Journal: Circulation

Sorted by: date / impact
Abstract

Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9.

Bai C, Su M, Zhang Y, Lin Y, ... Li H, Chen J
Background
Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms.
Methods
Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein-protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays.
Results
We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that nonmuscle MYH9 (myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling.
Conclusions
Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.



Circulation: 29 Sep 2022:101161CIRCULATIONAHA121057178; epub ahead of print
Bai C, Su M, Zhang Y, Lin Y, ... Li H, Chen J
Circulation: 29 Sep 2022:101161CIRCULATIONAHA121057178; epub ahead of print | PMID: 36172862
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Abstract

Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Wolfrum S, Roedl K, Hanebutte A, Pfeifer R, ... Thiele H, Kluge S
Background
This study was conducted to determine the effect of hypothermic temperature control after in-hospital cardiac arrest (IHCA) on mortality and functional outcome as compared with normothermia.
Methods
An investigator initiated, open-label, blinded-outcome-assessor, multicenter, randomized controlled trial comparing hypothermic temperature control (32-34°C) for 24 h with normothermia after IHCA in 11 hospitals in Germany. The primary endpoint was all-cause mortality after 180 days. Secondary end points included in-hospital mortality and favorable functional outcome using the Cerebral Performance Category scale after 180 days. A Cerebral Performance Category score of 1 or 2 was defined as a favorable functional outcome.
Results
A total of 1055 patients were screened for eligibility and 249 patients were randomized: 126 were assigned to hypothermic temperature control and 123 to normothermia. The mean age of the cohort was 72.6±10.4 years, 64% (152 of 236) were male, 73% (166 of 227) of cardiac arrests were witnessed, 25% (57 of 231) had an initial shockable rhythm, and time to return of spontaneous circulation was 16.4±10.5 minutes. Target temperature was reached within 4.1 hours after IHCA in the hypothermic group and temperature was controlled for 48 hours at 37.0°±0.9°C in the normothermia group. Mortality by day 180 was 72.5% (87 of 120) in hypothermic temperature control arm, compared with 71.2% (84 of 118) in the normothermia group (relative risk, 1.03 [95% CI, 0.79-1.40]; P=0.822). In-hospital mortality was 62.5% (75 of 120) in the hypothermic temperature control as compared with 57.6% (68 of 118) in the normothermia group (relative risk, 1.11 [95% CI, 0.86-1.46, P=0.443). Favorable functional outcome (Cerebral Performance Category 1 or 2) by day 180 was 22.5% (27 of 120) in the hypothermic temperature control, compared with 23.7% (28 of 118) in the normothermia group (relative risk, 1.04 [95% CI, 0.78-1.44]; P=0.822). The study was prematurely terminated because of futility.
Conclusions
Hypothermic temperature control as compared with normothermia did not improve survival nor functional outcome at day 180 in patients presenting with coma after IHCA. The HACA-IHCA (Hypothermia After In-Hospital Cardiac Arrest) trial was underpowered and may have failed to detect clinically important differences between hypothermic temperature control and normothermia.
Registration
URL: ClinicalTrials.gov; Unique Identifier: NCT00457431.



Circulation: 28 Sep 2022:101161CIRCULATIONAHA122060106; epub ahead of print
Wolfrum S, Roedl K, Hanebutte A, Pfeifer R, ... Thiele H, Kluge S
Circulation: 28 Sep 2022:101161CIRCULATIONAHA122060106; epub ahead of print | PMID: 36168956
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Abstract

Features and Outcomes of Histologically Proven Myocarditis With Fulminant Presentation.

Kanaoka K, Onoue K, Terasaki S, Nakano T, ... Saito Y, Japanese Registry of Fulminant Myocarditis Investigators
Background
Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence.
Methods
This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis.
Results
This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion (<40%) on admission, and ventricular tachycardia or fibrillation on admission day were associated with worse 90-day survival. Severe histologic damage (damaged cardiomyocytes comprising ≥50% of the total cardiomyocytes) was associated with a worse 90-day prognosis in patients with lymphocytic myocarditis.
Conclusions
The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP.
Registration
URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000039763.



Circulation: 27 Sep 2022:101161CIRCULATIONAHA121058869; epub ahead of print
Kanaoka K, Onoue K, Terasaki S, Nakano T, ... Saito Y, Japanese Registry of Fulminant Myocarditis Investigators
Circulation: 27 Sep 2022:101161CIRCULATIONAHA121058869; epub ahead of print | PMID: 36164974
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Abstract

Contemporary Socioeconomic and Childhood Opportunity Disparities in Congenital Heart Surgery.

Sengupta A, Gauvreau K, Bucholz EM, Newburger JW, Del Nido PJ, Nathan M
Background
While singular measures of socioeconomic status have been associated with outcomes after surgery for congenital heart disease, the multifaceted pathways through which a child\'s environment impacts similar outcomes remain incompletely characterized. We sought to evaluate the association between childhood opportunity level and adverse outcomes after congenital heart surgery.
Methods
Data from patients undergoing congenital cardiac surgery from January 2011 to January 2020 at a quaternary referral center were retrospectively reviewed. Outcomes of interest included predischarge (early) mortality or transplant, postoperative hospital length-of-stay, inpatient cost of hospitalization, postdischarge (late) mortality or transplant, and late unplanned reintervention. The primary predictor was a US Census tract-based, nationally-normed composite metric of contemporary child neighborhood opportunity comprising 29 indicators across 3 domains (education, health and environment, and socioeconomic), categorized as very low, low, moderate, high, and very high. Associations between childhood opportunity level and outcomes were evaluated using logistic regression (early mortality), generalized linear (length-of-stay and cost), Cox proportional hazards (late mortality), or competing risk (late reintervention) models, adjusting for baseline patient-related factors, case complexity, and residual lesion severity.
Results
Of 6133 patients meeting entry criteria, the median age was 2.0 years (interquartile range, 3.6 months-8.3 years). There were 124 (2.0%) early deaths or transplants, the median postoperative length-of-stay was 7 days (interquartile range, 5-13), and the median inpatient cost was $76 000 (interquartile range, $50 000-130 000). No significant association between childhood opportunity level and early mortality or transplant was observed (P=0.21). On multivariable analysis, children with very low and low opportunity had significantly longer length-of-stay and incurred higher costs compared with those with very high opportunity (all P<0.05). Of 6009 transplant-free survivors of hospital discharge, there were 175 (2.9%) late deaths or transplants, and 1008 (16.8%) reinterventions at up to 10.5 years of follow-up. Patients with very low opportunity had a significantly greater adjusted risk of late death or transplant (hazard ratio, 1.7 [95% CI, 1.1-2.6]; P=0.030) and reintervention (subdistribution hazard ratio, 1.9 [95% CI, 1.5-2.3]; P<0.001), versus those with very high opportunity.
Conclusions
Childhood opportunity level is independently associated with adverse outcomes after congenital heart surgery. Children from resource-limited settings thus constitute an especially high-risk cohort that warrants closer surveillance and tailored interventions.



