Analysis.

Koop AC, Bossers GPL, Ploegstra MJ, Hagdorn QAJ, ... Silljé HHW, Bartelds B

Background Right ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta-analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease. Methods and Results Medline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat-models, inducing pressure load by hypoxia, Sugen-hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta-analysis revealed increased Hedges\' g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochondrial respiratory capacity and fatty acid uptake varied considerably between studies, yet there was a model effect in carbohydrate respiratory capacity in MCT-rats. Conclusions This systematic review and meta-analysis on metabolic remodeling in the pressure-loaded RV showed a consistent increase in glucose uptake and glycolysis, strongly suggest a downregulation of beta-oxidation, and showed divergent and model-specific changes regarding fatty acid uptake and oxidative metabolism. To translate metabolic results from animal models to human disease, more extensive characterization, including function, and uniformity in methodology and studied variables, will be required.



J Am Heart Assoc: 04 Nov 2019; 8:e012086
Koop AC, Bossers GPL, Ploegstra MJ, Hagdorn QAJ, ... Silljé HHW, Bartelds B
J Am Heart Assoc: 04 Nov 2019; 8:e012086 | PMID: 31657265
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Predictors of Late Mortality in D-Transposition of the Great Arteries After Atrial Switch Repair: Systematic Review and Meta-Analysis.

Venkatesh P, Evans AT, Maw AM, Pashun RA, ... Bacha E, Singh HS

Background Existing data on predictors of late mortality and prevention of sudden cardiac death after atrial switch repair surgery for D-transposition of the great arteries (D-TGA) are heterogeneous and limited by statistical power. Methods and Results We conducted a systematic review and meta-analysis of 29 observational studies, comprising 5035 patients, that reported mortality after atrial switch repair with a minimum follow-up of 10 years. We also examined 4 additional studies comprising 105 patients who reported rates of implantable cardioverter-defibrillator therapy in this population. Average survival dropped to 65% at 40 years after atrial switch repair, with sudden cardiac death accounting for 45% of all reported deaths. Mortality was significantly lower in cohorts that were more recent and operated on younger patients. Patient-level risk factors for late mortality were history of supraventricular tachycardia (odds ratio [OR] 3.8, 95% CI 1.4-10.7), Mustard procedure compared with Senning (OR 2.9, 95% CI 1.9-4.5) and complex D-TGA compared with simple D-TGA (OR 4.4, 95% CI 2.2-8.8). Significant risk factors for sudden cardiac death were history of supraventricular tachycardia (OR 4.7, 95% CI 2.2-9.8), Mustard procedure (OR 2.2, 95% CI 1.1-4.1), and complex D-TGA (OR 5.7, 95% CI 1.8-18.0). Out of a total 124 implantable cardioverter-defibrillator discharges over 330 patient-years in patients with implantable cardioverter-defibrillators for primary prevention, only 8% were appropriate. Conclusions Patient-level risk of both mortality and sudden cardiac death after atrial switch repair are significantly increased by history of supraventricular tachycardia, Mustard procedure, and complex D-TGA. This knowledge may help refine current selection practices for primary prevention implantable cardioverter-defibrillator implantation, given disproportionately high rates of inappropriate discharges.



J Am Heart Assoc: 04 Nov 2019; 8:e012932
Venkatesh P, Evans AT, Maw AM, Pashun RA, ... Bacha E, Singh HS
J Am Heart Assoc: 04 Nov 2019; 8:e012932 | PMID: 31642369
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Early Discontinuation of P2Y Antagonists and Adverse Clinical Events Post-Percutaneous Coronary Intervention: A Hospital and Primary Care Linked Cohort.

Harris DE, Lacey A, Akbari A, Obaid DR, ... Gravenor MB, Halcox JP

Background Early discontinuation of P2Y antagonists post-percutaneous coronary intervention may increase risk of stent thrombosis or nonstent recurrent myocardial infarction. Our aims were to (1) analyze the early discontinuation rate of P2Y antagonists post-percutaneous coronary intervention, (2) explore factors associated with early discontinuation, and (3) analyze the risk of major adverse cardiovascular events (death, acute coronary syndrome, revascularization, or stroke) associated with discontinuation from a prespecified prescribing instruction of 1 year. Method and Results We studied 2090 patients (2011-2015) who were recommended for clopidogrel for 12 months (+aspirin) post-percutaneous coronary intervention within a retrospective observational population cohort. Relationships between clopidogrel discontinuation and major adverse cardiac events were evaluated over 18-month follow-up. Discontinuation of clopidogrel in the first 4 quarters was low at 1.1%, 2.6%, 3.7%, and 6.1%, respectively. Previous revascularization, previous ischemic stroke, and age >80 years were independent predictors of early discontinuation. In a time-dependent multiple regression model, clopidogrel discontinuation and bleeding (hazard ratio=1.82 [1.01-3.30] and hazard ratio=5.30 [3.14-8.94], respectively) were independent predictors of major adverse cardiac events as were age <49 and ≥70 years (versus those aged 50-59 years), hypertension, chronic kidney disease stage 4+, previous revascularization, ischemic stroke, and thromboembolism. Furthermore, in those with both bleeding and clopidogrel discontinuation, hazard ratio for major adverse cardiac events was 9.34 (3.39-25.70). Conclusions Discontinuation of clopidogrel is low in the first year post-percutaneous coronary intervention, where a clear discharge instruction to treat for 1 year is provided. Whereas this is reassuring from the population level, at an individual level discontinuation earlier than the intended duration is associated with an increased rate of adverse events, most notably in those with both bleeding and discontinuation.



J Am Heart Assoc: 04 Nov 2019; 8:e012812
Harris DE, Lacey A, Akbari A, Obaid DR, ... Gravenor MB, Halcox JP
J Am Heart Assoc: 04 Nov 2019; 8:e012812 | PMID: 31658860
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Early and Late Effects of Cardiac Resynchronization Therapy in Adult Congenital Heart Disease.

Yin Y, Dimopoulos K, Shimada E, Lascelles K, ... Babu-Narayan SV, Li W

Background There are limited data about cardiac resynchronization therapy (CRT) in adult congenital heart disease. We aimed to assess early and late outcomes of CRT among patients with adult congenital heart disease. Methods and Results We retrospectively studied 54 patients with adult congenital heart disease (median age, 46 years; range, 18-73 years; 74% men) who received CRT implantation (biventricular paced >90%) between 2004 and 2017. Clinical and echocardiographic data were analyzed at baseline and early (mean±SD: 1.8±0.8 years) and late (4.7±0.8 years) follow-up after CRT. Compared with baseline, CRT was associated with significant improvement at early follow-up in New York Heart Association functional class, QRS duration, and cardiothoracic ratio (<0.05 for all); improvement in New York Heart Association class was sustained at late follow-up. Among patients with a systemic left ventricle (LV; n=39), there was significant increase in LV ejection fraction and reduction in LV end-systolic volume at early and late follow-up (<0.05 for both). For patients with a systemic right ventricle (n=15), there was a significant early but not late reduction in systemic right ventricular basal and longitudinal diameters. Eleven patients died, and 2 had heart transplantation unrelated to systemic ventricular morphological characteristics. Thirty-five patients (65%) responded positively to CRT, but only baseline QRS duration was predictive of a positive response. Conclusions CRT results in sustained improvement in functional class, systemic LV size, and function. Patients with a systemic LV and prolonged QRS duration, independent of QRS morphological characteristics, were most likely to respond to CRT.



J Am Heart Assoc: 04 Nov 2019; 8:e012744
Yin Y, Dimopoulos K, Shimada E, Lascelles K, ... Babu-Narayan SV, Li W
J Am Heart Assoc: 04 Nov 2019; 8:e012744 | PMID: 31657270
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Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients.

Chesnaye NC, Szummer K, Bárány P, Heimbürger O, ... ,

Background People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced-stage CKD patients not on dialysis. Methods and Results The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ≥65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high-sensitivity cTnT (hs-cTnT) trajectory over 4 years. Almost all patients had at least 1 hs-cTnT measurement elevated above the 99th percentile of the general reference population (≤14 ng/L). On average, hs-cTnT increased by 16%/year (95% CI, 13-19; <0.0001). Each 15 mL/min/1.73 m lower mean estimated GFR was associated with a 23% (95% CI, 14-31; <0.0001) higher baseline hs-cTnT and 9% (95% CI, 5-13%; <0.0001) steeper increase in hs-cTnT. The effect of estimated GFR on hs-cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%). Conclusions In CKD patients, hs-cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m lower) is independently associated with a steeper hs-cTnT increase over time in the same range as other established cardiovascular risk factors.



J Am Heart Assoc: 04 Nov 2019; 8:e013091
Chesnaye NC, Szummer K, Bárány P, Heimbürger O, ... ,
J Am Heart Assoc: 04 Nov 2019; 8:e013091 | PMID: 31662068
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Prevalence and Impact of Treatment Crossover in Cardiac Surgery Randomized Trials: A Meta-Epidemiologic Study.

Gaudino M, Fremes SE, Ruel M, Di Franco A, ... Taggart DP, Biondi-Zoccai G

Background Crossover dilutes treatment effect and reduces statistical power of intention-to-treat analysis. We examined incidence and impact on cardiac surgery randomized controlled trial (RCT) outcomes of crossover from experimental to control interventions, or vice versa. Methods and Results MEDLINE, EMBASE, and Cochrane Library were searched, and RCTs (≥100 patients) comparing ≥2 adult cardiac surgical interventions were included. Crossover from the initial treatment assignment and relative risks (RRs) for each trial\'s primary end point and mortality at longest available follow-up were extracted. All RRs were calculated as >1 favored control group and <1 favored experimental arm. Primary outcome was the effect estimate for primary end point of each RCT, and secondary outcome was all-cause mortality; both were appraised as RR at the longest follow-up available. Sixty articles reporting on 47 RCTs (25 440 patients) were identified. Median crossover rate from experimental to control group was 7.0% (first quartile, 2.0%; third quartile, 9.7%), whereas from control to experimental group, the rate was 1.3% (first quartile, 0%; third quartile, 3.6%). RRs for primary end point and mortality were higher in RCTs with higher crossover rate from experimental to control group (RR, 1.01 [95% CI, 0.94-1.07] versus RR, 0.80 [95% CI, 0.66-0.97] and RR, 1.02 [95% CI, 0.95-1.11] versus RR, 0.94 [95% CI, 0.82-1.07], respectively). Crossover from control to experimental group did not alter effect estimates for primary end point or mortality (RR, 0.82 [95% CI, 0.63-1.05] versus RR, 0.95 [95% CI, 0.86-1.04] and RR, 0.88 [95% CI, 0.73-1.07] versus RR, 1.02 [95% CI, 0.95-1.09], respectively). Conclusions Crossover from experimental to control group is associated with outcomes of cardiac surgery RCTs. Crossover should be minimized at designing stage and carefully appraised after study completion.



J Am Heart Assoc: 04 Nov 2019; 8:e013711
Gaudino M, Fremes SE, Ruel M, Di Franco A, ... Taggart DP, Biondi-Zoccai G
J Am Heart Assoc: 04 Nov 2019; 8:e013711 | PMID: 31663420
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Changes in QRS Area and QRS Duration After Cardiac Resynchronization Therapy Predict Cardiac Mortality, Heart Failure Hospitalizations, and Ventricular Arrhythmias.

Okafor O, Zegard A, van Dam P, Stegemann B, ... Marshall H, Leyva F

Background Predicting clinical outcomes after cardiac resynchronization therapy (CRT) and its optimization remain a challenge. We sought to determine whether pre- and postimplantation QRS area (QRS) predict clinical outcomes after CRT. Methods and Results In this retrospective study, QRS, derived from pre- and postimplantation vectorcardiography, were assessed in relation to the primary end point of cardiac mortality after CRT with or without defibrillation. Other end points included total mortality, total mortality or heart failure (HF) hospitalization, total mortality or major adverse cardiac events, and the arrhythmic end point of sudden cardiac death or ventricular arrhythmias with or without a shock. In patients (n=380, age 72.0±12.4 years, 68.7% male) undergoing CRT over 7.7 years (median follow-up: 3.8 years [interquartile range 2.3-5.3]), preimplantation QRS ≥102 μVs predicted cardiac mortality (HR: 0.36; <0.001), independent of QRS duration (QRSd) and morphology (<0.001). A QRS reduction ≥45 μVs after CRT predicted cardiac mortality (HR: 0.19), total mortality (HR: 0.50), total mortality or heart failure hospitalization (HR: 0.44), total mortality or major adverse cardiac events (HR: 0.43) (all <0.001) and the arrhythmic end point (HR: 0.26; <0.001). A concomitant reduction in QRS and QRSd was associated with the lowest risk of cardiac mortality and the arrhythmic end point (both HR: 0.12, <0.001). Conclusions Pre-implantation QRS, derived from vectorcardiography, was superior to QRSd and QRS morphology in predicting cardiac mortality after CRT. A postimplant reduction in both QRS and QRSd was associated with the best outcomes, including the arrhythmic end point.



J Am Heart Assoc: 04 Nov 2019; 8:e013539
Okafor O, Zegard A, van Dam P, Stegemann B, ... Marshall H, Leyva F
J Am Heart Assoc: 04 Nov 2019; 8:e013539 | PMID: 31657269
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Neonatal Risk in Children of Women With Congenital Heart Disease: A Cohort Study With Focus on Socioeconomic Status.

Kloster S, Tolstrup JS, Olsen MS, Johnsen SP, ... Nielsen DG, Ersbøll AK

Background We hypothesized that women with congenital heart disease (CHD) are at increased risk of giving birth preterm, including very and moderately preterm and giving birth to infants small for gestational age (SGA). We aimed to investigate this in a nation-wide study with focus on the potential modifying effect of socioeconomic status. Methods and Results We performed a cohort study using Danish nation-wide registers between 1997 and 2014. The exposure, maternal CHD, was subdivided into simple, moderate and complex based on severity of defects. Outcomes were preterm birth and SGA. Cox regression was used to estimate hazard ratios (HR). A total of 933 149 births including 3745 births among women with CHD were studied. The risk of giving birth preterm and SGA were higher among women with CHD as compared with women without CHD; for example, adjusted hazard ratios of preterm birth according to severity: simple 1.33 (95% CI, 1.11-1.59), moderate 1.45 (95% CI, 1.14-1.83) and complex 3.26 (95% CI, 2.41-4.40). Same pattern was seen for very and moderately preterm births and SGA. Education was a strong predictor of both preterm birth and SGA but did not modify the association between maternal congenital heart disease and preterm birth (=0.38) or SGA (=0.99). Conclusions Women with CHD were at increased risk of preterm birth both, moderately and very preterm, as well as giving birth to infants SGA. Education was a strong predictor of both preterm birth and SGA but the association between CHD and risk of preterm birth and SGA was independent of educational level.



J Am Heart Assoc: 04 Nov 2019; 8:e013491
Kloster S, Tolstrup JS, Olsen MS, Johnsen SP, ... Nielsen DG, Ersbøll AK
J Am Heart Assoc: 04 Nov 2019; 8:e013491 | PMID: 31656122
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Serum Lipopolysaccharide-Binding Protein Levels and the Incidence of Cardiovascular Disease in a General Japanese Population: The Hisayama Study.

Asada M, Oishi E, Sakata S, Hata J, ... Yamaura K, Ninomiya T

Background Epidemiological studies have reported a link between serum LBP (lipopolysaccharide-binding protein) levels and lifestyle-related diseases. However, there have been no longitudinal studies investigating the association of serum LBP levels and the incidence of cardiovascular disease (CVD) in general populations. Methods and Results A total of 2568 community-dwelling Japanese individuals 40 years and older without prior CVD were followed for 10 years (2002-2012). Serum LBP levels were divided into quartiles (quartile 1: 2.20-9.68 μg/mL; quartile 2: 9.69-10.93 μg/mL; quartile 3: 10.94-12.40 μg/mL; quartile 4: 12.41-24.34 μg/mL). The hazard ratios (HRs) and their 95% CIs for the incidence of CVD were computed using a Cox proportional hazards model. During the follow-up period, 180 individuals developed CVD. The age- and sex-adjusted cumulative incidence of CVD increased significantly with higher serum LBP levels ( for trend=0.005). Individuals with higher serum LBP levels had a significantly greater risk of the development of CVD after adjusting for conventional cardiovascular risk factors (quartile 1: HR, 1.00 [reference]; quartile 2: HR, 1.04 [95% CI, 0.60-1.78]; quartile 3: HR, 1.52 [95% CI, 0.92-2.51]; and quartile 4: HR, 1.90 [95% CI, 1.17-3.09];for trend=0.01). This association remained significant after additional adjustment for homeostasis model assessment of insulin resistance ( for trend=0.01). However, when additional adjustment was made for high-sensitivity C-reactive protein, the association was attenuated to the nonsignificant level ( for trend=0.08). Conclusions The present findings suggest that higher serum LBP levels are associated with increased risk of the development of CVD in the general Japanese population. Low-grade endotoxemia may contribute to the pathogenesis of CVD through chronic systemic inflammation.



J Am Heart Assoc: 04 Nov 2019; 8:e013628
Asada M, Oishi E, Sakata S, Hata J, ... Yamaura K, Ninomiya T
J Am Heart Assoc: 04 Nov 2019; 8:e013628 | PMID: 31657258
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Screening Glucose Challenge Test in Pregnancy Can Identify Women With an Adverse Postpartum Cardiovascular Risk Factor Profile: Implications for Cardiovascular Risk Reduction.

Retnakaran R, Ye C, Hanley AJ, Connelly PW, Sermer M, Zinman B

Background The 1-hour glucose challenge test (GCT) is routinely performed in pregnancy to screen for gestational diabetes mellitus. Remarkably, it has recently emerged that the GCT can also predict a woman\'s future risk of cardiovascular disease, although the mechanistic basis of this relationship is unclear. In this context we hypothesized that a higher GCT may identify women with an otherwise unrecognized adverse cardiovascular phenotype. Thus, we sought to evaluate the relationship between the antepartum GCT and subsequent postpartum cardiovascular risk factor profile. Methods and Results In this study 503 women completed a screening GCT in late second trimester and then underwent cardiometabolic characterization at 3 months postpartum, whereupon traditional (blood pressure, glucose, lipids) and nontraditional (apolipoprotein B, C-reactive protein, adiponectin) cardiovascular risk factors were compared across GCT tertiles. At 3 months postpartum, each of the following risk factors progressively worsened from the lowest to middle to highest GCT tertile: fasting glucose (=0.0002), 2-hour glucose (<0.0001), total cholesterol:high-density lipoprotein cholesterol (=0.0004), high-density lipoprotein cholesterol (=0.004), triglycerides (=0.001), apolipoprotein B (=0.001), and adiponectin (=0.02). On multiple linear regression analyses, the GCT emerged as a significant independent predictor of higher fasting glucose (=0.0006), 2-hour glucose (<0.0001), total cholesterol: high-density lipoprotein cholesterol (=0.0004), triglycerides (=0.001), low-density lipoprotein cholesterol (=0.01), and apolipoprotein B (=0.004) and of lower high-density lipoprotein cholesterol (=0.02) and adiponectin (=0.0099). Moreover, these independent associations persisted after excluding women who had gestational diabetes mellitus. Conclusions The antepartum GCT can identify women with an adverse underlying cardiovascular risk factor phenotype.



J Am Heart Assoc: 04 Nov 2019; 8:e014231
Retnakaran R, Ye C, Hanley AJ, Connelly PW, Sermer M, Zinman B
J Am Heart Assoc: 04 Nov 2019; 8:e014231 | PMID: 31657272
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Bleeding After Hospital Discharge Following Acute Coronary Syndrome: Incidence, Types, Timing, and Predictors.