Circulation: 27 Sep 2022:101161CIRCULATIONAHA122060030; epub ahead of print
Sengupta A, Gauvreau K, Bucholz EM, Newburger JW, Del Nido PJ, Nathan M
Circulation: 27 Sep 2022:101161CIRCULATIONAHA122060030; epub ahead of print | PMID: 36164982
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Abstract

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.

Thibord F, Klarin D, Brody JA, Chen MH, ... Johnson AD, Smith NL
Background
Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.
Methods
We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.
Results
In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.
Conclusions
Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.



Circulation: 26 Sep 2022:101161CIRCULATIONAHA122059675; epub ahead of print
Thibord F, Klarin D, Brody JA, Chen MH, ... Johnson AD, Smith NL
Circulation: 26 Sep 2022:101161CIRCULATIONAHA122059675; epub ahead of print | PMID: 36154123
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Abstract

Genetic Architecture of Acute Myocarditis and the Overlap with Inherited Cardiomyopathy.

Lota AS, Hazebroek MR, Theotokis P, Wassall R, ... Ware JS, Prasad SK
Background
Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis.
Methods
This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality.
Results
Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction<50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08).
Conclusions
We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.



Circulation: 26 Sep 2022; epub ahead of print
Lota AS, Hazebroek MR, Theotokis P, Wassall R, ... Ware JS, Prasad SK
Circulation: 26 Sep 2022; epub ahead of print | PMID: 36154167
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Abstract

Ninety-Day Risk-Standardized Home Time as a Performance Metric for Cardiac Surgery Hospitals in the United States.

Mentias A, Desai MY, Keshvani N, Gillinov AM, ... Svensson L, Pandey A
Background
Assessing hospital performance for cardiac surgery necessitates consistent and valid care quality metrics. The association of hospital-level risk-standardized home time for cardiac surgeries with other performance metrics such as mortality rate, readmission rate, and annual surgical volume has not been evaluated previously.
Methods
The study included Medicare beneficiaries who underwent isolated or concomitant coronary artery bypass graft, aortic valve, or mitral valve surgery from January 1, 2013, to October 1, 2019. Hospital-level performance metrics of annual surgical volume, 90-day risk-standardized mortality rate, 90-day risk-standardized readmission rate (RSRR), and 90-day risk-standardized home time were estimated starting from the day of surgery using generalized linear mixed models with a random intercept for the hospital. Correlations between the performance metrics were assessed using the Pearson correlation coefficient. Patient-level clinical outcomes were also compared across hospital quartiles by 90-day risk-standardized home time. Last, the temporal stability of each metric for each hospital during the study years was also assessed.
Results
Overall, 919 698 patients (age 74.2±5.8 years, 32% women) were included from 1179 hospitals. Median 90-day risk-standardized home time was 71.2 days (25th-75th percentile, 66.5-75.6), 90-day risk-standardized readmission rate was 26.0% (19.5%-35.7%), and 90-day risk-standardized mortality rate was 6.0% (4.0%-8.8%). Across 90-day home time quartiles, a graded decline was observed in the rates of in-hospital, 90-day, and 1-year mortality, and 90-day and 1-year readmission. Ninety-day home time had a significant positive correlation with annual surgical volume (r=0.31; P<0.001) and inverse correlation with 90-day risk-standardized readmission rate (r=-0.40) and 90-day risk-standardized mortality rate (r=-0.60). Use of 90-day home time as a performance metric resulted in a meaningful reclassification in performance ranking of 22.8% hospitals compared with annual surgical volume, 11.6% compared with 90-day risk-standardized mortality rate, and 19.9% compared with 90-day risk-standardized readmission rate. Across the 7 years of the study period, 90-day home time demonstrated the most temporal stability of the hospital performance metrics.
Conclusions
Ninety-day risk-standardized home time is a feasible, comprehensive, patient-centered metric to assess hospital-level performance in cardiac surgery with greater temporal stability than mortality and readmission measures.



Circulation: 26 Sep 2022:101161CIRCULATIONAHA122059496; epub ahead of print
Mentias A, Desai MY, Keshvani N, Gillinov AM, ... Svensson L, Pandey A
Circulation: 26 Sep 2022:101161CIRCULATIONAHA122059496; epub ahead of print | PMID: 36154237
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Abstract

Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study.