Ismail N, Jordan KP, Kadam UT, Edwards JJ, Kinnaird T, Mamas MA

Background The incidence and predictors of bleeding after acute coronary syndrome are unclear within the real-world setting. Our objective was to determine the incidence, types, timing, and predictors of bleeding complications following hospital discharge after acute coronary syndrome. Methods and Results We used the Clinical Practice Research Datalink, with linkage to Hospital Episode Statistics, to determine the incidence, timing, and types of bleeding events within 12 months after hospital discharge for acute coronary syndrome. We assessed independent associations between postdischarge bleeding and baseline patient characteristics using a competing risk regression model, accounting for death as a competing event. Among 27 660 patients surviving to hospital discharge, 3620 (13%) experienced bleeding complications at a median time of 123 days (interquartile range, 45-223 days) after discharge. The incidence of bleeding was 162/1000 person-years (95% CI, 157-167/1000 person-years) within the first 12 months after hospital discharge. Bruising (949 bleeds [26%]) was the most common type of first bleeding event, followed by gastrointestinal bleed (705 bleeds [20%]), whereas intracranial bleed was relatively rare (81 bleeds [2%]). Significant predictors of postdischarge bleeding included history of bleeding complication, oral anticoagulant prescription, history of peripheral vascular disease, chronic obstructive pulmonary disease, and advanced age (>80 years). Predictors for postdischarge bleeding varied, depending on the anatomic site of the bleeding event. Conclusions Bleeding complications after hospital discharge for acute coronary syndrome are common. Patients who experience these bleeding events have distinct baseline characteristics, which vary by anatomic site of the bleed. These characteristics can inform risk-benefit considerations in deciding on favorable combination and duration of secondary antithrombotic therapy.



J Am Heart Assoc: 04 Nov 2019; 8:e013679
Ismail N, Jordan KP, Kadam UT, Edwards JJ, Kinnaird T, Mamas MA
J Am Heart Assoc: 04 Nov 2019; 8:e013679 | PMID: 31657257
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Cardiac Biomarkers and Risk of Incident Heart Failure in Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study.

Bansal N, Zelnick L, Go A, Anderson A, ... ,

Background Cardiac biomarkers may signal mechanistic pathways involved in heart failure (HF), a leading complication in chronic kidney disease. We tested the associations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor-15 (GDF-15), and soluble ST2 (sST2) with incident HF in chronic kidney disease. Methods and Results We examined adults with chronic kidney disease enrolled in a prospective, multicenter study. All biomarkers were measured at baseline. The primary outcome was incident HF. Secondary outcomes included HF with preserved ejection fraction (EF≥50%) and reduced ejection fraction (EF<50%). Cox models were used to test the association of each cardiac biomarker with HF, adjusting for demographics, kidney function, cardiovascular risk factors, and medication use. Among 3314 participants, all biomarkers, with the exception of galectin-3, were significantly associated with increased risk of incident HF (hazard ratio per SD higher concentration of log-transformed biomarker): NT-proBNP (hazard ratio, 2.07; 95% CI, 1.79-2.39); hsTnT (hazard ratio, 1.38; 95% CI, 1.21-1.56); GDF-15 (hazard ratio, 1.44; 95% CI, 1.26-1.66) and sST2 (hazard ratio, 1.19; 95% CI, 1.05-1.35). Higher NT-proBNP, hsTnT, and GDF-15 were also associated with a greater risk of HF with reduced EF; while higher NT-proBNP GDF-15 and sST2 were associated with HF with preserved EF. Galectin-3 was not associated with either HF with reduced EF or HF with preserved EF. Conclusions In chronic kidney disease, elevations of NT-proBNP, hsTnT, GDF-15, sST2 were associated with incident HF. There was a borderline association of galectin-3 with incident HF. NT-proBNP and hsTnT were more strongly associated with HF with reduced EF, while the associations of the newer biomarkers GDF-15 and sST2 were stronger for HF with preserved EF.



J Am Heart Assoc: 04 Nov 2019; 8:e012336
Bansal N, Zelnick L, Go A, Anderson A, ... ,
J Am Heart Assoc: 04 Nov 2019; 8:e012336 | PMID: 31645163
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Diabetes Mellitus Severity and a Switch From Using Lipoprotein Lipase to Adipose-Derived Fatty Acid Results in a Cardiac Metabolic Signature That Embraces Cell Death.

Puri K, Lal N, Shang R, Ghosh S, ... Hussein B, Rodrigues B

Background Fatty acid (FA) provision to the heart is from cardiomyocyte and adipose depots, plus lipoprotein lipase action. We tested how a graded reduction in insulin impacts the source of FA used by cardiomyocytes and the cardiac adaptations required to process these FA. Methods and Results Rats injected with 55 (D55) or 100 (D100) mg/kg streptozotocin were terminated after 4 days. Although D55 and D100 were equally hyperglycemic, D100 showed markedly lower pancreatic and plasma insulin and loss of lipoprotein lipase, which in D55 hearts had expanded. There was minimal change in plasma FA in D55. However, D100 exhibited a 2- to 3-fold increase in various saturated, monounsaturated, and polyunsaturated FA in the plasma. D100 demonstrated dramatic cardiac transcriptomic changes with 1574 genes differentially expressed compared with only 49 in D55. Augmented mitochondrial and peroxisomal β-oxidation in D100 was not matched by elevated tricarboxylic acid or oxidative phosphorylation. With increasing FA, although control myocytes responded by augmenting basal respiration, this was minimized in D55 and reversed in D100. Metabolomic profiling identified significant lipid accumulation in D100 hearts, which also exhibited sizeable change in genes related to apoptosis and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. Conclusions With increasing severity of diabetes mellitus, when the diabetic heart is unable to control its own FA supply using lipoprotein lipase, it undergoes dramatic reprogramming that is linked to handling of excess FA that arise from adipose tissue. This transition results in a cardiac metabolic signature that embraces mitochondrial FA overload, oxidative stress, triglyceride storage, and cell death.



J Am Heart Assoc: 04 Nov 2019; 8:e014022
Puri K, Lal N, Shang R, Ghosh S, ... Hussein B, Rodrigues B
J Am Heart Assoc: 04 Nov 2019; 8:e014022 | PMID: 31665961
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Spatiotemporal and Demographic Trends and Disparities in Cardiovascular Disease Among Older Adults in the United States Based on 181 Million Hospitalization Records.

Singh GM, Becquart N, Cruz M, Acevedo A, Mozaffarian D, Naumova EN

Background The US population is aging, with concurrent increases in cardiovascular disease (CVD) burdens; however, spatiotemporal and demographic trends in CVD incidence in the US elderly have not been investigated in detail. This study aims to characterize trends from 1991 to 2014 in CVD hospitalizations among US Medicare beneficiaries, aged 65+ years, by single year of age/sex/race/state using records from the US Centers for Medicare & Medicaid, covering 98% of older Americans. Methods and Results We abstracted 181 202 758 US Centers for Medicare & Medicaid hospitalization records indicating CVD in any of 10 diagnosis codes; tabulated total cases of CVD by sex, age, race, state, and calendar year (1991-2014); and normalized hospitalization counts to standardize over data batches. Stratum-specific hospitalization rates were calculated using US Centers for Medicare & Medicaid records and US Census population counts; a cubic polynomial function was fit to year-specific distributions of rates by single year of age. Nationwide, CVD-related hospitalization rates increased from 1991 to 2014. Differences between hospitalization rates at age 65 and 66 years, representing magnitude of healthcare deferral until Medicare onset, increased by 7.49 per 100 people 1991 to 2006 overall, and were largest among blacks and Native Americans. Rates of CVD hospitalizations were consistently highest in the Midwest/Deep South. Evidence of misclassification of race/ethnicity in US Centers for Medicare & Medicaid hospitalization records in the 1990s was noted. Conclusions Trends in CVD-related hospitalization rates among older Americans highlight the essential need for targeted policies to reduce CVD burdens, to improve reporting of race/ethnicity in large administrative databases, and to enhance access to affordable healthcare.



J Am Heart Assoc: 04 Nov 2019; 8:e012727
Singh GM, Becquart N, Cruz M, Acevedo A, Mozaffarian D, Naumova EN
J Am Heart Assoc: 04 Nov 2019; 8:e012727 | PMID: 31658854
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Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 ().

Abdulrahim JW, Kwee LC, Grass E, Siegler IC, ... Gregory SG, Shah SH

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome-wide association study (EWAS) for all-cause mortality with whole-transcriptome data in a cardiovascular cohort (CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow-up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δβ). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated (<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate-adjusted <0.10: cg08215811 (; log fold change=-0.14); cg17845532 (; fold change=-0.26); and cg17944110 (castor zinc finger 1 []; FC=0.26; <0.0001; false discovery rate-adjusted =0.046-0.080). Meta-analysis identified 6 probes (false discovery rate-adjusted <0.05): the 3 above, cg20428720 (intergenic), cg17647904 (), and cg23198793 (). Messenger RNA expression of 2isoforms was lower in cases (fold change=-0.24 [=0.007] and fold change=-0.61 [=0.009]). The , , andtranscripts did not show differential expression (>0.05); thetranscript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element,(=0.01) and(=0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all-cause mortality. Methylation inmay serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.



J Am Heart Assoc: 04 Nov 2019; 8:e013228
Abdulrahim JW, Kwee LC, Grass E, Siegler IC, ... Gregory SG, Shah SH
J Am Heart Assoc: 04 Nov 2019; 8:e013228 | PMID: 31642367
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Trends in Cardiovascular Disease Morbidity and Mortality in American Indians Over 25 Years: The Strong Heart Study.

Muller CJ, Noonan CJ, MacLehose RF, Stoner JA, ... Devereux RB, Howard BV

Background American Indians experience high rates of cardiovascular disease. We evaluated whether cardiovascular disease incidence, mortality, and prevalence changed over 25 years among American Indians aged 30 to 85. Methods and Results The SHS (Strong Heart Study) and SHFS (Strong Heart Family Study) are prospective studies of cardiovascular disease in American Indians. Participants enrolled in 1989 to 1990 or 2000 to 2003 with birth years from 1915 to 1984 were followed for cardiovascular disease events through 2013. We used Poisson regression to analyze data for 5627 individuals aged 30 to 85 years during follow-up. Outcomes reflect change in age-specific cardiovascular disease incidence, mortality, and prevalence, stratified by sex. To illustrate generational change, 5-year relative risk compared most recent birth years for ages 45, 55, 65, and 75 to same-aged counterparts born 1 generation (23-25 years) earlier. At all ages, cardiovascular disease incidence was lower for people with more recent birth years. Cardiovascular disease mortality declined consistently among men, while prevalence declined among women. Generational comparisons were similar for women aged 45 to 75 (relative risk, 0.39-0.46), but among men magnitudes strengthened from age 45 to 75 (relative risk, 0.91-0.39). For cardiovascular disease mortality, risk was lower in the most recent versus the earliest birth years for women (relative risk, 0.56-0.83) and men (relative risk, 0.40-0.54), but results for women were inconclusive. Conclusions Cardiovascular disease incidence declined over a generation in an American Indian cohort. Mortality declined more for men, while prevalence declined more for women. These trends might reflect more improvement in case survival among men compared with women.



J Am Heart Assoc: 04 Nov 2019; 8:e012289
Muller CJ, Noonan CJ, MacLehose RF, Stoner JA, ... Devereux RB, Howard BV
J Am Heart Assoc: 04 Nov 2019; 8:e012289 | PMID: 31648583
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Lower Blood Pressure After Transcatheter or Surgical Aortic Valve Replacement is Associated with Increased Mortality.

Lindman BR, Goel K, Bermejo J, Beckman J, ... Popma JJ, Reardon MJ

Background Blood pressure (BP) guidelines for patients with aortic stenosis or a history of aortic stenosis treated with aortic valve replacement (AVR) match those in the general population, but this extrapolation may not be warranted. Methods and Results Among patients enrolled in the Medtronic intermediate, high, and extreme risk trials, we included those with a transcatheter AVR (n=1794) or surgical AVR (n=1103) who were alive at 30 days. The associations between early (average of discharge and 30 day post-AVR) systolic BP (SBP) and diastolic BP (DBP) measurements and clinical outcomes between 30 days and 1 year were evaluated. Among 2897 patients, after adjustment, spline curves demonstrated an association between lower SBP (<120 mm Hg, representing 21% of patients) and DBP (<60 mm Hg, representing 30% of patients) and increased all-cause and cardiovascular mortality and repeat hospitalization. These relationships were unchanged when patients with moderate-to-severe aortic regurgitation post-AVR were excluded. After adjustment, compared with DBP 60 to <80 mm Hg, DBP 30 to <60 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.62, 95% CI 1.23-2.14) and cardiovascular mortality (adjusted hazard ratio 2.13, 95% CI 1.52-3.00), but DBP 80 to <100 mm Hg was not. Similarly, after adjustment, compared with SBP 120 to <150 mm Hg, SBP 90 to <120 mm Hg was associated with increased all-cause (adjusted hazard ratio 1.63, 95% CI 1.21-2.21) and cardiovascular mortality (adjusted hazard ratio 1.81, 95% CI 1.25-2.61), but SBP 150 to <180 mm Hg was not. Conclusions Lower BP in the first month after transcatheter AVR or surgical AVR is common and associated with increased mortality and repeat hospitalization. Clarifying optimal BP targets in these patients ought to be a priority and may improve patient outcomes. Clinical Trial registration Information URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01586910, NCT01240902.



J Am Heart Assoc: 04 Nov 2019; 8:e014020
Lindman BR, Goel K, Bermejo J, Beckman J, ... Popma JJ, Reardon MJ
J Am Heart Assoc: 04 Nov 2019; 8:e014020 | PMID: 31665959
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Association of Body Mass Index and Extreme Obesity With Long-Term Outcomes Following Percutaneous Coronary Intervention.

Biswas S, Andrianopoulos N, Dinh D, Duffy SJ, ... Stub D, Chan W

Background Previous studies have reported a protective effect of obesity compared with normal body mass index (BMI) in patients undergoing percutaneous coronary intervention (PCI). However, it is unclear whether this effect extends to the extremely obese. In this large multicenter registry-based study, we sought to examine the relationship between BMI and long-term clinical outcomes following PCI, and in particular to evaluate the association between extreme obesity and long-term survival after PCI. Methods and Results This cohort study included 25 413 patients who underwent PCI between January 1, 2005 and June 30, 2017, who were prospectively enrolled in the Melbourne Interventional Group registry. Patients were stratified by World Health Organization-defined BMI categories. The primary end point was National Death Index-linked mortality. The median length of follow-up was 4.4 years (interquartile range 2.0-7.6 years). Of the study cohort, 24.8% had normal BMI (18.5-24.9 kg/m), and 3.3% were extremely obese (BMI ≥40 kg/m). Patients with greater degrees of obesity were younger and included a higher proportion of diabetics (<0.001). After adjustment for age and comorbidities, a J-shaped association was observed between different BMI categories and adjusted hazard ratio (HR) for long-term mortality (normal BMI, HR 1.00 [ref]; overweight, HR 0.85, 95% CI 0.78-0.93, <0.001; mild obesity, HR 0.85, 95% CI 0.76-0.94, =0.002; moderate obesity, HR 0.95, 95% CI 0.80-1.12, =0.54; extreme obesity HR 1.33, 95% CI 1.07-1.65, =0.01). Conclusions An obesity paradox is still apparent in contemporary practice, with elevated BMI up to 35 kg/m associated with reduced long-term mortality after PCI. However, this protective effect appears not to extend to patients with extreme obesity.



J Am Heart Assoc: 04 Nov 2019; 8:e012860
Biswas S, Andrianopoulos N, Dinh D, Duffy SJ, ... Stub D, Chan W
J Am Heart Assoc: 04 Nov 2019; 8:e012860 | PMID: 31648578
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Clinical and Laboratory Predictors for Plaque Erosion in Patients With Acute Coronary Syndromes.

Yamamoto E, Yonetsu T, Kakuta T, Soeda T, ... Fuster V, Jang IK

Background Plaque erosion is responsible for 25% to 40% of patients with acute coronary syndromes (ACS). Recent studies suggest that anti-thrombotic therapy without stenting may be an option for this subset of patients. Currently, however, an invasive procedure is required to make a diagnosis of plaque erosion. The aim of this study was to identify clinical or laboratory predictors of plaque erosion in patients with ACS to enable a diagnosis of erosion without additional invasive procedures. Methods and Results Patients with ACS who underwent optical coherence tomography imaging were selected from 11 institutions in 6 countries. The patients were classified into plaque rupture, plaque erosion, or calcified plaque, and predictors were identified using multivariable logistic modeling. Among 1241 patients with ACS, 477 (38.4%) patients were found to have plaque erosion. Plaque erosion was more frequent in non-ST-segment elevation-ACS than in ST-segment-elevation myocardial infarction (47.9% versus 29.8%, =0.0002). Multivariable logistic regression models showed 5 independent parameters associated with plaque erosion: age <68 years, anterior ischemia, no diabetes mellitus, hemoglobin >15.0 g/dL, and normal renal function. When all 5 parameters are present in a patient with non-ST-segment elevation-ACS, the probability of plaque erosion increased to 73.1%. Conclusions Clinical and laboratory parameters associated with plaque erosion are explored in this retrospective registry study. These parameters may be useful to identify the subset of ACS patients with plaque erosion and guide them to conservative management without invasive procedures. The results of this exploratory analysis need to be confirmed in large scale prospective clinical studies. Clinical Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03479723.



J Am Heart Assoc: 04 Nov 2019; 8:e012322
Yamamoto E, Yonetsu T, Kakuta T, Soeda T, ... Fuster V, Jang IK
J Am Heart Assoc: 04 Nov 2019; 8:e012322 | PMID: 31640466
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Symptoms of Depression and Risk of Abdominal Aortic Aneurysm: A HUNT Study.

Nyrønning LÅ, Stenman M, Hultgren R, Albrektsen G, Videm V, Mattsson E

Background Depression is associated with cardiovascular diseases, but the evidence is scarce regarding depression and risk of abdominal aortic aneurysms (AAA). The aim was to determine whether individuals with depressive symptoms have increased risk of AAA. Methods and Results This population-based prospective study included 59 136 participants (52.4% women) aged 50 to 106 years from the HUNT (Norwegian Nord-Trøndelag Health Study). Symptoms of depression were assessed using the depression subscale of the Hospital Anxiety and Depression Scale (HADS). During a median follow-up of 13 years, there were 742 incident cases of AAA (201 women). A total of 6401 individuals (12.3%) reported depressive symptoms (defined as HADS depression scale [HADS-D]) ≥8) (52.5% women). The annual incidence rate of AAA was 1.0 per 1000 individuals. At all ages, the estimated proportion of individuals diagnosed with AAA was higher among those with depressive symptoms (log-rank test, <0.001). People with HADS-D ≥8 were older than those with HADS-D<8 (median 57.8 versus 52.3 years, <0.001) and a statistically significantly higher proportion of them (<0.001) were smokers, overweight or obese, and reported a history of coronary heart disease, diabetes mellitus, and hypertension. In a Cox proportional hazard regression model adjusted for these factors, individuals with depressive symptoms had a ≈30% higher risk of AAA than those without (hazard ratio, 1.32, 95% CI 1.08-1.61, =0.007). Conclusions This study shows that individuals with depressive symptoms have significantly higher risk of incident AAA, after adjustments for established risk factors.



J Am Heart Assoc: 04 Nov 2019; 8:e012535
Nyrønning LÅ, Stenman M, Hultgren R, Albrektsen G, Videm V, Mattsson E
J Am Heart Assoc: 04 Nov 2019; 8:e012535 | PMID: 31642357
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Physical Activity and Subsequent Risk of Hospitalization With Peripheral Artery Disease and Critical Limb Ischemia in the ARIC Study.

Lu Y, Ballew SH, Kwak L, Selvin E, ... Matsushita K, Szklo M

Background Whether physical activity is a determinant of peripheral artery disease (PAD) remains unclear. We therefore assessed the association of physical activity (amount and intensity) with subsequent risk of hospitalization with PAD and its severe form, critical limb ischemia, in the ARIC (Atherosclerosis Risk in Communities) study. Methods and Results We included 12 513 participants free of cardiovascular disease at baseline (1987-1989), with a mean age of 53.9 years, 55.3% women, and 25.0% black. Physical activity was assessed using a modified Baecke questionnaire and categorized into poor (no moderate [3 to <6 metabolic equivalents] or vigorous [≥6 metabolic equivalents] exercise), intermediate (1-74 min/wk vigorous or 1-149 min/wk moderate plus vigorous exercise), and recommended (≥75 min/wk vigorous or ≥150 min/wk moderate plus vigorous exercise). We also modeled moderate and vigorous exercise individually. All analyses applied Cox regression models. Intermediate and recommended exercise were seen in 24.7% and 38.1%, respectively. During a median follow-up of 25.4 years, 434 incident hospitalizations with PAD (166 critical limb ischemia) were documented. Recommended versus poor activity was associated with a lower demographically adjusted PAD risk (hazard ratio, 0.68; 95% CI, 0.54-0.85) but attenuated after accounting for lifestyle factors (hazard ratio, 0.84; 95% CI, 0.66-1.05). When analyzing moderate and vigorous exercise separately, vigorous exercise was robustly related to lower risk of hospitalization with PAD, and critical limb ischemia in particular (hazard ratio, 0.72; 95% CI, 0.54-0.97 per 200 metabolic equivalents*min/wk increment in the most extended model). Conclusions Higher amount and intensity of physical activity were related to lower risks of hospitalization with PAD and critical limb ischemia, further highlighting the importance of engaging in physical activity for vascular health.



J Am Heart Assoc: 04 Nov 2019; 8:e013534
Lu Y, Ballew SH, Kwak L, Selvin E, ... Matsushita K, Szklo M
J Am Heart Assoc: 04 Nov 2019; 8:e013534 | PMID: 31642360
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Abstract

Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure.

Husain-Syed F, Birk HW, Ronco C, Schörmann T, ... Gall H, Ghofrani HA

Background Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods and Results We enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra-abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH-related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH-specific therapy escalation) and all-cause mortality for 1-year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (<0.0001) and was significantly associated with right heart and renal function, intra-abdominal pressure, and neurohormonal and hydration status. During follow-up, the morbidity/mortality end point occurred in 91 patients and was independently predicted by RVSI (RVSI in the third tertile versus referent: hazard ratio: 4.72 [95% CI, 2.10-10.59; <0.0001]). Receiver operating characteristic curves suggested superiority of RVSI to individual intrarenal venous flow patterns in predicting outcome (areas under the curve: 0.789 and 0.761, respectively; =0.038). Conclusions We propose RVSI as a conceptually new and integrative Doppler index of renal congestion. RVSI provides additional prognostic information to stratify PH for the propensity to develop right heart failure. Clinical Trial registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03039959.



J Am Heart Assoc: 04 Nov 2019; 8:e013584
Husain-Syed F, Birk HW, Ronco C, Schörmann T, ... Gall H, Ghofrani HA
J Am Heart Assoc: 04 Nov 2019; 8:e013584 | PMID: 31630601
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Abstract

Methodological and Clinical Heterogeneity and Extraction Errors in Meta-Analyses of Catheter Ablation for Atrial Fibrillation in Heart Failure.

Packer M

Background Meta-analyses are expected to follow a standardized process, and thus, they have become highly formulaic, although there is little evidence that such regimentation yields high-quality results. Methods and Results This article describes the results of a critical examination of 14 published meta-analyses of catheter ablation for atrial fibrillation in heart failure that were based on a nearly identical core set of 4 to 6 primary trials. Methodological issues included (1) the neglect of primary data or the failure to report any primary data; (2) the inaccurate recording of the number of randomized patients; (3) the lack of attention to data missingness or baseline imbalances; (4) the failure to contact investigators of primary trials for additional data; (5) the incorrect extraction of data, the misidentification of events, and the assignment of events to the wrong treatment groups; (6) the calculation of summary estimates based on demonstrably heterogenous data, methods of differing reliability, or unrelated end points; and (7) the development of conclusions based on sparse numbers of events or overly reliant on the results of 1 dominant trial. Conclusions These findings reinforce existing concerns about the methodological validity of meta-analyses and their current status in the hierarchy of medical evidence, and they raise new questions about the process by which meta-analyses undergo peer review by medical journals.



J Am Heart Assoc: 04 Nov 2019; 8:e013779
Packer M
J Am Heart Assoc: 04 Nov 2019; 8:e013779 | PMID: 31625420
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Abstract

Deficiency of MicroRNA miR-1954 Promotes Cardiac Remodeling and Fibrosis.

Chiasson V, Takano APC, Guleria RS, Gupta S

Background Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II (AngII) has been implicated in the development of cardiac fibrosis. Recently, microRNAs have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of microRNAs in cardiac fibrosis remains unclear. Next-generation sequencing analysis identified a novel characterized microRNA, miR-1954, that was significantly reduced in AngII-infused mice. The finding led us to hypothesize that deficiency of miR-1954 triggers cardiac fibrosis. Methods and Results A transgenic mouse was created using α-MHC (α-myosin heavy chain) promoter and was challenged with AngII infusion. AngII induced cardiac hypertrophy and remodeling. The in vivo overexpression of miR-1954 showed significant reduction in cardiac mass and blood pressure in AngII-infused mice. Further analysis showed significant reduction in cardiac fibrotic genes, hypertrophy marker genes, and an inflammatory gene and restoration of a calcium-regulated gene (Atp2a2 [ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2]; also known as SERCA2), but no changes were observed in apoptotic genes. THBS1 (thrombospondin 1) is indicated as a target gene for miR-1954. Conclusions Our findings provide evidence, for the first time, that miR-1954 plays a critical role in cardiac fibrosis by targeting THBS1. We conclude that promoting the level of miR-1954 would be a promising strategy for the treatment of cardiac fibrosis.



J Am Heart Assoc: 04 Nov 2019; 8:e012880
Chiasson V, Takano APC, Guleria RS, Gupta S
J Am Heart Assoc: 04 Nov 2019; 8:e012880 | PMID: 31640463
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Abstract

Does Information on Blood Heavy Metals Improve Cardiovascular Mortality Prediction?

Wang X, Mukherjee B, Park SK

Background To evaluate whether blood markers of lead, cadmium, and mercury can improve prediction for cardiovascular disease (CVD) mortality when added individually, jointly, or as an integrative index/Environmental Risk Score (ERS), in a model with established risk factors. Methods and Results Our study sample comprised 16 028 adults aged ≥40 years who were enrolled in the National Health and Nutrition Examination Survey 1999-2012 and followed up through December 31, 2015. The study sample was randomly split into training for the ERS construction (n=8043) and testing for the evaluation of prediction performance (n=7985). ERS was computed using elastic-net penalized Cox\'s model based on the selected metal predictors predicting CVD mortality. During median follow-up of 7.2 years, 517 died from CVD. In the training set, linear terms of cadmium and mercury, squared terms of lead and mercury, and all 3 pairwise interactions were selected by elastic-net for ERS construction. In the testing set, the C-statistic increased from 0.845 when only established CVD risk factors were in the model to 0.854 when the ERS was additionally added to the model. Addition of all linear, squared, and pairwise interaction terms of blood metals to the Cox\'s models improved C-statistic from 0.845 to 0.857. The improvement remained significant when it was assessed by net reclassification improvement and integrated discrimination improvement. Conclusions Our findings suggest that blood markers of toxic metals can improve CVD risk prediction over the established risk factors and highlight their potential utility for CVD risk assessment, prevention, and precision health.



J Am Heart Assoc: 04 Nov 2019; 8:e013571
Wang X, Mukherjee B, Park SK
J Am Heart Assoc: 04 Nov 2019; 8:e013571 | PMID: 31631727
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Abstract

Chest Pain Center Accreditation Is Associated With Improved In-Hospital Outcomes of Acute Myocardial Infarction Patients in China: Findings From the CCC-ACS Project.

Fan F, Li Y, Zhang Y, Li J, ... Huo Y,

Background Chest pain center (CPC) accreditation plays an important role in the management of acute myocardial infarction (AMI). However, no evidence shows whether the outcomes of AMI patients are improved with CPC accreditation in China. Methods and Results This retrospective analysis is based on a predesigned nationwide registry, CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome). The primary outcome was major adverse cardiovascular events (MACE), including all-cause death, reinfarction, stent thrombosis, stroke, and heart failure. A total of 15 344 AMI patients, from 40 CPC-accredited hospitals, were enrolled, including 7544 admitted before and 7800 after accreditation. In propensity score matching, 6700 patients in each group were matched. The incidence of 7-day MACE (6.7% versus 8.0%; =0.003) and all-cause death (1.1% versus 1.6%; =0.021) was lower after accreditation. In multivariate adjusted mixed-effects Cox proportional hazards models, CPC accreditation was associated with significantly decreased risk of MACE (hazard ratio: 0.78; 95% CI, 0.68-0.91) and all-cause death (hazard ratio: 0.71; 95% CI, 0.51-0.99). The risk of MACE and all-cause death both followed a reverse J-shaped trend: the risk of MACE and all-cause death decreased gradually after achieving CPC accreditation, with minimal risk occurring in the first year, but increased in the second year and after. Conclusions Based on a large-scale national registry data set, CPC accreditation was associated with better in-hospital outcomes for AMI patients. However, the benefits seemed to attenuate over time, and reaccreditation may be essential for maintaining AMI care quality and outcomes.



J Am Heart Assoc: 04 Nov 2019; 8:e013384
Fan F, Li Y, Zhang Y, Li J, ... Huo Y,
J Am Heart Assoc: 04 Nov 2019; 8:e013384 | PMID: 31630594
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Abstract

Metformin Use Is Associated With a Lower Risk of Hospitalization for Heart Failure in Patients With Type 2 Diabetes Mellitus: a Retrospective Cohort Analysis.

Tseng CH

Background A beneficial effect of metformin on heart failure requires confirmation. Methods and Results Patients with new-onset type 2 diabetes mellitus during 1999 to 2005 were enrolled from Taiwan\'s National Health Insurance database and followed up from January 1, 2006, until December 31, 2011. Main analyses were conducted in an unmatched cohort (172 542 metformin ever users and 43 744 never users) and a propensity score matched-pair cohort (matched cohort I, 41 714 ever users and 41 714 never users). Hazard ratios were estimated by Cox hazard regression incorporated with the inverse probability of treatment weighting using the propensity score in the unmatched cohort and by naïve method in the matched cohort I. Results showed that the respective incidence rates of heart failure hospitalization in ever users and never users were 304.25 and 864.31 per 100 000 person-years in the unmatched cohort (hazard ratio, 0.350; 95% CI, 0.329-0.373) and were 469.66 and 817.01 per 100 000 person-years in the matched cohort I (hazard ratio, 0.571; 95% CI, 0.526-0.620). A dose-response pattern was consistently observed while estimating hazard ratios for the tertiles of cumulative duration of metformin therapy. Findings were supported by another propensity score-matched cohort created after excluding 10 potential instrumental variables in the estimation of propensity score (matched cohort II). An approximately 40% lower risk was consistently observed among ever users in different models derived from the matched cohorts I and II, but models from the matched cohort II were less subject to model misspecification. Conclusions Metformin use is associated with a lower risk of heart failure hospitalization.



J Am Heart Assoc: 04 Nov 2019; 8:e011640
Tseng CH
J Am Heart Assoc: 04 Nov 2019; 8:e011640 | PMID: 31630591
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Abstract

Trajectories of Lipids Profile and Incident Cardiovascular Disease Risk: A Longitudinal Cohort Study.

Dayimu A, Wang C, Li J, Fan B, ... Zhang T, Xue F

Background The association between low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides with cardiovascular disease (CVD) has been well studied. No previous studies considered trajectory of these lipids jointly. This study aims to characterize longitudinal trajectories of lipid profile jointly and examine its impact on incident CVD. Methods and Results A total of 9726 participants (6102 men), aged from 20 to 58 years who had lipids repeatedly measured 3 to 9 times, were included in the study. Three distinct trajectories were identified using the multivariate latent class growth mixture model: inverse U-shape (18.72%; n=1821), progressing (66.03%; n=6422), and U-shape (15.25%; n=1483). Compared with the U-shape class, the adjusted hazard ratio and 95% CI were 1.33 (1.05-1.68) and 1.49 (1.14-1.95) for the progressing and inverse U-shape class, respectively. The area under the curve was calculated using the integral of the model parameters. In the adjusted model, total and incremental area under the curve of lipid profile were significantly associated with CVD risk. Furthermore, the model-estimated levels and linear slopes of lipids were calculated at each age point according to the latent class growth mixture model model parameters and their first derivatives, respectively. After adjusting for covariates, standardized odds ratio of slope increases gradually from 1.11 (1.02, 1.21) to 1.21 (1.12, 1.31) at 20 to 40 years and then decreased to 1.02 (0.94, 1.11) until 60 years. Conclusions These results indicate that the lipids profile trajectory has a significant impact on CVD risk. Age between 20 and 42 years is a crucial period for incident CVD, which has implications for early lipids intervention.



J Am Heart Assoc: 04 Nov 2019; 8:e013479
Dayimu A, Wang C, Li J, Fan B, ... Zhang T, Xue F
J Am Heart Assoc: 04 Nov 2019; 8:e013479 | PMID: 31630587
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Abstract

Failure to Rescue as an Outcome Metric for Pediatric and Congenital Cardiac Catheterization Laboratory Programs: Analysis of Data From the IMPACT Registry.

O\'Byrne ML, Kennedy KF, Jayaram N, Bergersen LJ, ... Rome JJ, Glatz AC

Background Risk-adjusted adverse event (AE) rates have been used to measure the quality of pediatric and congenital cardiac catheterization laboratories. In other settings, failure to rescue (FTR) has demonstrated utility as a quality metric. Methods and Results A multicenter retrospective cohort study was performed using data from the IMPACT (Improving Adult and Congenital Treatment) Registry between January 2010 and December 2016. A modified FTR metric was developed for pediatric and congenital cardiac catheterization laboratories and then compared with pooled AEs. The associations between patient- and hospital-level factors and outcomes were evaluated using hierarchical logistic regression models. Hospital risk standardized ratios were then calculated. Rankings of risk standardized ratios for each outcome were compared to determine whether AEs and FTR identified the same high- and low-performing centers. During the study period, 77 580 catheterizations were performed at 91 hospitals. Higher annual hospital catheterization volume was associated with lower odds of FTR (odds ratio: 0.68 per 300 cases; =0.0003). No association was seen between catheterization volume and odds of AEs. Odds of AEs were instead associated with patient- and procedure-level factors. There was no correlation between risk standardized ratio ranks for FTR and pooled AEs (=0.46). Hospital ranks by catheterization volume and FTR were associated (=-0.28, =0.01) with the largest volume hospitals having the lowest risk of FTR. Conclusions In contrast to AEs, FTR was not strongly associated with patient- and procedure-level factors and was significantly associated with pediatric and congenital cardiac catheterization laboratory volume. Hospital rankings based on FTR and AEs were not significantly correlated. We conclude that FTR is a complementary measure of catheterization laboratory quality and should be included in future research and quality-improvement projects.



J Am Heart Assoc: 04 Nov 2019; 8:e013151
O'Byrne ML, Kennedy KF, Jayaram N, Bergersen LJ, ... Rome JJ, Glatz AC
J Am Heart Assoc: 04 Nov 2019; 8:e013151 | PMID: 31619106
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Abstract

Sixteen-Week Physical Activity Intervention in Subjects With Increased Cardiometabolic Risk Shifts Innate Immune Function Towards a Less Proinflammatory State.

Noz MP, Hartman YAW, Hopman MTE, Willems PHGM, ... Thijssen DHJ, Riksen NP

Background Low-grade inflammation, largely mediated by monocyte-derived macrophages, contributes to atherosclerosis. Sedentary behavior is associated with atherosclerosis and cardiovascular diseases (CVD). We examined whether reducing sedentary behavior and improving walking time improves monocyte inflammatory phenotype in subjects with increased cardiovascular risk. Methods and Results Across 2 waves, 16 individuals with increased cardiovascular risk performed a 16-week intervention study (age 64±6 years, body mass index 29.9±4.3 kg/m), using a device with vibration feedback to promote physical activity. Before and after intervention, we objectively examined physical activity (ActivPAL), cytokine production capacity after ex vivo stimulation in peripheral blood mononuclear cells, metabolism of peripheral blood mononuclear cells, circulating cytokine concentrations, and monocyte immunophenotype. Overall, no significant increase in walking time was found (1.9±0.7 to 2.2±1.2 h/day, =0.07). However, strong, inverse correlations were observed between the change in walking time and the change in production of interleukin (IL)-1β, IL-6, IL-8, and IL-10 after lipopolysaccharide stimulation (=-0.655, -0.844, -0.672, and -0.781, respectively, all <0.05). After intervention optimization based on feedback from wave 1, participants in wave 2 (n=8) showed an increase in walking time (2.2±0.8 to 3.0±1.3 h/day, =0.001) and attenuated cytokine production of IL-6, IL-8, and IL-10 (all <0.05). Glycolysis (=0.08) and maximal OXPHOS (=0.04) of peripheral blood mononuclear cells decreased after intervention. Lower IL-6 concentrations (=0.06) and monocyte percentages (<0.05), but no changes in monocyte subsets were found. Conclusions Successfully improving walking time shifts innate immune function towards a less proinflammatory state, characterized by a lower capacity to produce inflammatory cytokines, in individuals with increased cardiovascular risk. Clinical Trial registration Information URL: http://www.trialregister.nl. Unique identifier: NTR6387.



J Am Heart Assoc: 04 Nov 2019; 8:e013764
Noz MP, Hartman YAW, Hopman MTE, Willems PHGM, ... Thijssen DHJ, Riksen NP
J Am Heart Assoc: 04 Nov 2019; 8:e013764 | PMID: 31623506
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Abstract

Association of Hospital Racial Composition and Payer Mix With Mortality in Acute Coronary Syndrome.

Srivastava PK, Fonarow GC, Bahiru E, Ziaeian B

Background Patient characteristics insufficiently explain disparities in cardiovascular outcomes among hospitalized patients, suggesting a role for community or hospital-level factors. Here, we evaluate the association of hospital racial composition and payer mix with all-cause inpatient mortality for patients hospitalized with acute coronary syndrome (ACS). Methods and Results Using the National Inpatient Sample, we identified adult hospitalizations from 2014 with a primary diagnosis of ACS (n=550 005). We divided National Inpatient Sample hospitals into quartiles based on percent of minority (black, Hispanic, Asian or Pacific Islander, Native American race/ethnicity) and low-income payer (Medicaid or uninsured) discharges in 2014. We utilized logistic regression to determine whether hospital minority or low-income payer makeup associated with all-cause inpatient mortality among those admitted for ACS . In adjusted models, ACS patients admitted to hospitals with >12.4% to 25.4% (Quartile 2), >25.4% to 44.3% (Q3), and >44.3% (Q4) minority discharges experienced a 14% (OR 1.14, 95% CI 1.06-1.23), 13% (OR 1.13, 95% CI 1.04-1.23), and 15% (OR 1.15, 95% CI 1.04-1.26) increased odds of all-cause inpatient mortality compared with hospitals with ≤12.4% (Q1) minority discharges. ACS patients admitted to hospitals with >18.7% to 25.7% (Q2) and >34.0% (Q4) low-income payer discharges experienced a 9% (OR 1.09, 1.01-1.17) and 9% (OR 1.09, 1.00-1.19) increased odds of all-cause inpatient mortality when compared with hospitals with ≤18.7% (Q1) low-income payer discharges. Conclusions Hospital minority and low-income payer makeup positively associate with odds of all-cause inpatient mortality among patients admitted for acute coronary syndrome.



J Am Heart Assoc: 04 Nov 2019; 8:e012831
Srivastava PK, Fonarow GC, Bahiru E, Ziaeian B
J Am Heart Assoc: 04 Nov 2019; 8:e012831 | PMID: 31623505
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Abstract

Five-Year Outcomes in Patients With Diabetes Mellitus Treated With Biodegradable Polymer Sirolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents.