Lubitz SA, Faranesh AZ, Selvaggi C, Atlas SJ, ... Pantelopoulos A, Foulkes AS
Background
Morbidity from undiagnosed atrial fibrillation (AF) may be preventable with early detection. Many consumer wearables contain optical photoplethysmography (PPG) sensors to measure pulse rate. PPG-based software algorithms that detect irregular heart rhythms may identify undiagnosed AF in large populations using wearables, but minimizing false-positive detections is essential.
Methods
We performed a prospective remote clinical trial to examine a novel PPG-based algorithm for detecting undiagnosed AF from a range of wrist-worn devices. Adults aged ≥22 years in the United States without AF, using compatible wearable Fitbit devices and Android or iOS smartphones, were included. PPG data were analyzed using a novel algorithm that examines overlapping 5-minute pulse windows (tachograms). Eligible participants with an irregular heart rhythm detection (IHRD), defined as 11 consecutive irregular tachograms, were invited to schedule a telehealth visit and were mailed a 1-week ambulatory ECG patch monitor. The primary outcome was the positive predictive value of the first IHRD during ECG patch monitoring for concurrent AF.
Results
A total of 455 699 participants enrolled (median age 47 years, 71% female, 73% White) between May 6 and October 1, 2020. IHRDs occurred for 4728 (1%) participants, and 2070 (4%) participants aged ≥65 years during a median of 122 (interquartile range, 110-134) days were at risk for an IHRD. Among 1057 participants with an IHRD notification and subsequent analyzable ECG patch monitor, AF was present in 340 (32.2%). Of the 225 participants with another IHRD during ECG patch monitoring, 221 had concurrent AF on the ECG and 4 did not, resulting in an IHRD positive predictive value of 98.2% (95% CI, 95.5%-99.5%). For participants aged ≥65 years, the IHRD positive predictive value was 97.0% (95% CI, 91.4%-99.4%).
Conclusions
A novel PPG software algorithm for wearable Fitbit devices exhibited a high positive predictive value for concurrent AF and identified participants likely to have AF on subsequent ECG patch monitoring. Wearable devices may facilitate identifying individuals with undiagnosed AF.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT04380415.



Circulation: 23 Sep 2022:101161CIRCULATIONAHA122060291; epub ahead of print
Lubitz SA, Faranesh AZ, Selvaggi C, Atlas SJ, ... Pantelopoulos A, Foulkes AS
Circulation: 23 Sep 2022:101161CIRCULATIONAHA122060291; epub ahead of print | PMID: 36148649
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Abstract

Results of the North American Complex Abdominal Aortic Debranching (NACAAD) Registry.

Escobar GA, Oderich GS, Farber M, de Souza LR, ... Tenorio ER, NACAAD Investigators
Background
Hybrid debranching repair of pararenal and thoracoabdominal aortic aneurysms was initially designed as a better alternative to standard open repair, addressing the limitations of endovascular repair involving the visceral aorta. We reviewed the collective outcomes of hybrid debranching repairs using extra-anatomic, open surgical debranching of the renal-mesenteric arteries, followed by endovascular aortic stenting.
Methods
Data from patients who underwent hybrid repair in 14 North American institutions during 10 years were retrospectively reviewed. Society of Vascular Surgery scores were used to assess comorbidity risk. Early and late outcomes, including mortality, morbidity, reintervention, and patency were analyzed.
Results
A total of 208 patients (118 male; mean age, 71±8 years old) were treated by hybrid repair with extraanatomic reconstruction of 657 renal and mesenteric arteries (mean 3.2 vessels/patient). Mean aneurysm diameter was 6.6±1.3 cm. Thoracoabdominal aortic aneurysms were identified in 163 (78%) patients and pararenal aneurysms in 45 (22%). A single-stage repair was performed in 92 (44%) patients. The iliac arteries were the most common source of inflow (n=132; 63%), and most (n=150; 72%) had 3 or more bypasses. There were 30 (14%) early deaths, ranging widely across sites (0%-21%). A Society of Vascular Surgery comorbidity score >15 was the primary predictor of early mortality (P<0.01), whereas mortality was 3% in a score ≤9. Early complications occurred in 140 (73%) patients and included respiratory complications in 45 patients (22%) and spinal cord ischemia in 22 (11%), of whom 10 (45%) fully recovered. At 5 years, survival was 61±5%, primary graft patency was 90±2%, and secondary patency was 93±2%. The most significant predictor of late mortality was renal insufficiency (P<0.0001).
Conclusions
Mortality after hybrid repair and visceral debranching is highly variable by center, but strongly affected by preoperative comorbidities and the centers\' experience with the technique. With excellent graft patency at 5 years, the outcomes of hybrid repair done at centers of excellence and in carefully selected patients may be comparable (or better) than traditional open or even totally endovascular approaches. However, in patients already considered as high-risk for surgery, it may not offer better outcomes.



Circulation: 23 Sep 2022:101161CIRCULATIONAHA120045894; epub ahead of print
Escobar GA, Oderich GS, Farber M, de Souza LR, ... Tenorio ER, NACAAD Investigators
Circulation: 23 Sep 2022:101161CIRCULATIONAHA120045894; epub ahead of print | PMID: 36148651
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Abstract

Assessing the Impact of the American Heart Association\'s Research Portfolio: A Scientific Statement From the American Heart Association.

Creager MA, Hernandez AF, Bender JR, Foster MH, ... Roger VL, American Heart Association Research Committee
A task force composed of American Heart Association (AHA) Research Committee members established processes to measure the performance of the AHA\'s research portfolio and evaluated key outcomes that are fundamental to the overall success of the program. This report reviews progress that the AHA research program has had in achieving its goals relevant to the research programs in the AHA\'s research portfolio from 2008 to 2017. Comprehensive performance metrics were identified to assess the impact of AHA funding on researchers\' career progress and research outcomes. Metrics included bibliometric analysis (ie, tracking of publications and their impact) and career development measures (ie, subsequent grant funding, intellectual property, faculty appointment/promotion, or industry position). Publication rates ranged from ≈0.5 to 4 publications per year, with a strong correlation between number of publications per year and later career stage. The Field-Weighted Citation Index, a metric of bibliometric impact, was between 1.5 and 3.0 for all programs, indicating that AHA awardee publications had a higher citation impact compared with similar publications. To gain insight into the career progression of AHA awardees, a 2-year postaward survey was distributed. Of the Postdoctoral Fellowship recipient respondents, 72% obtained academic research positions, with the remaining working in industry or government research settings; 72% of those in academic positions obtained additional funding. Among respondents who were Beginning Grant-in-Aid and Scientist Development Grant awardees, 45% received academic promotions and 83% obtained additional funding. Measuring performance of the AHA\'s research portfolio is critical to ensure that its strategic goals are met and to show the AHA\'s commitment to high-quality, impactful research.