Iglesias JF, Heg D, Roffi M, Tüller D, ... Windecker S, Pilgrim T

Background The choice of optimal drug-eluting stent therapy for patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention remains uncertain. We aimed to assess the long-term clinical outcomes after percutaneous coronary intervention with biodegradable polymer sirolimus-eluting stents (BP-SES) versus durable polymer everolimus-eluting stents (DP-EES) in patients with DM. Methods and Results In a prespecified subgroup analysis of the BIOSCIENCE (Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularization) trial (NCT01443104), patients randomly assigned to ultrathin-strut BP-SES or thin-strut DP-EES were stratified according to diabetic status. The primary end point was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization, at 5 years. Among 2119 patients, 486 (22.9%) presented with DM. Compared with individuals without DM, patients with DM were older and had a greater baseline cardiac risk profile. In patients with DM, target lesion failure at 5 years occurred in 74 patients (cumulative incidence, 31.0%) treated with BP-SES and 57 patients (25.8%) treated with DP-EES (risk ratio, 1.23; 95% CI, 0.87-1.73 [=0.24]). In individuals without DM, target lesion failure at 5 years occurred in 124 patients (16.8%) treated with BP-SES and 132 patients (16.8%) treated with DP-EES (risk ratio, 0.98; 95% CI, 0.77-1.26 [=0.90;for interaction=0.31]). Cumulative 5-year incidence rates of cardiac death, target vessel myocardial infarction, clinically indicated target lesion revascularization, and definite stent thrombosis were similar among patients with DM treated with BP-SES or DP-EES. There was no interaction between diabetic status and treatment effect of BP-SES versus DP-EES. Conclusions In a prespecified subgroup analysis of the BIOSCIENCE trial, we found no difference in clinical outcomes throughout 5 years between patients with DM treated with ultrathin-strut BP-SES or thin-strut DP-EES. Clinical Trial registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01443104.



J Am Heart Assoc: 18 Nov 2019; 8:e013607
Iglesias JF, Heg D, Roffi M, Tüller D, ... Windecker S, Pilgrim T
J Am Heart Assoc: 18 Nov 2019; 8:e013607 | PMID: 31696762
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Abstract

Characterizing Patient-Centered Postoperative Recovery After Adult Cardiac Surgery: A Systematic Review.

Mori M, Angraal S, Chaudhry SI, Suter LG, ... Wallach JD, Krumholz HM

Background Improving postoperative recovery is important, with a national focus on postacute care, but the volume and quality of evidence in this area are not well characterized. We conducted a systematic review to characterize studies on postoperative recovery after adult cardiac surgery using patient-reported outcome measures. Methods and Results From MEDLINE and Web of Science, studies were included if they prospectively assessed postoperative recovery on adult patients undergoing cardiac surgery using patient-reported outcome measures. Six recovery domains were defined by prior literature: nociceptive symptoms, mental health, physical function, activities of daily living, sleep, and cognitive function. Of the 3432 studies, 105 articles met the inclusion criteria. The studies were small (median sample size, 119), and mostly conducted in single-center settings (n=81; 77%). Study participants were predominantly men (71%) and white (88%). Coronary artery bypass graft was included in 93% (n=98). Studies commonly selected for elective cases (n=56; 53%) and patients with less comorbidity (n=67; 64%). Median follow-up duration was 91 (interquartile range, 42-182) days. Studies most commonly assessed 1 domain (n=42; 40%). The studies also varied in the instruments used and differed in their reporting approach. Studies commonly excluded patients who died during the follow-up period (n=48; 46%), and 45% (n=47) did not specify how those patients were analyzed. Conclusions Studies of postoperative patient-reported outcome measures are low in volume, most often single site without external validation, varied in their approach to missing data, and narrow in the domains and diversity of patients. The evidence base for postoperative patient-reported outcome measures needs to be strengthened.



J Am Heart Assoc: 04 Nov 2019; 8:e013546
Mori M, Angraal S, Chaudhry SI, Suter LG, ... Wallach JD, Krumholz HM
J Am Heart Assoc: 04 Nov 2019; 8:e013546 | PMID: 31617435
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Abstract

Blood Pressure and Heart Rate Variability in Preschool Children Exposed to Smokeless Tobacco in Fetal Life.

Nordenstam F, Norman M, Wickström R

Background Maternal smoking during pregnancy has been associated with higher blood pressure and autonomic imbalance in the offspring. However, it has been difficult to determine the selective prenatal and postnatal contributions as children frequently have been exposed to smoking both before and after birth. The specific role of nicotine is also unclear. We aimed to determine whether exclusive prenatal exposure to nicotine from maternal use of smokeless tobacco (Swedish snus) in pregnancy was associated with blood pressure and autonomic heart rate control in their children. Methods and Results We measured oscillometric blood pressures in forty 5- to 6-year-old children with snus exposure in fetal life (n=21) and in tobacco-free controls (n=19). Taking the child\'s age and height into account, snus-exposed children had 4.2 (95% CI, 0.2-8.1) mm Hg higher systolic blood pressure than controls (=0.038). The corresponding sex-, age-, and height-standardized systolic blood pressure centiles were 61 and 46 (95% CI of the difference, 2-28) (=0.029). Heart rate variability was tested in 30 of the children. The spectral heart rate variability variable low-frequency/high-frequency ratio was higher (median, 0.69; interquartile range, 0.45-1.21) in snus-exposed children than in controls (median, 0.21; interquartile range, 0.32-0.57; =0.034). Conclusions Prenatal snus exposure was associated with higher systolic blood pressure and altered heart rate variability at 6 years of age. These findings may indicate adverse prenatal programming of nicotine, but implications for cardiovascular health in later life remain to be studied. Meanwhile, women should be recommended to abstain from all types of tobacco and nicotine products during pregnancy.



J Am Heart Assoc: 04 Nov 2019; 8:e012629
Nordenstam F, Norman M, Wickström R
J Am Heart Assoc: 04 Nov 2019; 8:e012629 | PMID: 31615305
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Abstract

Pathophysiologic and Prognostic Implications of Right Atrial Hypertension in Adults With Tetralogy of Fallot.

Egbe AC, Bonnichsen C, Reddy YNV, Anderson JH, Borlaug BA

Background Right atrial pressure (RAP), a composite metric of right ventricular diastolic function, volume status, and right heart compliance, is a predictor of mortality in patients with heart failure due to acquired heart disease. Because patients with tetralogy of Fallot (TOF) might have abnormal right atrial and ventricular mechanics caused by myocardial injury and remodeling, we hypothesized that RAP would be associated with disease severity and cardiovascular adverse events in this population. Methods and Results We performed a cohort study of adults with TOF who underwent right heart catheterization at the Mayo Clinic Rochester between 1990 and 2017. The objective was to determine the association between RAP and multiple domains of disease severity in TOF (percentage of predicted peak oxygen consumption, atrial or ventricular arrhythmia, and heart failure hospitalization), as well as cardiovascular adverse events, defined as sustained ventricular tachycardia, resuscitated or aborted sudden death, heart transplantation, or death. Among 225 patients (113 male; mean age: 39±14 years), mean RAP was 10.7±5.2 mm Hg and median was 10 mm Hg (interquartile range: 7-13 mm Hg). Increasing RAP was associated with atrial or ventricular arrhythmias (odds ratio: 5.01; 95% CI, 1.22-23.49; <0.001), heart failure hospitalization (odds ratio: 1.47; 95% CI, 1.10-2.39; =0.033) per 5 mm Hg, and worsening exercise capacity (peak oxygen consumption; =0.74, =-0.86, <0.001). RAP was a predictor of cardiovascular adverse events (hazard ratio: 1.28; 95% CI, 1.10-1.47; =0.028) per 5 mm Hg. Conclusions In symptomatic patients with TOF, increasing RAP correlates with multiple domains of disease severity (risk stratification) and predicts future cardiovascular events (prognostication). These data have potential clinical implications in the target population of symptomatic TOF patients.



J Am Heart Assoc: 18 Nov 2019; 8:e014148
Egbe AC, Bonnichsen C, Reddy YNV, Anderson JH, Borlaug BA
J Am Heart Assoc: 18 Nov 2019; 8:e014148 | PMID: 31701796
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Abstract

Evaluation of Cardiac Function in Women With a History of Preeclampsia: A Systematic Review and Meta-Analysis.

Reddy M, Wright L, Rolnik DL, Li W, ... Wallace EM, Palmer K

Background Women with a history of preeclampsia are at increased risk of cardiovascular morbidity and mortality. However, the underlying mechanisms of disease association, and the ideal method of monitoring this high-risk group, remains unclear. This review aims to determine whether women with a history of preeclampsia show clinical or subclinical cardiac changes when evaluated with an echocardiogram. Methods and Results A systematic search of MEDLINE, EMBASE, and CINAHL databases was performed to identify studies that examined cardiac function in women with a history of preeclampsia, in comparison with those with normotensive pregnancies. In the 27 included studies, we found no significant differences between preeclampsia and nonpreeclampsia women with regard to left ventricular ejection fraction, isovolumetric relaxation time, or deceleration time. Women with a history of preeclampsia demonstrated a higher left ventricular mass index and relative wall thickness with a mean difference of 4.25 g/m (95% CI, 2.08, 6.42) and 0.03 (95% CI, 0.01, 0.05), respectively. In comparison with the nonpreeclampsia population, they also demonstrated a lower E/A and a higher E/e\' ratio with a mean difference of -0.08 (95% CI, -0.15, -0.01) and 0.84 (95% CI, 0.41, 1.27), respectively. Conclusions In comparison with women who had a normotensive pregnancy, women with a history of preeclampsia demonstrated a trend toward altered cardiac structure and function. Further studies with larger sample sizes and consistent echocardiogram reporting with the use of sensitive preclinical markers are required to assess the role of echocardiography in monitoring this high-risk population group.



J Am Heart Assoc: 18 Nov 2019; 8:e013545
Reddy M, Wright L, Rolnik DL, Li W, ... Wallace EM, Palmer K
J Am Heart Assoc: 18 Nov 2019; 8:e013545 | PMID: 31698969
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Abstract

Prognostic Impact of Baseline Hemoglobin Levels on Long-Term Thrombotic and Bleeding Events After Percutaneous Coronary Interventions.

Nagao K, Watanabe H, Morimoto T, Inada T, ... Kimura T,

Background Association of baseline hemoglobin levels with long-term adverse events after percutaneous coronary interventions has not been yet thoroughly defined. We aimed to assess the clinical impact of baseline hemoglobin on long-term ischemic and bleeding risk after percutaneous coronary intervention. Methods and Results Using the pooled individual patient-level data from the 3 percutaneous coronary intervention studies, we categorized 19 288 patients into 4 groups: high-normal hemoglobin (≥14.0 g/dL; n=7555), low-normal hemoglobin (13.0-13.9 g/dL in men and 12.0-13.9 g/dL in women; n=5303), mild anemia (11.0-12.9 g/dL in men and 11.0-11.9 g/dL in women; n=4117), and moderate/severe anemia (<11.0 g/dL; n=2313). Median follow-up duration was 3 years. Low-normal hemoglobin, mild anemia, and moderate/severe anemia correlated with significant excess risk relative to high-normal hemoglobin for GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries Trial) moderate/severe bleeding, with adjusted hazard ratios of 1.22 (95% CI, 1.04-1.44), 1.73 (95% CI, 1.47-2.04), and 2.31 (95% CI, 1.92-2.78), respectively. Moderate/severe anemia also correlated with significant excess risk relative to high-normal hemoglobin for the ischemic composite end point of myocardial infarction/ischemic stroke (adjusted hazard ratio, 1.33; 95% CI, 1.11-1.60), whereas low-normal hemoglobin and mild anemia did not. However, the excess risk of low-normal hemoglobin, mild anemia, and moderate/severe anemia relative to high-normal hemoglobin remained significant for ischemic stroke and for mortality. Conclusions Decreasing baseline hemoglobin correlated with incrementally higher long-term risk for major bleeding, ischemic stroke, and mortality after percutaneous coronary intervention. Even within normal range, lower baseline hemoglobin level correlated with higher ischemic and bleeding risk.



J Am Heart Assoc: 18 Nov 2019; 8:e013703
Nagao K, Watanabe H, Morimoto T, Inada T, ... Kimura T,
J Am Heart Assoc: 18 Nov 2019; 8:e013703 | PMID: 31701786
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Abstract

Predictors and Clinical Outcomes of Vasoplegia in Patients Bridged to Heart Transplantation With Continuous-Flow Left Ventricular Assist Devices.

Asleh R, Alnsasra H, Daly RC, Schettle SD, ... Clavell AL, Kushwaha SS

Background The presence of a durable left ventricular assist device (LVAD) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation (HT). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD. Methods and Results We identified 94 patients who underwent HT after bridging with continuous-flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT. Patients with and without vasoplegia had similar preoperative LVAD, echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; =0.010), longer LVAD support (odds ratio: 1.06 per month; =0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; =0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; =0.044) were independent predictors of vasoplegia. After mean follow-up of 4.0 years after HT, vasoplegia was associated with increased risk of all-cause mortality (hazard ratio: 5.20; 95% CI, 1.71-19.28; =0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.



J Am Heart Assoc: 18 Nov 2019; 8:e013108
Asleh R, Alnsasra H, Daly RC, Schettle SD, ... Clavell AL, Kushwaha SS
J Am Heart Assoc: 18 Nov 2019; 8:e013108 | PMID: 31701791
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Abstract

Left Ventricular Unloading Increases the Coronary Collateral Flow Index Before Reperfusion and Reduces Infarct Size in a Swine Model of Acute Myocardial Infarction.

Briceno N, Annamalai SK, Reyelt L, Crowley P, ... Perera D, Kapur NK

Background Unloading the left ventricle and delaying reperfusion reduces infarct size in preclinical models of acute myocardial infarction. We hypothesized that a potential explanation for this effect is that left ventricular (LV) unloading before reperfusion increases collateral blood flow to ischemic myocardium. Methods and Results Acute myocardial infarction was induced by balloon occlusion of the left anterior descending artery for 120 minutes in adult swine, followed by reperfusion for 180 minutes. After 90 minutes of occlusion, animals were assigned to 30 minutes of continued occlusion (n=6) or to 30 minutes of support with either an Impella CP (n=4) or venoarterial extracorporeal membrane oxygenation (n=5) with persistent occlusion. The primary end point was measures of microcirculatory blood flow including the collateral flow index (CFI) during left anterior descending artery occlusion as (P-RA)/(P-RA), where P, P, and RA are aortic, coronary wedge, and right atrial pressure, respectively. Infarct size was quantified using triphenyltetrazolium chloride. Compared with continued occlusion, Impella, not venoarterial extracorporeal membrane oxygenation, reduced infarct size relative to the area at risk. Before reperfusion, Impella reduced LV stroke work by 25% and increased the CFI by 75%, but venoarterial extracorporeal membrane oxygenation did not. Among all groups, the change in CFI between 90 and 120 minutes correlated inversely with the change in LV stroke work (=0.44, =0.01) and infarct size (=0.41, =0.02). Conclusions We report for the first time that 30 minutes of LV unloading during coronary occlusion increases the CFI, which correlates inversely with LV stroke work and infarct size. Venoarterial extracorporeal membrane oxygenation failed to increase the CFI and did not reduce infarct size.



J Am Heart Assoc: 18 Nov 2019; 8:e013586
Briceno N, Annamalai SK, Reyelt L, Crowley P, ... Perera D, Kapur NK
J Am Heart Assoc: 18 Nov 2019; 8:e013586 | PMID: 31698989
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Abstract

Newly Identified Peptide, Peptide Lv, Promotes Pathological Angiogenesis.

Shi L, Zhao M, Abbey CA, Tsai SH, ... Kuo L, Ko GY

Background We recently discovered a small endogenous peptide, peptide Lv, with the ability to activate vascular endothelial growth factor receptor 2 and its downstream signaling. As vascular endothelial growth factor through vascular endothelial growth factor receptor 2 contributes to normal development, vasodilation, angiogenesis, and pathogenesis of various diseases, we investigated the role of peptide Lv in vasodilation and developmental and pathological angiogenesis in this study. Methods and Results The endothelial cell proliferation, migration, and 3-dimensional sprouting assays were used to test the abilities of peptide Lv in angiogenesis in vitro. The chick chorioallantoic membranes and early postnatal mice were used to examine its impact on developmental angiogenesis. The oxygen-induced retinopathy and laser-induced choroidal neovascularization mouse models were used for in vivo pathological angiogenesis. The isolated porcine retinal and coronary arterioles were used for vasodilation assays. Peptide Lv elicited angiogenesis in vitro and in vivo. Peptide Lv and vascular endothelial growth factor acted synergistically in promoting endothelial cell proliferation. Peptide Lv-elicited vasodilation was not completely dependent on nitric oxide, indicating that peptide Lv had vascular endothelial growth factor receptor 2/nitric oxide-independent targets. An antibody against peptide Lv, anti-Lv, dampened vascular endothelial growth factor-elicited endothelial proliferation and laser-induced vascular leakage and choroidal neovascularization. While the pathological angiogenesis in mouse eyes with oxygen-induced retinopathy was enhanced by exogenous peptide Lv, anti-Lv dampened this process. Furthermore, deletion of peptide Lv in mice significantly decreased pathological neovascularization compared with their wild-type littermates. Conclusions These results demonstrate that peptide Lv plays a significant role in pathological angiogenesis but may be less critical during development. Peptide Lv is involved in pathological angiogenesis through vascular endothelial growth factor receptor 2-dependent and -independent pathways. As anti-Lv dampened the pathological angiogenesis in the eye, anti-Lv may have a therapeutic potential to treat pathological angiogenesis.



J Am Heart Assoc: 18 Nov 2019; 8:e013673
Shi L, Zhao M, Abbey CA, Tsai SH, ... Kuo L, Ko GY
J Am Heart Assoc: 18 Nov 2019; 8:e013673 | PMID: 31698979
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Abstract

Ischemic and Bleeding Risk After Percutaneous Coronary Intervention in Patients With Prior Ischemic and Hemorrhagic Stroke.

Natsuaki M, Morimoto T, Watanabe H, Nakagawa Y, ... Kimura T,

Background Prior stroke is regarded as risk factor for bleeding after percutaneous coronary intervention (PCI). However, there is a paucity of data on detailed bleeding risk of patients with prior hemorrhagic and ischemic strokes after PCI. Methods and Results In a pooled cohort of 19 475 patients from 3 Japanese PCI studies, we assessed the influence of prior hemorrhagic (n=285) or ischemic stroke (n=1773) relative to no-prior stroke (n=17 417) on ischemic and bleeding outcomes after PCI. Cumulative 3-year incidences of the co-primary bleeding end points of intracranial hemorrhage, non-intracranial global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) moderate/severe bleeding, and the primary ischemic end point of ischemic stroke/myocardial infarction were higher in the prior hemorrhagic and ischemic stroke groups than in the no-prior stroke group (6.8%, 2.5%, and 1.3%, <0.0001, 8.8%, 8.0%, and 6.0%, =0.001, and 12.7%, 13.4%, and 7.5%, <0.0001). After adjusting confounders, the excess risks of both prior hemorrhagic and ischemic strokes relative to no-prior stroke remained significant for intracranial hemorrhage (hazard ratio (HR) 4.44, 95% CI 2.64-7.01, <0.0001, and HR 1.52, 95% CI 1.06-2.12, =0.02), but not for non-intracranial bleeding (HR 1.18, 95% CI 0.76-1.73, =0.44, and HR 0.94, 95% CI 0.78-1.13, =0.53). The excess risks of both prior hemorrhagic and ischemic strokes relative to no-prior stroke remained significant for ischemic events mainly driven by the higher risk for ischemic stroke (HR 1.46, 95% CI 1.02-2.01, =0.04, and HR 1.49, 95% CI 1.29-1.72, <0.0001). Conclusions Patients with prior hemorrhagic or ischemic stroke as compared with those with no-prior stroke had higher risk for intracranial hemorrhage and ischemic events, but not for non-intracranial bleeding after PCI.



J Am Heart Assoc: 18 Nov 2019; 8:e013356
Natsuaki M, Morimoto T, Watanabe H, Nakagawa Y, ... Kimura T,
J Am Heart Assoc: 18 Nov 2019; 8:e013356 | PMID: 31701821
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Abstract

Risk of Major Adverse Cardiovascular Events and Major Hemorrhage Among White and Black Patients Undergoing Percutaneous Coronary Intervention.

Cai A, Dillon C, Hillegass WB, Beasley M, ... Prabhu SD, Limdi NA

Background Data on racial disparities in major adverse cardiovascular events (MACE) and major hemorrhage (HEM) after percutaneous coronary intervention are limited. Factors contributing to these disparities are unknown. Methods and Results PRiME-GGAT (Pharmacogenomic Resource to Improve Medication Effectiveness-Genotype-Guided Antiplatelet Therapy) is a prospective cohort. Patients aged ≥18 years undergoing percutaneous coronary intervention were enrolled and followed for up to 1 year. Racial disparities in risk of MACE and HEM were assessed using an incident rate ratio. Sequential cumulative adjustment analyses were performed to identify factors contributing to these disparities. Data from 919 patients were included in the analysis. Compared with white patients, black patients (n=203; 22.1% of the cohort) were younger and were more likely to be female, to be a smoker, and to have higher body mass index, lower socioeconomic status, higher prevalence of diabetes mellitus and moderate to severe chronic kidney disease, and presentation with acute coronary syndrome and to undergo urgent percutaneous coronary intervention. The incident rates of MACE (34.1% versus 18.2% per 100 person-years, <0.001) and HEM (17.7% versus 10.3% per 100 person-years, =0.02) were higher in black patients. The incident rate ratio was 1.9 (95% CI, 1.3-2.6; <0.001) for MACE and 1.7 (95% CI, 1.1-2. 7; =0.02) for HEM. After adjustment for nonclinical and clinical factors, black race was not significantly associated with outcomes. Rather, differences in socioeconomic status, comorbidities, and coronary heart disease severity were attributed to racial disparities in outcomes. Conclusions Despite receiving similar treatment, racial disparities in MACE and HEM still exist. Opportunities exist to narrow these disparities by mitigating the identified contributors.



J Am Heart Assoc: 18 Nov 2019; 8:e012874
Cai A, Dillon C, Hillegass WB, Beasley M, ... Prabhu SD, Limdi NA
J Am Heart Assoc: 18 Nov 2019; 8:e012874 | PMID: 31701784
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Abstract

Is a Hypertension Diagnosis Associated With Improved Dietary Outcomes Within 2 to 4 Years? A Fixed-Effects Analysis From the China Health and Nutrition Survey.

Aburto TC, Gordon-Larsen P, Poti JM, Howard AG, ... Avery CL, Popkin BM

Background Evidence shows that dietary factors play an important role in blood pressure. However, there is no clear understanding of whether hypertension diagnosis is associated with dietary modifications. The aim of this study is to estimate the longitudinal association between hypertension diagnosis and subsequent changes (within 2-4 years) in dietary sodium, potassium, and sodium-potassium (Na/K) ratio. Methods and Results We included adults (18-75 years, n=16 264) from up to 9 waves (1991-2015) of the China Health and Nutrition Survey. Diet data were collected using three 24-hour dietary recalls and a household food inventory. We used fixed-effects models to estimate the association between newly self-reported diagnosed hypertension and subsequent within-individual changes in sodium, potassium, and Na/K ratio. We also examined changes among couples and at the household level. Results suggest that on average, men who were diagnosed with hypertension decreased their sodium intake by 251 mg/d and their Na/K ratio by 0.19 within 2 to 4 years after diagnosis (<0.005). Among spouse pairs, sodium intake and Na/K ratio of women decreased when their husbands were diagnosed (<0.05). Household average sodium density and Na/K ratio decreased, and household average potassium density increased after a man was diagnosed. In contrast, changes were not statistically significant when women were diagnosed. Conclusions Our findings suggest that hypertension diagnosis for a man may result in modest dietary improvements for him, his wife, and other household members. Yet, diagnosis for a woman does not seem to result in dietary changes for her or her household members.



J Am Heart Assoc: 04 Nov 2019; 8:e012703
Aburto TC, Gordon-Larsen P, Poti JM, Howard AG, ... Avery CL, Popkin BM
J Am Heart Assoc: 04 Nov 2019; 8:e012703 | PMID: 31657282
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Abstract

Cost Effectiveness of Assessing Ultrasound Plaque Characteristics to Risk Stratify Asymptomatic Patients With Carotid Stenosis.

Baradaran H, Gupta A, Anzai Y, Mushlin AI, Kamel H, Pandya A

Background Imaging may play an important role in identifying high-risk plaques in patients who have carotid disease and who could benefit from surgical revascularization. We sought to evaluate the cost effectiveness of a decision-making rule based on the ultrasound imaging assessment of plaque echolucency in patients with asymptomatic carotid stenosis. Methods and Results We used a decision-analytic model to project lifetime quality-adjusted life years and costs for 5 stroke prevention strategies: (1) medical therapy only; (2) revascularization ifplaque echolucency and stenosis progression to >90% are present; (3) revascularization only if plaque echolucency is present; (4) revascularization only if stenosis progression >90% is present; or (5) either plaque echolucency or stenosis progression is present. Risks of clinical events, costs, and quality-of-life values were estimated based on published sources and the analysis was conducted from a healthcare system perspective for asymptomatic patients with 70% to 89% carotid stenosis at presentation. Patients who did not undergo revascularization had the highest stroke events (17.6%) and lowest life-years (8.45), while those who underwent revascularization on the basis of either presence of plaque echolucency on ultrasound or progression of carotid stenosis had the lowest stroke events (12.0%) and longest life-years (14.41). Theplaque echolucency or progression-based revascularization group had an incremental cost-effectiveness ratio of $110 000/quality-adjusted life years compared with the plaque echolucency-based strategy, which had an incremental cost-effectiveness ratio of $29 000/quality-adjusted life years compared with the joint echolucency and progression-based strategy. Conclusions Plaque echolucency on ultrasound can be a cost-effective tool to identify patients with asymptomatic carotid artery stenosis most likely to benefit from carotid endarterectomy.



J Am Heart Assoc: 04 Nov 2019; 8:e012739
Baradaran H, Gupta A, Anzai Y, Mushlin AI, Kamel H, Pandya A
J Am Heart Assoc: 04 Nov 2019; 8:e012739 | PMID: 31645165
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Abstract

Thrombocytopenia and Mortality Risk in Patients With Atrial Fibrillation: An Analysis From the START Registry.

Pastori D, Antonucci E, Violi F, Palareti G, ... ,

Background Thrombocytopenia is associated with increased mortality in the general population, but few data exist in patients with atrial fibrillation (AF) taking oral anticoagulants. We investigated factor determinants of thrombocytopenia in a large cohort of patients affected by AF and its association with total mortality. Methods and Results Multicenter prospective cohort study, including 5215 patients with AF from the START (Survey on Anticoagulated Patients Register) registry, 3877 (74.3%) and 1338 (25.7%) on vitamin K or non-vitamin K antagonist oral anticoagulants, respectively. Thrombocytopenia was defined by a platelet count <150×10/L. Determinants of thrombocytopenia were investigated, and all-cause mortality was the primary survival end point of the study. Thrombocytopenia was present in 592 patients (11.4%). At multivariable logistic regression analysis, chronic kidney disease (odds ratio [OR], 1.257; =0.030), active cancer (OR, 2.065; =0.001), liver cirrhosis (OR, 7.635; <0.001), and the use of diuretics (OR, 1.234; =0.046) were positively associated with thrombocytopenia, whereas female sex (OR, 0.387; <0.001) and the use of calcium channel blockers (OR, 0.787; =0.032) were negatively associated. During a median follow-up of 19.2 months (9942 patient-years), 391 deaths occurred (rate, 3.93%/year). Mortality rate increased from 3.8%/year to 9.9%/year in patients with normal platelet count and in those with moderate-severe thrombocytopenia, respectively (log-rank test, =0.009). The association between moderate-severe thrombocytopenia and mortality persisted after adjustment for CHADS VASc score (hazard ratio, 2.431; 95% CI, 1.254-4.713; =0.009), but not in the fully adjusted multivariable Cox regression analysis model. Conclusions Thrombocytopenia is common in patients with AF. Despite an increased incidence of mortality, thrombocytopenia was not associated with mortality at multivariable analysis. Thrombocytopenia may reflect the presence of comorbidities associated with poor survival in AF.



J Am Heart Assoc: 04 Nov 2019; 8:e012596
Pastori D, Antonucci E, Violi F, Palareti G, ... ,
J Am Heart Assoc: 04 Nov 2019; 8:e012596 | PMID: 31656119
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Abstract

Derivation and Validation of a Nomogram to Predict In-Hospital Complications in Children with Tetralogy of Fallot Repaired at an Older Age.

Liu H, Zheng SQ, Li XY, Zeng ZH, ... Liu XC, Shao YF

Background We aimed to develop and validate a prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age. Methods and Results A total of 513 pediatric patients from the Tianjin data set formed a derivation cohort, and 158 pediatric patients from the Hefei and Xiamen data sets formed validation cohorts. We applied least absolute shrinkage and selection operator analysis for variable selection and logistic regression coefficients for risk scoring. We classified patients into different risk categorizations by threshold analysis and investigated the association with in-hospital complications using logistic regression. In-hospital complications were defined as death, need for extensive pharmacologic support (vasoactive-inotrope score of ≥20), and need for mechanical circulatory support. We developed a nomogram based on risk classifier and independent baseline variables using a multivariable logistic model. Based on risk scores weighted by 11 preoperative and 4 intraoperative selected variables, we classified patients as low, intermediate, and high risk in the derivation cohort. With reference to the low-risk group, the intermediate- and high-risk groups conferred significantly higher in-hospital complication risks (adjusted odds ratio: 2.721 [95% CI, 1.267-5.841], =0.0102; 9.297 [95% CI, 4.601-18.786], <0.0001). A nomogram integrating the ARIAR-Risk classifier (absolute and relative low risk, intermediate risk, and aggressive and refractory high risk) with age and mean blood pressure showed good discrimination and goodness-of-fit for derivation (area under the receiver operating characteristic curve: 0.785 [95% CI, 0.731-0.839]; Hosmer-Lemeshow test, =0.544) and external validation (area under the receiver operating characteristic curve: 0.759 [95% CI, 0.636-0.881]; Hosmer-Lemeshow test, =0.508). Conclusions A risk-classifier-oriented nomogram is a reliable prediction model for in-hospital complications in children with tetralogy of Fallot repaired at an older age, and strengthens risk/benefit-based decision-making.



J Am Heart Assoc: 04 Nov 2019; 8:e013388
Liu H, Zheng SQ, Li XY, Zeng ZH, ... Liu XC, Shao YF
J Am Heart Assoc: 04 Nov 2019; 8:e013388 | PMID: 31645167
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Abstract

TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling.

Xu W, Zhang L, Zhang Y, Zhang K, Wu Y, Jin D

Background After acute myocardial infarction, the recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which reduces the efficacy of myocardial reperfusion. Ways to reduce and prevent myocardial ischemia/reperfusion (I/R) injury are of great clinical significance in the treatment of patients with acute myocardial infarction. TRAF1 (tumor necrosis factor receptor-associated factor 1) is an important adapter protein that is implicated in molecular events regulating immunity, inflammation, and cell death. Little is known about the role and impact of TRAF1 in myocardial I/R injury. Methods and Results TRAF1 expression is markedly induced in wild-type mice and cardiomyocytes after I/R or hypoxia/reoxygenation stimulation. I/R models were established in TRAF1 knockout mice and wild type mice (n=10 per group). We demonstrated that TRAF1 deficiency protects against myocardial I/R-induced loss of heat function, inflammation, and cardiomyocyte death. In addition, overexpression of TRAF1 in primary cardiomyocytes promotes hypoxia/reoxygenation-induced inflammation and apoptosis in vitro. Mechanistically, TRAF1 promotes myocardial I/R injury through regulating ASK1 (apoptosis signal-regulating kinase 1)-mediated JNK/p38 (c-Jun N-terminal kinase/p38) MAPK (mitogen-activated protein kinase) cascades. Conclusions Our results indicated that TRAF1 aggravates the development of myocardial I/R injury by enhancing the activation of ASK1-mediated JNK/p38 cascades. Targeting the TRAF1-ASK1-JNK/p38 pathway provide feasible therapies for cardiac I/R injury.



J Am Heart Assoc: 04 Nov 2019; 8:e012575
Xu W, Zhang L, Zhang Y, Zhang K, Wu Y, Jin D
J Am Heart Assoc: 04 Nov 2019; 8:e012575 | PMID: 31650881
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Abstract

Mortality Risk in Acute Ischemic Stroke Patients With Large Vessel Occlusion Treated With Mechanical Thrombectomy.

Katsanos AH, Malhotra K, Goyal N, Palaiodimou L, ... Alexandrov AV, Tsivgoulis G

Background Recent randomized controlled clinical trials have provided solid evidence that mechanical thrombectomy (MT) coupled with best medical therapy (BMT) improve functional outcomes of acute ischemic stroke patients with large vessel occlusion compared with BMT alone. However, they provided inconclusive evidence on the benefit of MT on mortality. Methods and Results We evaluated the association of MT+BMT compared with BMT with the risk of 3-month mortality using aggregate data from all available randomized controlled clinical trials. We also sought to identify potential predictors on the mortality risk and performed univariate meta-regression analyses. Our literature search identified 11 eligible randomized controlled clinical trials, including a total of 2460 patients. The pooled rates of 3-month mortality were 15% (95% CI:12%-19%) and 19% (95% CI:16%-23%), respectively, in the MT+BMT and BMT groups. In the overall analysis MT+BMT was associated with a significantly lower risk for 3-month mortality compared with BMT (risk ratio=0.83, 95% CI:0.69-0.99; =0.04), without heterogeneity across included studies (I=3%,for Cochran Q=0.41). No evidence of publication bias was present in funnel plot inspection and Egger statistical test (=0.762). In meta-regression analyses no moderating effect on the aforementioned association was detected with patient age (=0.254), sex (=0.702), admission systolic blood pressure (=0.601), admission glucose (=0.277), onset-to-groin puncture time (=0.985), administration of intravenous alteplase before MT (=0.804), MT under general anesthesia (=0.735), and successful reperfusion following MT (=0.663). Conclusions Our meta-analysis provides evidence that MT+BMT reduces the risk of 3-month mortality compared with BMT alone. This association appears not to be moderated by individual patient or procedural characteristics.



J Am Heart Assoc: 04 Nov 2019; 8:e014425
Katsanos AH, Malhotra K, Goyal N, Palaiodimou L, ... Alexandrov AV, Tsivgoulis G
J Am Heart Assoc: 04 Nov 2019; 8:e014425 | PMID: 31657277
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Abstract

Identification of Markers Associated With Development of Stroke in \"Clinically Low-Risk\" Atrial Fibrillation Patients.

Shin SY, Han SJ, Kim JS, Im SI, ... Lip GYH, Lim HE

Background Stroke and thromboembolic events may still occur in \"clinically low-risk\" atrial fibrillation (AF) patients as categorized by CHADS-VASc score. Our aim was to assess the proportion of \"clinically low-risk\" patients using a nongender CHADS-VASc (ie, CHADS-VA) score of 0 to 1 among patients who experienced AF-associated stroke and to identify markers associated with stroke in \"clinically low-risk\" patients. Methods and Results We retrospectively recruited nonvalvular AF patients who experienced embolic stroke between 2013 and 2016 from 9 institutes in Korea. AF patients with CHADS-VA score of 0 to 1 at the time of stroke were analyzed and compared with \"clinically low-risk\" AF patients without stroke. A total of 3033 subjects with AF-associated stroke were recruited. Of these, 583 patients (19.2%) had CHADS-VA score of 0 to 1. On multivariate analysis, age (≥60 years), N-terminal pro B-type natriuretic peptide (≥300 pg/mL), creatinine clearance (<50 mL/min), and left atrial dimension (≥45 mm) were independently associated with stroke. With the combined application of these 4 factors (collectively, ABCD score) to the \"clinically low-risk\" patients, the c-index was 0.858 (95% CI 0.838-0.877; <0.001). Conclusions The present study suggests a new insight into how additional use of markers can further refine stroke risk differentiation among AF patients initially classified as \"clinically low-risk.\" Clinical Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03147911.



J Am Heart Assoc: 04 Nov 2019; 8:e012697
Shin SY, Han SJ, Kim JS, Im SI, ... Lip GYH, Lim HE
J Am Heart Assoc: 04 Nov 2019; 8:e012697 | PMID: 31668140
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Abstract

Does Race Influence Decision Making for Advanced Heart Failure Therapies?

Breathett K, Yee E, Pool N, Hebdon M, ... Calhoun E, Sweitzer NK

Background Race influences medical decision making, but its impact on advanced heart failure therapy allocation is unknown. We sought to determine whether patient race influences allocation of advanced heart failure therapies. Methods and Results Members of a national heart failure organization were randomized to clinical vignettes that varied by patient race (black or white man) and were blinded to study objectives. Participants (N=422) completed Likert scale surveys rating factors for advanced therapy allocation and think-aloud interviews (n=44). Survey results were analyzed by least absolute shrinkage and selection operator and multivariable regression to identify factors influencing advanced therapy allocation, including interactions with vignette race and participant demographics. Interviews were analyzed using grounded theory. Surveys revealed no differences in overall racial ratings for advanced therapies. Least absolute shrinkage and selection operator regression selected no interactions between vignette race and clinical factors as important in allocation. However, interactions between participants aged ≥40 years and black vignette negatively influenced heart transplant allocation modestly (-0.58; 95% CI, -1.15 to -0.0002), with adherence and social history the most influential factors. Interviews revealed sequential decision making: forming overall impression, identifying urgency, evaluating prior care appropriateness, anticipating challenges, and evaluating trust while making recommendations. Race influenced each step: avoiding discussing race, believing photographs may contribute to racial bias, believing the black man was sicker compared with the white man, developing greater concern for trust and adherence with the black man, and ultimately offering the white man transplantation and the black man ventricular assist device implantation. Conclusions Black race modestly influenced decision making for heart transplant, particularly during conversations. Because advanced therapy selection meetings are conversations rather than surveys, allocation may be vulnerable to racial bias.



J Am Heart Assoc: 18 Nov 2019; 8:e013592
Breathett K, Yee E, Pool N, Hebdon M, ... Calhoun E, Sweitzer NK
J Am Heart Assoc: 18 Nov 2019; 8:e013592 | PMID: 31707940
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Abstract

Feasibility of Pre-Hospital Resuscitative Endovascular Balloon Occlusion of the Aorta in Non-Traumatic Out-of-Hospital Cardiac Arrest.

Brede JR, Lafrenz T, Klepstad P, Skjærseth EA, ... Søvik E, Krüger AJ

Background Few patients survive after out-of-hospital cardiac arrest and any measure that improve circulation during cardiopulmonary resuscitation is beneficial. Animal studies support that resuscitative endovascular balloon occlusion of the aorta (REBOA) during cardiopulmonary resuscitation might benefit patients suffering from out-of-hospital cardiac arrest, but human data are scarce. Methods and Results We performed an observational study at the helicopter emergency medical service in Trondheim (Norway) to assess the feasibility and safety of establishing REBOA in patients with out-of-hospital cardiac arrest. All patients received advanced cardiac life support during the procedure. End-tidal CO was measured before and after REBOA placement as a proxy measure of central circulation. A safety-monitoring program assessed if the procedure interfered with the quality of advanced cardiac life support. REBOA was initiated in 10 patients. The mean age was 63 years (range 50-74 years) and 7 patients were men. The REBOA procedure was successful in all cases, with 80% success rate on first cannulation attempt. Mean procedural time was 11.7 minutes (SD 3.2, range 8-16). Mean end-tidal CO increased by 1.75 kPa after 60 seconds compared with baseline (<0.001). Six patients achieved return of spontaneous circulation (60%), 3 patients were admitted to hospital, and 1 patient survived past 30 days. The safety-monitoring program identified no negative influence on the advanced cardiac life support quality. Conclusions To our knowledge, this is the first study to demonstrate that REBOA is feasible during non-traumatic out-of-hospital cardiac arrest. The REBOA procedure did not interfere with the quality of the advanced cardiac life support. The significant increase in end-tidal CO after occlusion suggests improved organ circulation during cardiopulmonary resuscitation. Clinical Trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03534011.