Circulation: 22 Sep 2022:101161CIR0000000000001094; epub ahead of print
Creager MA, Hernandez AF, Bender JR, Foster MH, ... Roger VL, American Heart Association Research Committee
Circulation: 22 Sep 2022:101161CIR0000000000001094; epub ahead of print | PMID: 36134568
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Abstract

Coronary Arterial Spasm During Pulsed Field Ablation to Treat Atrial Fibrillation.

Reddy VY, Petru J, Funasako M, Kopriva K, ... Kralovec S, Neuzil P
Background
Pulsed field ablation (PFA) has a unique safety profile when used to treat atrial fibrillation, largely related to its preferentiality for myocardial tissue ablation, in particular, esophageal sparing. A pentaspline catheter was the first such PFA system studied clinically for atrial fibrillation ablation; in these initial regulatory trials, the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation. Since its regulatory approval in Europe, in clinical practice, physicians have ablated pulmonary vein isolation and left atrial posterior wall ablation to expanded lesion sets in closer proximity to coronary arteries. This is an unstudied important issue because preclinical and clinical data have raised the potential for coronary arterial spasm. Herein, we studied the vasospastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries.
Methods
During routine atrial fibrillation ablation using the pentaspline PFA catheter, coronary angiography was performed before, during, and after pulsed field applications. The lesion sets studied included: (1) those remote from the coronary arteries such as pulmonary vein isolation (n=25 patients) and left atrial posterior wall ablation (n=5), and (2) ablation of the cavotricuspid isthmus (n=20) that is situated adjacent to the right coronary artery.
Results
During pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur, but cavotricuspid isthmus ablation provoked severe subtotal vasospasm in 5 of 5 (100%) consecutive patients, and this was relieved by intracoronary nitroglycerin in 5.5±3.5 minutes. ST-segment elevation was not observed. However, no patient (0%, P=0.004) had severe spasm if first administered parenteral nitroglycerin, either intracoronary (n=5) or intravenous (n=10), before treatment.
Conclusions
Coronary vasospasm was not provoked during PFA at locations remote from coronary arteries, but when the energy is delivered adjacent to a coronary artery, PFA routinely provokes subclinical vasospasm. This phenomenon is attenuated by nitroglycerin, administered either post hoc to treat spasm or as prophylaxis.



Circulation: 22 Sep 2022:101161CIRCULATIONAHA122061497; epub ahead of print
Reddy VY, Petru J, Funasako M, Kopriva K, ... Kralovec S, Neuzil P
Circulation: 22 Sep 2022:101161CIRCULATIONAHA122061497; epub ahead of print | PMID: 36134574
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Abstract

FGF21-Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity.

Jin L, Geng L, Ying L, Shu L, ... Lian Q, Xu A
Background
Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms.
Methods
The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction.
Results
Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM.
Conclusions
The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03240978.



Circulation: 22 Sep 2022:101161CIRCULATIONAHA122059631; epub ahead of print
Jin L, Geng L, Ying L, Shu L, ... Lian Q, Xu A
Circulation: 22 Sep 2022:101161CIRCULATIONAHA122059631; epub ahead of print | PMID: 36134579
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Abstract

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

Knight R, Walker V, Ip S, Cooper JA, ... Sterne JAC, CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study
Background
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear.
Methods
We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history.
Results
Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses.
Conclusions
High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.



Circulation: 20 Sep 2022; 146:892-906
Knight R, Walker V, Ip S, Cooper JA, ... Sterne JAC, CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study
Circulation: 20 Sep 2022; 146:892-906 | PMID: 36121907
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Impact:
Abstract

Artificial Intelligence for Contrast-free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-based Virtual Native Enhancement (VNE).

Zhang Q, Burrage MK, Shanmuganathan M, Gonzales RA, ... Ferreira VM, Oxford Acute Myocardial Infarction (OxAMI) Study
Background
Myocardial scar is currently assessed non-invasively using cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) as an imaging gold-standard. However, a contrast-free approach would provide many advantages, including a faster and cheaper scan, without contrast-associated problems.
Methods
Virtual Native Enhancement (VNE) is a novel technology that can produce virtual LGE-like images, without the need for contrast. VNE combines cine imaging and native T1-maps to produce LGE-like images using artificial intelligence (AI). VNE was developed for patients with prior myocardial infarction on 4271 datasets (912 patients), where each dataset is comprised of slice position-matched cine, T1-maps and LGE images. After quality control, 3002 datasets (775 patients) were used for development, and 291 datasets (68 patients) for testing. The VNE generator was trained using generative adversarial networks, employing two adversarial discriminators to improve the image quality. The left ventricle was contoured semi-automatically. Myocardial scar volume was quantified using the full width at half maximum method. Scar transmurality was measured using the centerline chord method and visualized on bull\'s eye plots. Lesion quantification by VNE and LGE were compared using linear regression, Pearson correlation (R) and intraclass correlation coefficients (ICC). Proof-of-principle histopathological comparison of VNE in a porcine model of myocardial infarction was also performed.
Results
VNE provided significantly better image quality than LGE on blinded analysis by 5 independent operators on 291 datasets (all p<0.001). VNE correlated strongly with LGE in quantifying scar size (R=0.89, ICC=0.94) and transmurality (R=0.84, ICC=0.90) in 66 patients (277 test datasets). Two CMR experts reviewed all test image slices and reported an overall accuracy of 84% of VNE in detecting scar when compared with LGE, with specificity of 100% and sensitivity of 77%. VNE also showed excellent visuospatial agreement with histopathology in 2 cases of a porcine model of myocardial infarction.
Conclusions
VNE demonstrated high agreement with LGE-CMR for myocardial scar assessment in patients with prior myocardial infarction in visuospatial distribution and lesion quantification, with superior image quality. VNE is a potentially transformative AI-based technology, with promise to reduce scan times and costs, increase clinical throughput, and improve the accessibility of CMR in the very-near future.



Circulation: 20 Sep 2022; epub ahead of print
Zhang Q, Burrage MK, Shanmuganathan M, Gonzales RA, ... Ferreira VM, Oxford Acute Myocardial Infarction (OxAMI) Study
Circulation: 20 Sep 2022; epub ahead of print | PMID: 36124774
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Abstract

Physician Wellness in Academic Cardiovascular Medicine: A Scientific Statement From the American Heart Association.

Bradley EA, Winchester D, Alfonso CE, Carpenter AJ, ... Sivaram CA, American Heart Association Fellows in Training and Early Career Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; and Stroke Council
Academic medicine as a practice model provides unique benefits to society. Clinical care remains an important part of the academic mission; however, equally important are the educational and research missions. More specifically, the sustainability of health care in the United States relies on an educated and expertly trained physician workforce directly provided by academic medicine models. Similarly, the research charge to deliver innovation and discovery to improve health care and to cure disease is key to academic missions. Therefore, to support and promote the growth and sustainability of academic medicine, attracting and engaging top talent from fellows in training and early career faculty is of vital importance. However, as the health care needs of the nation have risen, clinicians have experienced unprecedented demand, and individual wellness and burnout have been examined more closely. Here, we provide a close look at the unique drivers of burnout in academic cardiovascular medicine and propose system-level and personal interventions to support individual wellness in this model.



Circulation: 19 Sep 2022:101161CIR0000000000001093; epub ahead of print
Bradley EA, Winchester D, Alfonso CE, Carpenter AJ, ... Sivaram CA, American Heart Association Fellows in Training and Early Career Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; and Stroke Council
Circulation: 19 Sep 2022:101161CIR0000000000001093; epub ahead of print | PMID: 36120864
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Abstract

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-up Outcomes of Multicenter Randomized Controlled BEST Trial.

Ahn JM, Kang DY, Yun SC, Hur SH, ... Park DW, Park SJ
Background
Long-term comparative outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stent and coronary-artery bypass grafting (CABG) are limited in patients with multivessel coronary artery disease.
Methods
This prospective, multicenter, randomized, controlled trial was conducted in 27 international heart centers and was designed to randomly assign 1776 patients with angiographic multivessel coronary artery disease to receive PCI with everolimus-eluting stent or CABG. After inclusion of 880 patients (438 in the PCI group and 442 in the CABG group) between July 2008 and September 2013, the study was terminated early due to slow enrollment. The primary end point was the composite of death from any cause, myocardial infarction, or target-vessel revascularization.
Results
During a median follow-up of 11.8 years (interquartile range, 10.6 to 12.5 years, maximum 13.7 years), the primary end point occurred in 151 patients (34.5%) in the PCI group and 134 patients (30.3%) in the CABG group (hazard ratio [HR] 1.18; 95% confidence interval [CI], 0.88 to 1.56; P=0.26). No significant differences were seen in the occurrence of a safety composite of death, myocardial infarction, or stroke between groups (28.8% and 27.1%, HR 1.07; 95% CI 0.75 to 1.53; P=0.70) as well as the occurrence of death from any cause (20.5% and 19.9%, HR 1.04; 95% CI 0.65 to 1.67; P=0.86). However, spontaneous myocardial infarction (7.1% and 3.8%, HR 1.86; 95% CI 1.06 to 3.27; P=0.031) and any repeat revascularization (22.6% and 12.7%, HR 1.92; 95% CI 1.58 to 2.32; P<0.001) were more frequent after PCI than after CABG.
Conclusions
In patients with multivessel coronary artery disease, there were no significant differences between PCI and CABG in the incidence of major adverse cardiac events, safety composite end point, and all-cause mortality during extended-follow-up.



Circulation: 19 Sep 2022; epub ahead of print
Ahn JM, Kang DY, Yun SC, Hur SH, ... Park DW, Park SJ
Circulation: 19 Sep 2022; epub ahead of print | PMID: 36121700
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Abstract

Management of Patients at Risk for and With Left Ventricular Thrombus: A Scientific Statement From the American Heart Association.

Levine GN, McEvoy JW, Fang JC, Ibeh C, ... Lip GYH, American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Stroke Council
Despite the many advances in cardiovascular medicine, decisions concerning the diagnosis, prevention, and treatment of left ventricular (LV) thrombus often remain challenging. There are only limited organizational guideline recommendations with regard to LV thrombus. Furthermore, management issues in current practice are increasingly complex, including concerns about adding oral anticoagulant therapy to dual antiplatelet therapy, the availability of direct oral anticoagulants as a potential alternative option to traditional vitamin K antagonists, and the use of diagnostic modalities such as cardiac magnetic resonance imaging, which has greater sensitivity for LV thrombus detection than echocardiography. Therefore, this American Heart Association scientific statement was commissioned with the goals of addressing 8 key clinical management questions related to LV thrombus, including the prevention and treatment after myocardial infarction, prevention and treatment in dilated cardiomyopathy, management of mural (laminated) thrombus, imaging of LV thrombus, direct oral anticoagulants as an alternative to warfarin, treatments other than oral anticoagulants for LV thrombus (eg, dual antiplatelet therapy, fibrinolysis, surgical excision), and the approach to persistent LV thrombus despite anticoagulation therapy. Practical management suggestions in the form of text, tables, and flow diagrams based on careful and critical review of actual study data as formulated by this multidisciplinary writing committee are given.



Circulation: 15 Sep 2022:101161CIR0000000000001092; epub ahead of print
Levine GN, McEvoy JW, Fang JC, Ibeh C, ... Lip GYH, American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Stroke Council
Circulation: 15 Sep 2022:101161CIR0000000000001092; epub ahead of print | PMID: 36106537
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Abstract

Influence of Age on the Diagnosis of Myocardial Infarction.