J Am Heart Assoc: 18 Nov 2019; 8:e014394
Brede JR, Lafrenz T, Klepstad P, Skjærseth EA, ... Søvik E, Krüger AJ
J Am Heart Assoc: 18 Nov 2019; 8:e014394 | PMID: 31707942
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Abstract

Development and Evaluation of Novel Electronic Medical Record Tools For Avoiding Bleeding After Percutaneous Coronary Intervention.

Ebinger J, Henry T, Kim S, Inkelas M, Cheng S, Nuckols T

Background Bleeding remains the most common complication of percutaneous coronary intervention. Guidelines recommend assessing bleeding risk before percutaneous coronary intervention to target use of bleeding avoidance strategies and mitigate bleeding events. Cedars-Sinai Medical Center undertook an initiative to integrate these recommendations into the electronic medical record. Methods and Results The intervention included a voluntary clinical decision alert to assess bleeding risk before percutaneous coronary intervention, a bleeding risk calculator tool based on the NCDR (National Cardiovascular Data Registry) risk prediction model and, when indicated, a second alert to consider 4 bleeding avoidance strategies. We tested for changes in the use of bleeding avoidance strategies and bleeding event rates by comparing procedures performed before versus after implementation of the electronic medical record-based intervention and with versus without use of the bleeding risk calculator tool. Use of radial access increased (47.6% versus 64.8%; <0.001) and glycoprotein IIb/IIIa inhibitors decreased (12.8% versus 3.17%; <0.001) from before to after implementation, though risk-adjusted bleeding event rates were stable (odds ratio, 0.82; =0.164), even for high-risk procedures. Use versus nonuse of the bleeding risk calculator tool was associated with increased radial access and reductions in glycoprotein IIb/IIIa inhibitors, but no change in bleeding events. Conclusions Integrating guideline recommendations into the electronic medical record to promote assessments of bleeding risk and use of bleeding avoidance strategies was feasible and associated with changes in clinical practice. Future work is needed to ensure that bleeding avoidance strategies are not overused among lower-risk patients, and that, for high-risk patients, the potential benefits of elective percutaneous coronary intervention are carefully weighed against the risk of bleeding.



J Am Heart Assoc: 18 Nov 2019; 8:e013954
Ebinger J, Henry T, Kim S, Inkelas M, Cheng S, Nuckols T
J Am Heart Assoc: 18 Nov 2019; 8:e013954 | PMID: 31707946
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Abstract

Effects of Race on Statin Prescribing for Primary Prevention With High Atherosclerotic Cardiovascular Disease Risk in a Large Healthcare System.

Dorsch MP, Lester CA, Ding Y, Joseph M, Brook RD

Background Although guidelines recommend statins with a high level of evidence for 4 primary prevention benefit groups, prescribing disparities still exist. The objective of this study was to evaluate the effects of race on statin prescribing for primary prevention. Methods and Results A retrospective cohort analysis of patients within a large academic health system was performed to investigate statin prescribing among primary prevention groups. The statin benefits groups were patients diagnosed with diabetes mellitus, with an low-density lipoprotein ≥190 mg/dL, or with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk ≥7.5%. Statin prescribing was 20% in the ASCVD ≥7.5% group, followed by 37.8% in the low-density lipoprotein ≥190 mg/dL group and 40.5% in the diabetes mellitus group. Blacks were less likely to be prescribed a statin compared with whites in the diabetes mellitus (odds ratio, 0.64; 95% CI, 0.49-0.82; =0.001) and ASCVD ≥7.5% groups (odds ratio, 0.38; 95% CI, 0.26-0.54; <0.0001). Blacks 60 to 69 years of age (odds ratio, 7.97; 95% CI, 3.14-20.2; =0.003) and 70 to 79 years of age (odds ratio, 4.21; 95% CI, 1.81-9.79; =0.008) were more likely to be prescribed a statin compared with blacks <60 years of age in the ASCVD ≥7.5% group. Conclusions Blacks are less likely to be prescribed statins in diabetes mellitus and ASCVD ≥7.5% groups compared with whites. Younger blacks with ASCVD risk ≥7.5% are less likely to be prescribed statins compared with older blacks. Future research should focus on tailored interventions to address statin prescribing disparities in blacks.



J Am Heart Assoc: 18 Nov 2019; 8:e014709
Dorsch MP, Lester CA, Ding Y, Joseph M, Brook RD
J Am Heart Assoc: 18 Nov 2019; 8:e014709 | PMID: 31707943
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Abstract

Pacemaker Implantation and Dependency After Transcatheter Aortic Valve Replacement in the REPRISE III Trial.

Meduri CU, Kereiakes DJ, Rajagopal V, Makkar RR, ... Feldman TE, Reardon MJ

Background As transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long-term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve. Methods and Results A total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System-Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre-specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent. Conclusions Pacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker. Clinical Trial registration URL: https://www.clinicaltrials.gov/. Unique identifier NCT02202434.



J Am Heart Assoc: 04 Nov 2019; 8:e012594
Meduri CU, Kereiakes DJ, Rajagopal V, Makkar RR, ... Feldman TE, Reardon MJ
J Am Heart Assoc: 04 Nov 2019; 8:e012594 | PMID: 31640455
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Abstract

Comparisons of Rivaroxaban Following Different Dosage Criteria (ROCKET AF or J-ROCKET AF Trials) in Asian Patients With Atrial Fibrillation.

Chan YH, Lee HF, Wang CL, Chang SH, ... Chen SA, Kuo CT

Background The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) evaluated rivaroxaban (20/15 mg/d) versus warfarin in patients with atrial fibrillation. A separate trial, J-ROCKET AF (Japanese ROCKET AF), compared rivaroxaban (15/10 mg/d) and warfarin in Japanese patients with atrial fibrillation. Data about rivaroxaban following J-ROCKET AF criteria compared with warfarin and ROCKET AF dosage were limited. Methods and Results This retrospective study used medical data from a multicenter healthcare provider in Taiwan that included 3162 patients taking rivaroxaban. Among 2320 patients with an estimated glomerular filtration rate (eGFR) ≥50 mL/min per 1.73 m, 384 and 1936 patients followed the ROCKET AF (20 mg/d) and J-ROCKET AF (15 mg/d) recommendation, respectively. Among 842 patients with an eGFR <50 mL/min per 1.73 m, 422 and 420 patients followed the ROCKET AF (15 mg/d) and J-ROCKET AF (10 mg/d) recommendation, respectively. A total of 2053 patients with atrial fibrillation receiving warfarin were identified. Rivaroxaban following either ROCKET AF or J-ROCKET AF dosage criteria was associated with a comparable risk of thromboembolism but a lower risk of bleeding than warfarin. For patients with an eGFR ≥50 mL/min per 1.73 m, risks of clinical events did not differ significantly between the 2 dosage criteria of rivaroxaban. For patients with an eGFR <50 mL/min per 1.73 m, the ROCKET AF dosage was associated with a higher risk of major bleeding compared with the J-ROCKET AF dosage (hazard ratio, 2.70; =0.0445) without significant differences regarding the risk of ischemic events. Conclusions In Asian patients with atrial fibrillation, the J-ROCKET AF dosage was as effective as the ROCKET AF dosage irrespective of renal function. The risk of major bleeding was lower with the J-ROCKET AF dosage in patients with an eGFR <50 mL/min per 1.73 m. Compared with warfarin, rivaroxaban following either dosage criteria was effective and even safer.



J Am Heart Assoc: 04 Nov 2019; 8:e013053
Chan YH, Lee HF, Wang CL, Chang SH, ... Chen SA, Kuo CT
J Am Heart Assoc: 04 Nov 2019; 8:e013053 | PMID: 31623498
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Abstract

Prevalence and Clinical Correlates of Poststroke Behavioral Dysexecutive Syndrome.

Tang WK, Lau CG, Liang Y, Wang L, ... Uchiyama S, Kim JS

Background Behavioral dysexecutive syndrome (BDES) is a common phenomenon following stroke. To date, research has focused mainly on individual behavioral symptoms rather than a more comprehensive characterization of goal-directed behavior in stroke survivors. This cross-sectional study evaluated the prevalence and clinical correlates of BDES in Hong Kong stroke survivors. Methods and Results A total of 369 stroke survivors were recruited from a regional hospital at 3 months after their index stroke. Patients\' demographic and clinical characteristics were extracted from a comprehensive stroke database. BDES was measured with the Chinese version of the Dysexecutive Questionnaire. Four neurocognitive batteries assessed domains of cognitive executive functions. The prevalence of BDES 3 months poststroke was 18.7%. At that time point, the Hospital Anxiety Depression Scale and Mini-Mental State Examination scores and the presence of depression were significant predictors of BDES in a multivariate logistic regression analysis. These parameters remained significant predictors of the Dysexecutive Questionnaire score in a linear stepwise regression analysis and together accounted for 28.5% of the variance. Current depression was predictive of the Dysexecutive Questionnaire score in patients with BDES, with a variance of 9.7%. Furthermore, compared with the non-BDES group, patients with BDES exhibited poor performance-based executive function in the Chinese version of the Frontal Assessment Battery and color trails, arrow, and category fluency tests. Conclusions Symptoms of anxiety, current depression, and global cognitive function may be independent predictors of the presence and severity of BDES 3 months poststroke. Stroke survivors with BDES exhibit poor executive functioning, including goal maintenance and semantic memory.



J Am Heart Assoc: 18 Nov 2019; 8:e013448
Tang WK, Lau CG, Liang Y, Wang L, ... Uchiyama S, Kim JS
J Am Heart Assoc: 18 Nov 2019; 8:e013448 | PMID: 31694442
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Abstract

Discretionary Thrombophilia Test Acquisition and Outcomes in Patients With Venous Thromboembolism in a Real-World Clinical Setting.

Kozak PM, Xu M, Farber-Eger E, Gailani D, Wells QS, Beckman JA

Background The value of thrombophilia test acquisition in improving risk prediction beyond clinical presentation remains unknown. We investigated the effect of thrombophilia test acquisition on venous thromboembolism (VTE) outcomes. Methods and Results We performed a retrospective cohort study of adult patients over a 15-year period (September 2001 and May 2016) with first diagnosis of VTE in a single academic medical center. Participants were identified by(),() codes and medication history. Participants with thrombophilia testing were matched to control participants without thrombophilia testing using a propensity model. Primary outcomes included recurrent VTE, anticoagulant use 12 months after the index VTE event, bleeding-related hospitalization, and death. From 3590 unique patients who met the inclusion criteria, 747 participants with VTE who underwent thrombophilia testing were matched to a control participant without testing. Tested participants were more likely to have a recurrent event (46.1% versus 28.5%; <0.001) and an anticoagulant prescription 12 months from the index event (53.9% versus 37.1%; <0.001) but had no significant difference in bleeding-related hospitalization (11.4% versus 11.8%; =0.81) compared with untested participants. An abnormal thrombophilia test result, per se, did not predict recurrent VTE (47.8% versus 44.1%; =0.13), longer duration anticoagulation (53.2% versus 54.8%; =0.51), bleeding (11.5% versus 11.3%; =0.70), or mortality (12.2% versus 16.1%; =0.18) compared with participants who had normal test results. Conclusions The decision to perform thrombophilia testing, but not the test result, is associated with a high risk of recurrent VTE despite a greater likelihood of long-duration anticoagulation.



J Am Heart Assoc: 18 Nov 2019; 8:e013395
Kozak PM, Xu M, Farber-Eger E, Gailani D, Wells QS, Beckman JA
J Am Heart Assoc: 18 Nov 2019; 8:e013395 | PMID: 31696751
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Abstract

Prevalence and Impact of Venous and Arterial Thromboembolism in Patients With Embolic Stroke of Undetermined Source With or Without Active Cancer.

Ha J, Lee MJ, Kim SJ, Park BY, ... Bang OY, Chung CS

Background An increased risk of acute ischemic stroke is recognized among patients with cancer. However, the mechanism behind cancer-related stroke is unclear. In this study, we determined the presence of associated venous thromboembolism and arterial thromboembolism and their clinical impact on patients with cancer-related stroke. Methods and Results Patients with embolic stroke of undetermined source with or without cancer were evaluated for venous thromboembolism (deep vein thrombosis [DVT] and/or pulmonary embolism) and arterial thromboembolism by using Doppler sonography to determine the presence of lower-extremity DVT and the microembolic signal of the symptomatic cerebral circulation, respectively. Infarct volume was determined by diffusion-weighted magnetic resonance imaging. The multivariable linear regression and Cox proportional hazard analysis were used to investigate the effect of DVT and microembolic signal on infarct volume and 1-year survival, respectively. Of 142 screened patients, 118 were included (37 with, 81 without cancer). Those with cancer had a higher prevalence of DVT or microembolic signal than did the noncancer group (62.2% versus 19.8%; <0.001). Among patients with cancer-related stroke, DVT was associated with a greater infarct volume in magnetic resonance imaging (beta, 13.14; 95% CI, 1.62-24.66; =0.028). Presence of DVT (hazard ratio, 16.79; 95% CI, 2.05-137.75; =0.009) and microembolic signal (hazard ratio, 8.16; 95% CI, 1.36-48.85; =0.022) were independent predictors of poor 1-year survival. Conclusions Patients with cancer-associated embolic stroke of undetermined source have an elevated risk of associated venous thromboembolism and arterial thromboembolism, both of which have a significant negative impact on 1-year survival. The results of this study may enhance our understanding of cancer-associated stroke and improve risk stratification of patients with this disease. Clinical Trial registration URL: https://www.clinicaltrials.gov/.Unique identifier: NCT02212496.



J Am Heart Assoc: 04 Nov 2019; 8:e013215
Ha J, Lee MJ, Kim SJ, Park BY, ... Bang OY, Chung CS
J Am Heart Assoc: 04 Nov 2019; 8:e013215 | PMID: 31640456
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Abstract

Effect of the Number of Neurointerventionalists on Off-Hour Endovascular Therapy for Acute Ischemic Stroke Within 12 Hours of Symptom Onset.

Kim JG, Choi JC, Kim DJ, Bae HJ, ... ,

Background Off-hour presentation can affect treatment delay and clinical outcomes in endovascular therapy (EVT) for acute ischemic stroke. We aimed to examine the treatment delays and clinical outcomes of EVT between on- and off-hour admission and to evaluate the effect of hospital procedure volume and the number of neurointerventionalists on off-hour EVT. Methods and Results From a multicenter registry, we identified patients who were treated with EVT within 12 hours of symptom. Annual hospital procedure volume was divided as low (<30), medium (30-60), and high (>60). The effect of the number of neurointerventionalists and annual hospital procedure volume on clinical outcome was estimated by the generalized estimation equation. Of the 31 133 stroke patients, 1564 patients met the eligibility criteria (mean age: 69±12 years; median baseline National Institutes of Health stroke scale score, 15 [interquartile range, 10-19]). Of 1564 patients, 893 (57.1%) arrived during off-hour. The off-hour patients had greater median door-to-puncture time (110  versus 95 minutes; <0.001) compared with on-hour patients. Despite the treatment delay, the functional outcome at 3 months did not differ between off- and on-hour (odds ratio with 95% CI for 3-month modified Rankin Scale 0-2, 0.99 [0.78-1.25]; =0.90). The presence of three neurointerventionalists was significantly associated with favorable outcomes at 3 months during on- and off-hour (2.07 [1.53-2.81]; <0.001). The association was not observed for annual hospital procedural volume and the functional outcomes. Conclusions The number of neurointerventionalists was more crucial to effective around-the-clock EVT for acute stroke patients than hospital procedural volume.



J Am Heart Assoc: 04 Nov 2019; 8:e011933
Kim JG, Choi JC, Kim DJ, Bae HJ, ... ,
J Am Heart Assoc: 04 Nov 2019; 8:e011933 | PMID: 31625423
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Abstract

CTRP9 Ameliorates Atrial Inflammation, Fibrosis, and Vulnerability to Atrial Fibrillation in Post-Myocardial Infarction Rats.

Liu M, Li W, Wang H, Yin L, ... Tang Y, Huang C

Background Inflammation and fibrosis play an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). CTRP9 (C1q/tumor necrosis factor-related protein-9) as a secreted glycoprotein can reverse left ventricle remodeling post-MI, but its effects on MI-induced atrial inflammation, fibrosis, and associated AF are unknown. Methods and Results MI model rats received adenoviral supplementation of CTRP9 (Ad-CTRP9) by jugular-vein injection. Cardiac function, inflammatory, and fibrotic indexes and related signaling pathways, electrophysiological properties, and AF inducibility of atria in vivo and ex vivo were detected in 3 or 7 days after MI. shCTRP9 (short hairpin CTRP9) and shRNA were injected into rat and performed similar detection at day 5 or 10. Adverse atrial inflammation and fibrosis, cardiac dysfunction were induced in both MI and Ad-GFP (adenovirus-encoding green fluorescent protein)+MI rats. Systemic CTRP9 treatment improved cardiac dysfunction post-MI. CTRP9 markedly ameliorated macrophage infiltration and attenuated the inflammatory responses by downregulating interleukin-1β and interleukin-6, and upregulating interleukin-10, in 3 days post-MI; depressed left atrial fibrosis by decreasing the expressions of collagen types I and III, α-SMA, and transforming growth factor β1 in 7 days post-MI possibly through depressing the Toll-like receptor 4/nuclear factor-κB and Smad2/3 signaling pathways. Electrophysiologic recordings showed that increased AF inducibility and duration, and prolongation of interatrial conduction time induced by MI were attenuated by CTRP9; moreover, CTRP9 was negatively correlated with interleukin-1β and AF duration. Downregulation of CTRP9 aggravated atrial inflammation, fibrosis, susceptibility of AF and prolonged interatrial conduction time, without affecting cardiac function. Conclusions CTRP9 is effective at attenuating atrial inflammation and fibrosis, possibly via its inhibitory effects on the Toll-like receptor 4/nuclear factor-κB and Smad2/3 signaling pathways, and may be an original upstream therapy for AF in early phase of MI.



J Am Heart Assoc: 04 Nov 2019; 8:e013133
Liu M, Li W, Wang H, Yin L, ... Tang Y, Huang C
J Am Heart Assoc: 04 Nov 2019; 8:e013133 | PMID: 31623508
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Abstract

Incremental Value of Computed Tomography Perfusion for Final Infarct Prediction in Acute Ischemic Cerebellar Stroke.