Lowry MTH, Doudesis D, Wereski R, Kimenai DM, ... Anand A, High-STEACS Investigators
Background
The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction.
Methods
In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50-74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds.
Results
In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5-82.9), 80.6% (95% CI, 79.2-82.1), and 81.6% (95% CI, 79.8-83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1-98.5) to 95.5% (95% CI, 95.2-95.8), and 82.6% (95% CI, 81.9-83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%-91.9%] versus 82.6% [95% CI, 81.9%-83.4%]) and positive predictive value (59.3% [57.0%-61.5%] versus 51.5% [49.9%-53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%-57.9%] versus 81.6% [79.8%-83.3%].
Conclusion
Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population.



Circulation: 15 Sep 2022:101161CIRCULATIONAHA122059994; epub ahead of print
Lowry MTH, Doudesis D, Wereski R, Kimenai DM, ... Anand A, High-STEACS Investigators
Circulation: 15 Sep 2022:101161CIRCULATIONAHA122059994; epub ahead of print | PMID: 36106552
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Abstract

TBX20 Improves Contractility and Mitochondrial Function During Direct Human Cardiac Reprogramming.

Tang Y, Aryal S, Geng X, Zhou X, ... Lu R, Zhou Y
Background
Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying molecular mechanisms are not well studied.
Methods
To discover potential missing factors for human direct reprogramming, we performed transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes.
Results
We identified TBX20 (T-box transcription factor 20) as the top cardiac gene that is unable to be activated by the MGT133 reprogramming cocktail (MEF2C, GATA4, TBX5, and miR-133). TBX20 is required for normal heart development and cardiac function in adult cardiomyocytes, yet its role in cardiac reprogramming remains undefined. We show that the addition of TBX20 to the MGT133 cocktail (MGT+TBX20) promotes cardiac reprogramming and activates genes associated with cardiac contractility, maturation, and ventricular heart. Human induced cardiomyocytes produced with MGT+TBX20 demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondria numbers and mitochondrial respiration. Mechanistically, comprehensive transcriptomic, chromatin occupancy, and epigenomic studies revealed that TBX20 colocalizes with MGT reprogramming factors at cardiac gene enhancers associated with heart contraction, promotes chromatin binding and co-occupancy of MGT factors at these loci, and synergizes with MGT for more robust activation of target gene transcription.
Conclusions
TBX20 consolidates MGT cardiac reprogramming factors to activate cardiac enhancers to promote cardiac cell fate conversion. Human induced cardiomyocytes generated with TBX20 showed enhanced cardiac function in contractility and mitochondrial respiration.



Circulation: 14 Sep 2022:101161CIRCULATIONAHA122059713; epub ahead of print
Tang Y, Aryal S, Geng X, Zhou X, ... Lu R, Zhou Y
Circulation: 14 Sep 2022:101161CIRCULATIONAHA122059713; epub ahead of print | PMID: 36102189
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Abstract

Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction.

Butler J, Filippatos G, Jamal Siddiqi T, Pedro Ferreira J, ... Packer M, Anker SD
Background
Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).
Methods
The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed.
Results
Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score.
Conclusions
Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03057951.



Circulation: 13 Sep 2022:101161CIRCULATIONAHA122059755; epub ahead of print
Butler J, Filippatos G, Jamal Siddiqi T, Pedro Ferreira J, ... Packer M, Anker SD
Circulation: 13 Sep 2022:101161CIRCULATIONAHA122059755; epub ahead of print | PMID: 36098051
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Abstract

Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy.

Shah AM, Claggett B, Prasad N, Li G, ... Solomon SD, Pfeffer MA
Background
Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI.
Methods
In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes.
Results
Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e\'lat (P=0.005), decrease in E/e\'lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure.
Conclusions
Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort.
Registration
URL: https://clinicaltrials.gov; Unique identifier: NCT02924727.



Circulation: 09 Sep 2022:101161CIRCULATIONAHA122059210; epub ahead of print
Shah AM, Claggett B, Prasad N, Li G, ... Solomon SD, Pfeffer MA
Circulation: 09 Sep 2022:101161CIRCULATIONAHA122059210; epub ahead of print | PMID: 36082663
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Abstract

Contractile Force of Transplanted Cardiomyocytes Actively Supports Heart Function After Injury.

Stüdemann T, Rössinger J, Manthey C, Geertz B, ... Eschenhagen T, Weinberger F
Background
Transplantation of pluripotent stem cell-derived cardiomyocytes represents a promising therapeutic strategy for cardiac regeneration, and the first clinical studies in patients with heart failure have commenced. Yet, little is known about the mechanism of action underlying graft-induced benefits. Here, we explored whether transplanted cardiomyocytes actively contribute to heart function.
Methods
We injected cardiomyocytes with an optogenetic off-on switch in a guinea pig cardiac injury model.
Results
Light-induced inhibition of engrafted cardiomyocyte contractility resulted in a rapid decrease of left ventricular function in ≈50% (7/13) animals that was fully reversible with the offset of photostimulation.
Conclusion
Our optogenetic approach demonstrates that transplanted cardiomyocytes can actively participate in heart function, supporting the hypothesis that the delivery of new force-generating myocardium can serve as a regenerative therapeutic strategy.



Circulation: 08 Sep 2022:101161CIRCULATIONAHA122060124; epub ahead of print
Stüdemann T, Rössinger J, Manthey C, Geertz B, ... Eschenhagen T, Weinberger F
Circulation: 08 Sep 2022:101161CIRCULATIONAHA122060124; epub ahead of print | PMID: 36073365
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Abstract

ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease.

Ma Q, Yang Q, Xu J, Zhang X, ... Ben-Sahra I, Huo Y
Background
Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined.
Methods
De novo purine synthesis in proliferative VSMCs was evaluated by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of ATIC-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesions.
Results
In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis.
Conclusions
These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases.



Circulation: 08 Sep 2022:101161CIRCULATIONAHA121058901; epub ahead of print
Ma Q, Yang Q, Xu J, Zhang X, ... Ben-Sahra I, Huo Y
Circulation: 08 Sep 2022:101161CIRCULATIONAHA121058901; epub ahead of print | PMID: 36073366
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Abstract

Early Versus Delayed Non-Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study.

Oldgren J, Åsberg S, Hijazi Z, Wester P, ... Norrving B, National TIMING Collaborators
Background
There are no evidence-based recommendations on the optimal time point to initiate non-vitamin K antagonist oral anticoagulants (NOACs) after acute ischemic stroke in patients with atrial fibrillation. We aimed to investigate the efficacy and safety of early versus delayed initiation of NOAC in these patients.
Methods
TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) was a registry-based, randomized, noninferiority, open-label, blinded end-point study at 34 stroke units using the Swedish Stroke Register for enrollment and follow-up. Within 72 hours from stroke onset, patients were randomized to early (≤4 days) or delayed (5-10 days) NOAC initiation, with choice of NOAC at the investigators\' discretion. The primary outcome was the composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days. The prespecified noninferiority margin was 3%. Secondary outcomes included the individual components of the primary outcome.
Results
Between April 2, 2017, and December 30, 2020, 888 patients were randomized to either early (n=450) or delayed (n=438) initiation of NOAC. No patient was lost to 90-day follow-up. Mean age was 78.3 years (SD, 9.9 years); 46.2% were women; 49.1% had previously known atrial fibrillation; and 17.5% prior stroke. The primary outcome occurred in 31 patients (6.89%) assigned to early initiation and in 38 patients (8.68%) assigned to delayed NOAC initiation (absolute risk difference, -1.79% [95% CI, -5.31% to 1.74%]; Pnoninferiority=0.004). Ischemic stroke rates were 3.11% and 4.57% (risk difference, -1.46% [95% CI, -3.98% to 1.07%]) and all-cause mortality rates were 4.67% and 5.71% (risk difference, -1.04% [95% CI, -3.96% to 1.88%]) in the early and delayed groups, respectively. No patient in either group experienced symptomatic intracerebral hemorrhage.
Conclusions
Early initiation was noninferior to delayed start of NOAC after acute ischemic stroke in patients with atrial fibrillation. Numerically lower rates of ischemic stroke and death and the absence of symptomatic intracerebral hemorrhages implied that the early start of NOAC was safe and should be considered for acute secondary stroke prevention in patients eligible for NOAC treatment.
Registration
URL: http://www.
Clinicaltrials
gov; Unique identifier: NCT02961348.



Circulation: 06 Sep 2022:101161CIRCULATIONAHA122060666; epub ahead of print
Oldgren J, Åsberg S, Hijazi Z, Wester P, ... Norrving B, National TIMING Collaborators
Circulation: 06 Sep 2022:101161CIRCULATIONAHA122060666; epub ahead of print | PMID: 36065821
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Abstract

Protecting Cardiovascular Health From Wildfire Smoke.

Hadley MB, Henderson SB, Brauer M, Vedanthan R
Wildfire smoke is a rapidly growing threat to global cardiovascular health. We review the literature linking wildfire smoke exposures to cardiovascular effects. We find substantial evidence that short-term exposures are associated with key cardiovascular outcomes, including mortality, hospitalization, and acute coronary syndrome. Wildfire smoke exposures will continue to increase over the majority of Earth\'s surface. For example, the United States alone has experienced a 5-fold increase in annual area burned since 1972, with 82 million individuals estimated to be exposed to wildfire smoke by midcentury. The associated rise in excess morbidity and mortality constitutes a growing global public health crisis. Fortunately, the effect of wildfire smoke on cardiovascular health is modifiable at the individual and population levels through specific interventions. Health systems therefore have an opportunity to help safeguard patients from smoke exposures. We provide a roadmap of evidence-based interventions to reduce risk and protect cardiovascular health. Key interventions include preparing health systems for smoke events; identifying and educating vulnerable patients; reducing outdoor activities; creating cleaner air environments; using air filtration devices and personal respirators; and aggressive management of chronic diseases and traditional risk factors. Further research is needed to test the efficacy of interventions on reducing cardiovascular outcomes.



Circulation: 06 Sep 2022; 146:788-801
Hadley MB, Henderson SB, Brauer M, Vedanthan R
Circulation: 06 Sep 2022; 146:788-801 | PMID: 36067276
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Abstract

Management of Infective Endocarditis in People Who Inject Drugs: A Scientific Statement From the American Heart Association.

Baddour LM, Weimer MB, Wurcel AG, McElhinney DB, ... American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Commingttee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiovascular Surgery and Aniesthesia; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease
Background
The American Heart Association has sponsored both guidelines and scientific statements that address the diagnosis, management, and prevention of infective endocarditis. As a result of the unprecedented and increasing incidence of infective endocarditis cases among people who inject drugs, the American Heart Association sponsored this original scientific statement. It provides a more in-depth focus on the management of infective endocarditis among this unique population than what has been provided in prior American Heart Association infective endocarditis-related documents.
Methods
A writing group was named and consisted of recognized experts in the fields of infectious diseases, cardiology, addiction medicine, and cardiovascular surgery in October 2021. A literature search was conducted in Embase on November 19, 2021, and multiple terms were used, with 1345 English-language articles identified after removal of duplicates.
Conclusions
Management of infective endocarditis in people who inject drugs is complex and requires a unique approach in all aspects of care. Clinicians must appreciate that it requires involvement of a variety of specialists and that consultation by addiction-trained clinicians is as important as that of more traditional members of the endocarditis team to improve infective endocarditis outcomes. Preventive measures are critical in people who inject drugs and are cured of an initial bout of infective endocarditis because they remain at extremely high risk for subsequent bouts of infective endocarditis, regardless of whether injection drug use is continued.



Circulation: 31 Aug 2022:101161CIR0000000000001090; epub ahead of print
Baddour LM, Weimer MB, Wurcel AG, McElhinney DB, ... American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Commingttee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiovascular Surgery and Aniesthesia; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease
Circulation: 31 Aug 2022:101161CIR0000000000001090; epub ahead of print | PMID: 36043414
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Impact:
Abstract

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

Bonaca MP, Morrow DA, Bergmark BA, Berg DD, ... George RT, Sabatine MS
Background
High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction.
Methods
REAL-TIMI 63B (A Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012.
Results
A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 145.5 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1%. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events.
Conclusions
Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03578809.