Fabritius MP, Reidler P, Froelich MF, Rotkopf LT, ... Puhr-Westerheide D, Kunz WG

Background The diagnosis of ischemic cerebellar stroke is challenging because of nonspecific symptoms and very limited accuracy of commonly applied computed tomography (CT) imaging. Advances in CT perfusion imaging provide increasing value in the detection of posterior circulation stroke, but the prognostic value remains unclear. We aimed to identify imaging parameters that predict morphologic outcome in cerebellar stroke patients using advanced CT including whole-brain CT perfusion (WB-CTP). Methods and Results We selected all subjects with cerebellar WB-CTP perfusion deficits and follow-up-confirmed cerebellar infarction from a consecutive cohort with suspected stroke who underwent WB-CTP. Posterior-circulation-Acute-Stroke-Prognosis-Early-CT-Score (pc-ASPECTS) was determined on noncontrast CT, CT angiography source images, and on parametric WB-CTP maps. Cerebellar perfusion deficit volumes on all maps and the final infarction volume on follow-up imaging were quantified. Uni- and multivariate regression analyses were performed. Sixty patients fulfilled the inclusion criteria. pc-ASPECTS on CT angiography source images (ß, -9.239; 95% CI, -14.220 to -4.259; <0.001) and cerebral blood flow deficit volume (ß, 0.886; 95% CI, 0.684 to 1.089; <0.001) were significantly associated with final infarction volume in univariate linear regression analysis. The association of cerebral blood flow deficit volume (ß, 0.830; 95% CI, 0.605-1.055; <0.001) was confirmed in a multivariate linear regression model adjusted for age, sex, pc-ASPECTS on noncontrast CT, and CT angiography source images and the National Institutes of Health Stroke Scale score on admission. No other clinical or imaging parameters were associated with cerebellar stroke final infarction volume (>0.05). Conclusions In contrast to noncontrast CT and CT angiography, WB-CTP imaging contains prognostic information for morphologic outcome in patients with acute cerebellar stroke.



J Am Heart Assoc: 04 Nov 2019; 8:e013069
Fabritius MP, Reidler P, Froelich MF, Rotkopf LT, ... Puhr-Westerheide D, Kunz WG
J Am Heart Assoc: 04 Nov 2019; 8:e013069 | PMID: 31631729
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Abstract

Novel Screening Method Identifies PI3Kα, mTOR, and IGF1R as Key Kinases Regulating Cardiomyocyte Survival.

Elmadani M, Khan S, Tenhunen O, Magga J, ... Wennerberg K, Kerkelä R

Background Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for methods to predict their cardiotoxicity. Here, we utilized a novel computational method to identify protein kinases crucial for cardiomyocyte viability. Methods and Results One hundred forty KIs were screened for their toxicity in cultured neonatal cardiomyocytes. The kinase targets of KIs were determined based on integrated data from binding assays. The key kinases mediating the toxicity of KIs to cardiomyocytes were identified by using a novel machine learning method for target deconvolution that combines the information from the toxicity screen and from the kinase profiling assays. The top kinases identified by the model were phosphoinositide 3-kinase catalytic subunit alpha, mammalian target of rapamycin, and insulin-like growth factor 1 receptor. Knockdown of the individual kinases in cardiomyocytes confirmed their role in regulating cardiomyocyte viability. Conclusions Combining the data from analysis of KI toxicity on cardiomyocytes and KI target profiling provides a novel method to predict cardiomyocyte toxicity of KIs.



J Am Heart Assoc: 04 Nov 2019; 8:e013018
Elmadani M, Khan S, Tenhunen O, Magga J, ... Wennerberg K, Kerkelä R
J Am Heart Assoc: 04 Nov 2019; 8:e013018 | PMID: 31617439
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Abstract

Comparison of Urinary Sodium and Blood Pressure Relationship From the Spot Versus 24-Hour Urine Samples.

Naser AM, Rahman M, Unicomb L, Doza S, ... Clasen TF, Narayan KMV

Background We compared the relationship between sodium (Na) intake and blood pressure when Na intake was estimated from first- and second-morning spot urine samples using the INTERSALT (International Study on Salt and Blood Pressure) formula, versus directly measured 24-hour samples. Methods and Results We collected 24-hour urine and first- and second-morning voids of 383 participants in coastal Bangladesh for 2 visits. We measured participants\' blood pressure using an Omron HEM-907 monitor. To assess the shape of the relationship between urinary Na and blood pressure, we created restricted cubic spline plots adjusted for age, sex, body mass index, smoking and alcohol consumption, physical activities, religion, sleep hours, and household wealth. To assess multicollinearity, we reported variance inflation factors, tolerances, and Leamer\'s and Klein\'s statistics following linear regression models. The mean daily urinary Na was 122 (SD 26) mmol/d for the first; 122 (SD 27) mmol/d for the second; and 134 (SD 70) mmol/d for the 24-hour samples. The restricted cubic spline plots illustrated no association between first-morning urinary Na and systolic blood pressure until the 90th percentile distribution followed by a downward relationship; a nonlinear inverse-V-shaped relationship between second-morning urinary Na and systolic blood pressure; and a monotonic upward relationship between 24-hour urinary Na and systolic blood pressure. We found no evidence of multicollinearity for the 24-hour urinary Na model. Conclusions The urinary Na and systolic blood pressure relationship varied for 3 urinary Na measurements. Twenty-four-hour urinary Na captured more variability of Na intake compared with spot urine samples, and its regression models were not affected by multicollinearity.



J Am Heart Assoc: 04 Nov 2019; 8:e013287
Naser AM, Rahman M, Unicomb L, Doza S, ... Clasen TF, Narayan KMV
J Am Heart Assoc: 04 Nov 2019; 8:e013287 | PMID: 31615314
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Abstract

Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality.

Chowdhury EK, Nelson MR, Wing LMH, Jennings GLR, ... ,

Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long-term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24-hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow-up). Weighted day-night systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates asandbased on the baseline median BPV value and then classified BPV changes into , , , and . We observed an annual decline (mean±SD: -0.37±1.95; 95% CI, -0.54 to -0.19; <0.001) in weighted day-night systolic BPV between baseline and follow-up. Having constant stable: high BPV was associated with an increase in all-cause mortality (hazard ratio: 3.03; 95% CI, 1.67-5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62-8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow-up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow-up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long-term mortality.



J Am Heart Assoc: 04 Nov 2019; 8:e012630
Chowdhury EK, Nelson MR, Wing LMH, Jennings GLR, ... ,
J Am Heart Assoc: 04 Nov 2019; 8:e012630 | PMID: 31679444
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Association Between High Perceived Stress Over Time and Incident Hypertension in Black Adults: Findings From the Jackson Heart Study.

Spruill TM, Butler MJ, Thomas SJ, Tajeu GS, ... Sims M, Shimbo D

Background Chronic psychological stress has been associated with hypertension, but few studies have examined this relationship in blacks. We examined the association between perceived stress levels assessed annually for up to 13 years and incident hypertension in the Jackson Heart Study, a community-based cohort of blacks. Methods and Results Analyses included 1829 participants without hypertension at baseline (Exam 1, 2000-2004). Incident hypertension was defined as blood pressure≥140/90 mm Hg or antihypertensive medication use at Exam 2 (2005-2008) or Exam 3 (2009-2012). Each follow-up interval at risk of hypertension was categorized as low, moderate, or high perceived stress based on the number of annual assessments between exams in which participants reported \"a lot\" or \"extreme\" stress over the previous year (low, 0 high stress ratings; moderate, 1 high stress rating; high, ≥2 high stress ratings). During follow-up (median, 7.0 years), hypertension incidence was 48.5%. Hypertension developed in 30.6% of intervals with low perceived stress, 34.6% of intervals with moderate perceived stress, and 38.2% of intervals with high perceived stress. Age-, sex-, and time-adjusted risk ratios (95% CI) associated with moderate and high perceived stress versus low perceived stress were 1.19 (1.04-1.37) and 1.37 (1.20-1.57), respectively ( trend<0.001). The association was present after adjustment for demographic, clinical, and behavioral factors and baseline stress ( trend=0.001). Conclusions In a community-based cohort of blacks, higher perceived stress over time was associated with an increased risk of developing hypertension. Evaluating stress levels over time and intervening when high perceived stress is persistent may reduce hypertension risk.



J Am Heart Assoc: 04 Nov 2019; 8:e012139
Spruill TM, Butler MJ, Thomas SJ, Tajeu GS, ... Sims M, Shimbo D
J Am Heart Assoc: 04 Nov 2019; 8:e012139 | PMID: 31615321
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Abstract

Use of Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) and Ischemic Core Volume to Determine the Malignant Profile in Acute Stroke.

Yoshimoto T, Inoue M, Yamagami H, Fujita K, ... Ihara M, Toyoda K

Background Malignant profiles were identified by imaging profiles and unfavorable outcomes that have poor response to reperfusion therapy. Many trials have used this profile in their inclusion criteria including large-vessel occlusion acute ischemic stroke trials. We aimed to redefine the cutoff values for malignant profile in acute ischemic stroke patients with large-vessel occlusion regardless of reperfusion therapy. Methods and Results Consecutive acute ischemic stroke patients with anterior large-vessel occlusion were prospectively extracted from the National Cerebral and Cardiovascular Center Stroke Registry between March 2014 and December 2017. Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) and diffusion-weighted imaging lesion ischemic core volume (Vol) were measured in acute ischemic stroke patients with large-vessel occlusion with or without treatment. Unfavorable outcome was defined as a modified Rankin Scale score 5 to 6 at 3 months, and optimal DWI-ASPECTS and Vol for unfavorable outcome were assessed. In total, 198 patients (111 men, 77±13 years old) were enrolled. Median DWI-ASPECTS was 7 (5-9), and median Vol was 55 (6-134) mL. Among the patients, 72 (36%) patients underwent reperfusion therapy, and 83 (42%) had unfavorable outcomes. The threshold values for a malignant profile on receiver operating characteristic curve analysis for DWI-ASPECTS and Vol were 4 (area under the curve 0.78, <0.01; sensitivity 0.71, specificity 0.75) and 71 mL (area under the curve 0.80, <0.01; sensitivity 0.76, specificity 0.77), respectively. Conclusions The cutoff values for our redefined malignant profile were DWI-ASPECTS 4 and Vol 71 mL with no selection bias for reperfusion therapy in the real-world clinical practice. Clinical Trial registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02251665.



J Am Heart Assoc: 18 Nov 2019; 8:e012558
Yoshimoto T, Inoue M, Yamagami H, Fujita K, ... Ihara M, Toyoda K
J Am Heart Assoc: 18 Nov 2019; 8:e012558 | PMID: 31698986
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Abstract

Determinants of Patient and Surrogate Experiences With Acute Care Research Consent: A Key Informant Interview Study.

Scicluna VM, Goldkind SF, Mitchell AR, Pentz RD, ... Silbergleit R, Dickert NW

Background Informed consent for acute myocardial infarction and stroke research is challenging. Time for enrollment decisions is limited, patients and family are usually stressed, and being asked to participate in research is often unexpected. Despite these barriers, patients and surrogates have reported a preference for prospective involvement in research decisions and generally positive views of the consent process. It is unknown what drives positive or negative consent experiences. These data are crucial to making consent processes more context appropriate. Methods and Results We conducted a qualitative interview study with 27 patients and surrogates enrolled in acute myocardial infarction and stroke trials in the past 5 years. Purposive sampling from the P-CARE (Patient-Centered Approaches to Research Enrollment) study was based on participant characteristics and responses to initial patient-centered interviews. In-depth interviews used open-ended questions to explore factors influencing consent experiences. Qualitative descriptive analysis was performed utilizing a multilevel coding strategy. Participants identified specific researcher behaviors as important, including expressions of respect, professionalism, and nonpressuring communication. Participants preferred consent conversations focused on risks/benefits and the trial protocol. They had varying views of consent forms and communicated several reasons the form was valuable unrelated to informational content. Participants also valued postenrollment interactions as opportunities to ask questions and learn about the study. Conclusions Barriers to consent in acute myocardial infarction and stroke trials are unavoidable, but participants identified productive ways to demonstrate respect for patients during enrollment conversations. These include key researcher behaviors, concentrating consent discussions on what participants find most important, and structured postenrollment follow-up.



J Am Heart Assoc: 18 Nov 2019; 8:e012599
Scicluna VM, Goldkind SF, Mitchell AR, Pentz RD, ... Silbergleit R, Dickert NW
J Am Heart Assoc: 18 Nov 2019; 8:e012599 | PMID: 31698980
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Abstract

Improved Biomarker and Imaging Analysis for Characterizing Progressive Cardiac Fibrosis in a Mouse Model of Chronic Chagasic Cardiomyopathy.

Hoffman KA, Reynolds C, Bottazzi ME, Hotez P, Jones K

Background Chronic chagasic cardiomyopathy (CCC), caused byinfection, is an important public health problem attributable to progressive cardiomyopathy in patients, for which there is no cure. Chronic chagasic cardiomyopathy is characterized by myocarditis and cardiac fibrosis, which leads to life-threatening arrhythmogenic and circulatory abnormalities. This study aimed to investigate cardiac fibrosis progression in a mouse model of chronic chagasic cardiomyopathy. Methods and Results Cardiac cells infected withproduced significantly higher concentrations of transforming growth factor-β (TGF-β), connective tissue growth factor, endothelin-1, and platelet-derived growth factor-D than noninfected controls. Female Balb/c mice infected withwere compared with naïve mice. TGF-β genes and other TGF-β superfamily genes, as well as connective tissue growth factor, endothelin-1, and platelet-derived growth factor, were upregulated in infected mouse hearts. Serum concentrations of TGF-β, connective tissue growth factor, and platelet-derived growth factor-D were higher in infected mice and correlated with cardiac fibrosis. Strain analysis performed on magnetic resonance images at 111 and 140 days postinfection and echocardiography images at 212 days postinfection revealed significantly elevated left ventricular strain and cardiac fibrosis and concomitantly significantly decreased cardiac output in infected mice. Conclusions TGF-β, connective tissue growth factor and platelet-derived growth factor-D are potentially useful biomarkers of cardiac fibrosis, as they correlate with cardiac fibrosis. Strain analysis allows for use of noninvasive methods to measure fibrosis in the chronic stages of chagasic cardiomyopathy in a mouse model. These findings can be applied as noninvasive tools to study the effects of interventions and/or therapeutics on cardiac fibrosis development when using a mouse model of chronic chagasic cardiomyopathy.



J Am Heart Assoc: 18 Nov 2019; 8:e013365
Hoffman KA, Reynolds C, Bottazzi ME, Hotez P, Jones K
J Am Heart Assoc: 18 Nov 2019; 8:e013365 | PMID: 31718442
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Abstract

Effects of Mineralocorticoid Receptor Antagonists on Atrial Fibrillation Occurrence: A Systematic Review, Meta-Analysis, and Meta-Regression to Identify Modifying Factors.

Alexandre J, Dolladille C, Douesnel L, Font J, ... Parienti JJ, Milliez P

Background Mineralocorticoid receptor antagonists (MRAs) have emerged as potential atrial fibrillation (AF) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRAs on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRAs on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta-analyses to compute odds ratios with 95% CIs. Meta-regression was then applied to explore the sources of between-study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow-up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta-analyses showed a significant overall reduction in AF occurrence in the MRA-treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI, 0.44-0.70 [<0.00001]), with the greatest benefit regarding recurrent AF episodes (odds ratio, 0.42; 95% CI, 0.31-0.59 [<0.00001]) and with significant heterogeneity among the included studies (=54%; =0.0008). Meta-regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRAs seem to be effective in AF prevention, especially regarding recurrent AF episodes.



J Am Heart Assoc: 18 Nov 2019; 8:e013267
Alexandre J, Dolladille C, Douesnel L, Font J, ... Parienti JJ, Milliez P
J Am Heart Assoc: 18 Nov 2019; 8:e013267 | PMID: 31711383
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Abstract

Cardiomyocyte-Specific Prevents Inflammation in the Heart.

Thirugnanam K, Cossette SM, Lu Q, Chowdhury SR, ... Zou MH, Ramchandran R

Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed incardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out forin cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out forin endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased inknockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out forin CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2 macrophages was observed in basal and Ang II-infused states. In vitro analysis ofknockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline inknockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.



J Am Heart Assoc: 18 Nov 2019; 8:e012792
Thirugnanam K, Cossette SM, Lu Q, Chowdhury SR, ... Zou MH, Ramchandran R
J Am Heart Assoc: 18 Nov 2019; 8:e012792 | PMID: 31718444
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Abstract

Real-World Associations of Renin-Angiotensin-Aldosterone System Inhibitor Dose, Hyperkalemia, and Adverse Clinical Outcomes in a Cohort of Patients With New-Onset Chronic Kidney Disease or Heart Failure in the United Kingdom.

Linde C, Bakhai A, Furuland H, Evans M, ... Ayoubkhani D, Qin L

Background Dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real-world associations of RAASi dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAASi-prescribed patients with new-onset chronic kidney disease (n=100 572) or heart failure (n=13 113) first recorded between January 2006 and December 2015 in Clinical Practice Research Datalink and linked Hospital Episode Statistics databases. Odds ratios associating hyperkalemia and RAASi dose modification were estimated using logistic generalized estimating equations with normal (<5.0 mmol/L) serum potassium level as the reference category. Patients with serum potassium ≥5.0 mmol/L had higher risk of RAASi down-titration (adjusted odds ratios, chronic kidney disease: 1.79 [95% CI, 1.64-1.96]; heart failure: 1.33 [95% CI, 1.08-1.62]). Poisson models were used to estimate adjusted incident rate ratios of adverse outcomes based on total RAASi exposure (<50% and ≥50% of the guideline-recommended RAASi dose). Incidence of major adverse cardiac events and mortality was consistently higher in the lower dose group (adjusted incident rate ratios: chronic kidney disease: 5.60 [95% CI, 5.29-5.93] for mortality and 1.60 [95% CI, 1.55-1.66] for nonfatal major adverse cardiac events; heart failure: 7.34 [95% CI, 6.35-8.48] for mortality and 1.85 [95% CI, 1.71-1.99] for major adverse cardiac events). Conclusions The results of this real-world analysis highlight the potential negative impact of suboptimal RAASi dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation.



J Am Heart Assoc: 18 Nov 2019; 8:e012655
Linde C, Bakhai A, Furuland H, Evans M, ... Ayoubkhani D, Qin L
J Am Heart Assoc: 18 Nov 2019; 8:e012655 | PMID: 31711387
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Abstract

Outcomes of Multi-Organ Transplant in Adult Patients With Congenital Heart Disease.

Wong K, Tecson K, Cedars A

Background The prevalence of adult congenital heart disease (ACHD) is increasing in the United States because of improved survival into adulthood. The unique physiology of ACHD commonly leads to multiorgan dysfunction, prompting interest in outcomes after multiorgan (heart+X) transplantation. Methods and Results We queried the SRTR (Scientific Registry of Transplant Recipients) database to examine 5-year outcomes in ACHD patients (aged ≥18 years) who underwent dual organ (heart+kidney/liver/lung) transplantation between 2000 and 2016. Cox proportional hazards models were constructed to look at survival of dual organ transplant recipients versus heart-only recipients in the ACHD population and heart+lung recipients versus heart-only recipients in the ACHD populations and versus non-ACHD recipients of heart+lung transplant. We then constructed a multivariable model to investigate independent risk factors for 5-year mortality after multiorgan transplant. Overall, 5-year mortality was greater for multiorgan (heart+kidney/liver/lung) transplant compared with heart-only transplant. On further analysis, only heart+lung transplant was associated with increased mortality. Outcomes after heart+lung transplant were no different between the ACHD and non-ACHD population. Risk factors for increased risk of 5-year mortality in ACHD patients after multiorgan transplant included heart+lung transplant, previous cardiac surgery, and severe functional limitation. Conclusions The mortality risk associated with multiorgan heart transplant in ACHD patients is attributable primarily to heart+lung transplants. Multiorgan transplant in ACHD does not convey increased risk compared with the non-ACHD population. Need for multiorgan transplant should not be an impediment to listing ACHD patients needing a heart transplant.



J Am Heart Assoc: 18 Nov 2019; 8:e014088
Wong K, Tecson K, Cedars A
J Am Heart Assoc: 18 Nov 2019; 8:e014088 | PMID: 31718438
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Abstract

Sex-Specific Differences in Survival and Heart Failure Hospitalization After Cardiac Resynchronization Therapy With or Without Defibrillation.

Leyva F, Qiu T, Zegard A, McNulty D, ... Ray D, Gasparini M

Background Women are underrepresented in cardiac resynchronization therapy (CRT) trials. Some studies suggest that women fare better than men after CRT. We sought to explore clinical outcomes in women and men undergoing CRT-defibrillation or CRT-pacing in real-world clinical practice. Methods and Results A national database (Hospital Episode Statistics for England) was used to quantify clinical outcomes in 43 730 patients (women: 10 890 [24.9%]; men: 32 840 [75.1%]) undergoing CRT over 7.6 years, (median follow-up 2.2 years, interquartile range, 1-4 years). In analysis of the total population, the primary end point of total mortality (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.69-0.76) and the secondary end point of total mortality or heart failure hospitalization (aHR, 0.79, 95% CI 0.75-0.82) were lower in women, independent of known confounders. Total mortality (aHR, 0.73; 95% CI, 0.70-0.76) and total mortality or heart failure hospitalization (aHR, 0.79; 95% CI, 0.75-0.82) were lower for CRT-defibrillation than for CRT-pacing. In analyses of patients with (aHR, 0.89; 95% CI, 0.80-0.98) or without (aHR, 0.70; 95% CI, 0.66-0.73) a myocardial infarction, women had a lower total mortality. In sex-specific analyses, total mortality was lower after CRT-defibrillation in women (aHR, 0.83; =0.013) and men (aHR, 0.69; <0.001). Conclusions Compared with men, women lived longer and were less likely to be hospitalized for heart failure after CRT. In both sexes, CRT-defibrillation was superior to CRT-pacing with respect to survival and heart failure hospitalization. The longest survival after CRT was observed in women without a history of myocardial infarction.



J Am Heart Assoc: 18 Nov 2019; 8:e013485
Leyva F, Qiu T, Zegard A, McNulty D, ... Ray D, Gasparini M
J Am Heart Assoc: 18 Nov 2019; 8:e013485 | PMID: 31718445
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Abstract

Differences in Inpatient Outcomes After Surgical Aortic Valve Replacement at Transcatheter Aortic Valve Replacement (TAVR) and Non-TAVR Centers.

Jack G, Arora S, Strassle PD, Sitammagari K, ... O\'Gara PT, Vavalle JP

Background Transcatheter aortic valve replacement (TAVR) has solidified the importance of a heart team and revolutionized patient selection for surgical aortic valve replacement (SAVR). It is unknown if hospital ability to offer TAVR impacts SAVR outcomes. We investigated outcomes after SAVR between TAVR and non-TAVR centers. Methods and Results Hospitalizations of patients aged ≥50 years, undergoing elective SAVR between January 2012 and September 2015, in the National Readmission Database (NRD) were included. Multivariable logistic, linear, and generalized logistic regression models were used to adjust for patient and hospital characteristics and estimate association between undergoing SAVR at a TAVR center, compared with a non-TAVR center. The association between TAVR volumes and these outcomes were also assessed. SAVR hospitalizations (n = 32 198) were identified; 22 066 (69%) at TAVR and 10 132 (31%) at non-TAVR centers. SAVRs at TAVR centers had lower odds of inpatient mortality (odds ratio 0.67, 95% CI 0.55-0.82) and discharge to skilled nursing facility (odds ratio 0.92, 95% CI 0.85-0.99), compared with non-TAVR centers. There was no difference in LOS (change in estimate -0.09, 95% CI -0.26 to 0.08) or 30-day re-admission (odds ratio 0.95, 95% CI 0.88-1.03). SAVRs performed at the highest TAVR volume centers had the lowest inpatient mortality, compared with non-TAVR centers (odds ratio 0.43 95% CI 0.29-0.63). Conclusions Patients undergoing SAVR at TAVR centers are more likely to survive and have better discharge disposition than patients undergoing SAVR at non-TAVR centers. Whether this represents benefits of a heart-team approach to care or differences in patient selection for SAVR when TAVR is unavailable requires further study.



J Am Heart Assoc: 18 Nov 2019; 8:e013794
Jack G, Arora S, Strassle PD, Sitammagari K, ... O'Gara PT, Vavalle JP
J Am Heart Assoc: 18 Nov 2019; 8:e013794 | PMID: 31718443
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Abstract

Metabolic Dysfunction in Continuous-Flow Left Ventricular Assist Devices Patients and Outcomes.

Nguyen AB, Imamura T, Besser S, Rodgers D, ... Sayer G, Uriel N

Background Metabolic impairment is common in heart failure patients. Continuous-flow left ventricular assist devices (CF-LVADs) improve hemodynamics and outcomes in patients with advanced heart failure; however, the effect of CF-LVADs on metabolic status is unknown. This study aims to evaluate the changes in metabolic status following CF-LVAD implantation and measure the correlation of metabolic status with outcomes. Methods and Results Prospective data on CF-LVAD patients were obtained. Metabolic evaluation, including hemoglobin A1C, free and total testosterone, thyroid-stimulating hormone (TSH), and free T4, was obtained before and at multiple time points following implantation. Patients with nonelevated thyroid-stimulating hormone and normal hemoglobin A1C and testosterone levels were defined as having normal metabolic status. Baseline characteristics, hemodynamics, and outcomes were collected. One hundred six patients were studied, of which 56 had paired data at baseline and 1- to 3-month follow-up. Before implantation, 75% of patients had insulin resistance, 86% of men and 39% of women had low free testosterone, and 44% of patients had abnormal thyroid function. There was a significant improvement in hemoglobin A1C, free testosterone, and thyroid-stimulating hormone following implantation (<0.001 for all). Patients with normal hemoglobin A1C (<5.7%) following implantation had higher 1-year survival free of heart failure readmissions (78% versus 23%; <0.001). Patients with normal metabolic status following implantation also had higher 1-year survival free of heart failure readmissions (92% versus 54%; =0.04). Conclusions Metabolic dysfunction is highly prevalent in advanced heart failure patients and improves after CF-LVAD implantation. Normal metabolic status is associated with a significantly higher rate of 1-year survival free of heart failure readmissions.



J Am Heart Assoc: 18 Nov 2019; 8:e013278
Nguyen AB, Imamura T, Besser S, Rodgers D, ... Sayer G, Uriel N
J Am Heart Assoc: 18 Nov 2019; 8:e013278 | PMID: 31718441
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Abstract

Pigment Epithelium-Derived Factor Increases Native Collateral Blood Flow to Improve Cardiac Function and Induce Ventricular Remodeling After Acute Myocardial Infarction.

Liu X, Liu Z, Chen J, Zhu L, ... Dong H, Zhang Z

Background We previously found that the structural defects of the coronary collateral microcirculation reserve (CCMR) prevent these preformed collateral vessels from continuously delivering the native collateral blood and supporting the ischemic myocardium in rats. Here, we tested whether these native collaterals can be remodeled by artificially increasing pigment epithelium-derived factor (PEDF) expression and demonstrated the mechanism for this stimulation. Methods and Results We performed intramyocardial gene delivery (PEDF-lentivirus, 2×10 TU) along the left anterior descending coronary artery to artificially increase the expression of PEDF in the tissue of the region for 2 weeks. By blocking the left anterior descending coronary artery, we examined the effects of PEDF on native collateral blood flow and CCMR. The results of positron emission tomography perfusion imaging showed that PEDF increased the native collateral blood flow and significantly inhibited its decline during acute myocardial infarction. In addition, the number of CCMR vessels decreased and the size increased. Similar results were obtained from in vitro experiments. We tested whether PEDF induces CCMR remodeling in a fluid shear stress-like manner by detecting proteins and signaling pathways that are closely related to fluid shear stress. The nitric oxide pathway and the Notch-1 pathway participated in the process of CCMR remodeling induced by PEDF. Conclusions PEDF treatment activates the nitric oxide pathway, and the Notch-1 pathway enabled CCMR remodeling. Increasing the native collateral blood flow can promote the ventricular remodeling process and improve prognosis after acute myocardial infarction.



J Am Heart Assoc: 18 Nov 2019; 8:e013323
Liu X, Liu Z, Chen J, Zhu L, ... Dong H, Zhang Z
J Am Heart Assoc: 18 Nov 2019; 8:e013323 | PMID: 31718448
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Abstract

Sphingomyelin Synthase 2 Inhibition Ameliorates Cerebral Ischemic Reperfusion Injury Through Reducing the Recruitment of Toll-Like Receptor 4 to Lipid Rafts.

Xue J, Yu Y, Zhang X, Zhang C, ... Jiang XC, Qin S

Background Inflammation is recognized as an important contributor of ischemia/reperfusion (I/R) damage after ischemic stroke. Sphingomyelin synthase 2 (SMS2), the key enzyme for the biosynthesis of sphingomyelin, can function as a critical mediator of inflammation. In the present study, we investigated the role of SMS2 in a mouse model of cerebral I/R. Methods and Results Cerebral I/R was induced by 60-minute transient middle cerebral artery occlusion in SMS2 knockout (SMS2) mice and wild-type mice. Brain injury was determined by neurological deficits and infarct volume at 24 and 72 hours after transient middle cerebral artery occlusion. Microglia activation and inflammatory factors were detected by immunofluorescence staining, flow cytometry, western blot, and RT-PCR. SMS2 deficiency significantly improved neurological function and minimized infarct volume at 72 hours after transient middle cerebral artery occlusion. The neuroprotective effects of SMS2 deficiency were associated with (1) suppression of microglia activation through Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells pathway and (2) downregulation of the level of galactin-3 and other proinflammatory cytokines. The mechanisms underlying the beneficial effects of SMS2 deficiency may include altering sphingomyelin components in lipid raft fractions, thus impairing the recruitment of Toll-like receptor 4 to lipid rafts and subsequently reducing Toll-like receptor 4/myeloid differentiation factor 2 complex formation on the surface of microglia. Conclusions SMS2 deficiency ameliorated inflammatory injury after cerebral I/R in mice, and SMS2 may be a key modulator of Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells activation by disturbing the membrane component homeostasis during cerebral I/R.



J Am Heart Assoc: 18 Nov 2019; 8:e012885
Xue J, Yu Y, Zhang X, Zhang C, ... Jiang XC, Qin S
J Am Heart Assoc: 18 Nov 2019; 8:e012885 | PMID: 31718447
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Abstract

Pigment Epithelial-Derived Factor Deficiency Accelerates Atherosclerosis Development via Promoting Endothelial Fatty Acid Uptake in Mice With Hyperlipidemia.

Wang H, Yang Y, Yang M, Li X, ... Chen H, Cai W

Background Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid (FA) transport. Pigment epithelial-derived factor (PEDF) is an important regulator in lipid metabolism. We hypothesized that PEDF is involved in endothelium-mediated FA uptake under hyperlipidemic conditions. Methods and Results Circulating PEDF levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum PEDF levels were confirmed in both wild-type and apolipoprotein E-deficient mice fed a long-term high-fat diet. Apolipoprotein E-deficient/PEDF-deficient mice were generated by crossing PEDF-deficient mice with apolipoprotein E-deficient mice, and then mice were fed with 24, 36, or 48 weeks of high-fat diet. Greater increases in body fat and plasma lipids were displayed in PEDF-deficient mice. In addition, PEDF deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno-associated virus encoding PEDF exerted opposite effects. Mechanistically, PEDF inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor-1 and neuropilin-1), and FA transport proteins 3 and 4, to suppress endothelial FA uptake, whereas PEDF deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation. Conclusions Decreasing expression of PEDF aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial FA uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.



J Am Heart Assoc: 18 Nov 2019; 8:e013028
Wang H, Yang Y, Yang M, Li X, ... Chen H, Cai W
J Am Heart Assoc: 18 Nov 2019; 8:e013028 | PMID: 31711388
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Abstract

Comparison of In-Hospital Mortality and Length of Stay in Acute ST-Segment-Elevation Myocardial Infarction Among Urban Teaching Hospitals in China and the United States.

Han H, Wei X, He Q, Yu Y, ... Herzog E, He J

Background The aim of the study is to compare in-hospital outcomes of acute ST-segment-elevation myocardial infarction (STEMI) between China and the United States. Methods and Results Urban teaching hospitals were queried for adult patients with a primary diagnosis of acute STEMI during 2007-2010. The primary outcome was in-hospital mortality, and the secondary outcome was length of stay. Multivariable analyses adjusting for potential confounders were conducted for comparison between countries. Subgroup analysis was performed in acute STEMI patients receiving revascularization. In total, 32 228 patients in China and 76 117 patients in the United States were included. Overall in-hospital mortality was 8.23% in China and 7.96% in the United States (<0.001). Multivariable analyses revealed that the 2 countries had similar overall in-hospital mortality (odds ratio, 0.97; 95% CI, 0.87-1.09; =0.59), whereas China had lower 3-day mortality (odds ratio, 0.78; 95% CI, 0.70-0.89; <0.001). In patients receiving primary percutaneous coronary interventions, Chinese hospitals had significant higher overall mortality (odds ratio, 2.39; 95% CI, 1.85-3.07; <0.001) and 3-day mortality (odds ratio, 2.39; 95% CI, 1.78-3.20; <0.001). For total acute STEMI patients, acute STEMI patients receiving percutaneous coronary intervention and coronary artery bypass grafting, median length of stay in China and the United States were 10 versus 3, 9 versus 3, and 25 versus 9 days, respectively (all <0.001). Conclusions Overall in-hospital mortality in acute STEMI patients was comparable among urban teaching hospitals between China and the United States during 2007-2010. In addition, 3-day mortality was lower in China. However, worse outcomes in patients undergoing early revascularization and longer length of stay in China need to be given more attention.



J Am Heart Assoc: 18 Nov 2019; 8:e012054
Han H, Wei X, He Q, Yu Y, ... Herzog E, He J
J Am Heart Assoc: 18 Nov 2019; 8:e012054 | PMID: 31718446
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Abstract

Physiological Versus Angiographic Guidance for Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation.

Lunardi M, Scarsini R, Venturi G, Pesarini G, ... Ferrero V, Ribichini F

Background Management of coronary artery disease in patients undergoing transcatheter aortic valve implantation is uncertain. Fractional flow reserve (FFR) has never been clinically validated in aortic stenosis. The study aim was to analyze the clinical outcome of FFR-guided revascularization in patients undergoing transcatheter aortic valve implantation. Methods and Results Patients with severe aortic stenosis and coronary artery disease at coronary angiography were included in this retrospective analysis and divided in 2 groups: angiography guided (122/216; 56.5%) versus FFR-guided revascularization (94/216; 43.5%). Patients were clinically followed up and evaluated for the occurrence of major adverse cardiac and cerebrovascular events at 2-year follow-up. Most lesions in the FFR group resulted negative according to the conventional 0.80 cutoff value (111/142; 78.2%) and were deferred. The FFR-guided group showed a better major adverse cardiac and cerebrovascular event-free survival compared with the angio-guided group (92.6% versus 82.0%; hazard ratio, 0.4; 95% CI, 0.2-1.0; =0.035). Patients with deferred lesions based on FFR presented better outcome compared with patients who underwent angio-guided percutaneous coronary intervention (91.4% versus 68.1%; hazard ratio, 0.3; 95% CI, 0.1-0.6; =0.001). Conclusions FFR guidance was associated with favorable outcome in this observational study in patients undergoing transcatheter aortic valve implantation. Randomized trials are needed to investigate the long-term effects of FFR-guided revascularization against angiographic guidance alone in patients with aortic stenosis.



J Am Heart Assoc: 18 Nov 2019; 8:e012618
Lunardi M, Scarsini R, Venturi G, Pesarini G, ... Ferrero V, Ribichini F
J Am Heart Assoc: 18 Nov 2019; 8:e012618 | PMID: 31718439
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Abstract

Left Ventricular Dysfunction in Patients With Primary Aldosteronism: A Propensity Score-Matching Follow-Up Study With Tissue Doppler Imaging.

Chang YY, Liao CW, Tsai CH, Chen CW, ... ,

Background Primary aldosteronism is the most common cause of secondary hypertension and is associated with left ventricular hypertrophy. However, whether aldosterone excess is responsible for left ventricular (LV) diastolic dysfunction is unknown. Methods and Results We prospectively enrolled 129 patients with aldosterone-producing adenoma and 120 patients with essential hypertension, and analyzed their clinical, biochemical, and echocardiographic data, including tissue Doppler images. The patients with aldosterone-producing adenoma were reevaluated 1 year after adrenalectomy. After propensity score matching, there were 105 patients in each group. The patients with aldosterone-producing adenoma had worse diastolic function than the patients with essential hypertension, as reflected by lower e\' (<0.001) and higher E/e\' (=0.003). Multivariate analysis showed that LV diastolic function was significantly correlated with age (<0.001), sex (<0.001), body mass index (=0.002), systolic blood pressure (=0.004), creatinine (=0.008), and log-transformed aldosterone-renin ratio (=0.003). After adrenalectomy, the patients with aldosterone-producing adenoma had significant improvements in LV diastolic function as reflected by an increase in e\' (=0.003) and decrease in E/e\' (=0.002). The change in E/e\' was independently correlated with baseline E/e\' (<0.001) and change in LV mass index (=0.006). Conclusions The patients with primary aldosteronism had worse LV diastolic function than the patients with essential hypertension after propensity score matching, and this could be reversed after adrenalectomy, suggesting that aldosterone excess may induce LV diastolic dysfunction.



J Am Heart Assoc: 18 Nov 2019; 8:e013263
Chang YY, Liao CW, Tsai CH, Chen CW, ... ,
J Am Heart Assoc: 18 Nov 2019; 8:e013263 | PMID: 31718437
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Abstract

Systematic Review and Meta-Analysis of Medication Reviews Conducted by Pharmacists on Cardiovascular Diseases Risk Factors in Ambulatory Care.

Martínez-Mardones F, Fernandez-Llimos F, Benrimoj SI, Ahumada-Canale A, ... S Tonin F, Garcia-Cardenas V

Background Pharmacists-led medication reviews (MRs) are claimed to be effective for the control of cardiovascular diseases; however, the evidence in the literature is conflicting. The main objective of this meta-analysis was to analyze the impact of pharmacist-led MRs on cardiovascular disease risk factors overall and in different ambulatory settings while exploring the effects of different components of MRs. Methods and Results Searches were conducted in PubMed, Web of Science, Embase, the Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library Central Register of Controlled Trials database. Randomized and cluster randomized controlled trials of pharmacist-led MRs compared with usual care were included. Settings were community pharmacies and ambulatory clinics. The classification used for MRs was the Pharmaceutical Care Network Europe as basic (type 1), intermediate (type 2), and advanced (type 3). Meta-analyses in therapeutic goals used odds ratios to standardize the effect of each study, and for continuous data (eg, systolic blood pressure) raw differences were calculated using baseline and final values, with 95% CIs. Prediction intervals were calculated to account for heterogeneity. Sensitivity analyses were conducted to test the robustness of results. Meta-analyses included 69 studies with a total of 11 644 patients. Sample demographic characteristics were similar between studies. MRs increased control of hypertension (odds ratio, 2.73; 95% prediction interval, 1.05-7.08), type 2 diabetes mellitus (odds ratio, 3.11; 95% prediction interval, 1.17-5.88), and high cholesterol (odds ratio, 1.91; 95% prediction interval, 1.05-3.46). In ambulatory clinics, MRs produced significant effects in control of diabetes mellitus and cholesterol. For community pharmacies, systolic blood pressure and low-density lipoprotein values decreased significantly. Advanced MRs had larger effects than intermediate MRs in diabetes mellitus and dyslipidemia outcomes. Most intervention components had no significant effect on clinical outcomes and were often poorly described. CIs were significant in all analyses but prediction intervals were not in continuous clinical outcomes, with high heterogeneity present. Conclusions Intermediate and advanced MRs provided by pharmacists may improve control of blood pressure, cholesterol, and type 2 diabetes mellitus, as statistically significant prediction intervals were found. However, most continuous clinical outcomes failed to achieve statistical significance, with high heterogeneity present, although positive trends and effect sizes were found. Studies should use a standardized method for MRs to diminish sources of these heterogeneities.



J Am Heart Assoc: 18 Nov 2019; 8:e013627
Martínez-Mardones F, Fernandez-Llimos F, Benrimoj SI, Ahumada-Canale A, ... S Tonin F, Garcia-Cardenas V
J Am Heart Assoc: 18 Nov 2019; 8:e013627 | PMID: 31711390
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This program is still in alpha version.