Circulation: 30 Aug 2022:101161CIRCULATIONAHA122059325; epub ahead of print
Bonaca MP, Morrow DA, Bergmark BA, Berg DD, ... George RT, Sabatine MS
Circulation: 30 Aug 2022:101161CIRCULATIONAHA122059325; epub ahead of print | PMID: 36039762
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Impact:
Abstract

Impact on Mortality and Major Bleeding of Radial Versus Femoral Artery Access for Coronary Angiography or Percutaneous Coronary Intervention: a Meta-analysis of Individual Patient Data from Seven Multicenter Randomized Clinical Trials.

Gargiulo G, Giacoppo D, Jolly SS, Cairns J, ... Valgimigli M, Radial Trialists\' Collaboration
Background
In some randomized controlled trials (RCTs), transradial (TRA) compared with transfemoral access (TFA) was associated with lower mortality in coronary artery disease patients undergoing invasive management. We analyzed the effects of TRA versus TFA across multicenter RCTs and whether these associations are modified by patient or operator characteristics.
Methods
We performed an individual patient data meta-analysis of multicenter RCTs comparing TRA versus TFA among patients undergoing coronary angiography with or without percutaneous coronary intervention (PCI) (PROSPERO; CRD42018109664). The primary outcome was all-cause mortality and the co-primary outcome was major bleeding at 30 days. The primary analysis was conducted by one-stage mixed-effects models based on the intention-to-treat cohort. The impact of access-site on mortality and major bleeding was further assessed by multivariable analysis. The relationship among access-site, bleeding, and mortality was investigated by natural effect model mediation analysis with multivariable adjustment.
Results
A total of 21,600 patients (TRA=10,775 vs. TFA=10,825) from 7 RCTs were included. Median age was 63.9 years, 31.9% were female, 95% presented with acute coronary syndrome (ACS), and 75.2% underwent PCI. All-cause mortality (1.6% vs. 2.1%; HR 0.77, 95% CI 0.63-0.95, p=0.012) and major bleeding (1.5% vs. 2.7%; OR 0.55, 95% CI 0.45- 0.67, p<0.001) were lower with TRA. Subgroup analyses for mortality showed consistent results, except for baseline hemoglobin (pinteraction=0.033), indicating that the benefit of TRA was substantial in patients with significant anemia, while it was not significant in patients with milder or no baseline anemia. After adjustment, TRA remained associated with 24% and 51% relative risk reduction of all-cause mortality and major bleeding. A mediation analysis showed that the benefit of TRA on mortality was only partially driven by major bleeding prevention, and ancillary mechanisms are required to fully explain the causal association.
Conclusions
TRA is associated with lower all-cause mortality and major bleeding at 30 days, compared with TFA. The effect on mortality was driven by patients with anemia. The reduction in major bleeding only partially explains the mortality benefit.



Circulation: 29 Aug 2022; epub ahead of print
Gargiulo G, Giacoppo D, Jolly SS, Cairns J, ... Valgimigli M, Radial Trialists' Collaboration
Circulation: 29 Aug 2022; epub ahead of print | PMID: 36036610
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Impact:
Abstract

Association Between Device-Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of 94 739 UK Biobank Participants.

Ho FK, Zhou Z, Petermann-Rocha F, Para-Soto S, ... Pell JP, Celis-Morales C
Background
Studies of objectively measured physical activity (PA) have investigated acute cardiovascular outcomes but not heart failure (HF), an emerging chronic condition. This study aimed to investigate the dose-response relationship between device-measured PA and HF by intensity of PA.
Methods
This was a prospective cohort study of 94 739 UK Biobank participants who had device-measured PA in 2013 to 2015 and were free from myocardial infarction and HF. PA was measured with a wrist-worn accelerometer, and time spent on light-, moderate-, and vigorous-intensity PA was extracted. Incident HF was ascertained from linked hospital and death records. Cox proportional hazard models with cubic penalized splines were used to study the associations, which were adjusted for sociodemographic and lifestyle factors. Competing risk was handled with cause-specific hazard ratios.
Results
The overall incidence of HF was 98.5 per 10 000 person-years over a median 6.1 years of follow-up. Compared with participants who undertook no moderate- to vigorous-intensity PA, those who performed 150 to 300 min/wk of moderate intensity PA (hazard ratio, 0.37 [95% CI, 0.34-0.41]) and 75 to 150 min/wk of vigorous-intensity PA (hazard ratio, 0.34 [95% CI, 0.25-0.46]) were at lower HF risk. The association between vigorous-intensity PA and HF was reverse-J shaped with a potentially lower risk reduction above 150 min/wk.
Conclusions
Device-measured PA, especially moderate-intensity PA, was associated with a lower risk of HF. Current vigorous-intensity PA recommendations should be encouraged but not increased. In contrast, increasing moderate-intensity PA may be beneficial even among those meeting current recommendations.



Circulation: 29 Aug 2022; epub ahead of print
Ho FK, Zhou Z, Petermann-Rocha F, Para-Soto S, ... Pell JP, Celis-Morales C
Circulation: 29 Aug 2022; epub ahead of print | PMID: 36036153
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Impact:
Abstract

Long-Term Evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease.

O\'Donoghue ML, Giugliano RP, Wiviott SD, Atar D, ... Abbasi S, Sabatine MS
Background
In FOURIER, the PCSK9 inhibitor evolocumab reduced LDL-C and risk of cardiovascular events and was safe and well-tolerated over 2.2 years median follow-up. However, large-scale, long-term data are lacking.
Methods
The parent FOURIER trial randomized 27,564 patients with ASCVD and LDL-C ≥70mg/dl on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in two open-label extension studies (FOURIER-OLE) in the United States and Europe; primary analyses were pooled across studies. The primary endpoint was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected.
Results
6,635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dl and 63.2% achieved LDL-C <40 mg/dl on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long-term did not exceed those for placebo-treated patients during parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, MI, stroke, hospitalization for unstable angina or coronary revascularization (HR 0.85 [95% CI 0.75-0.96]; P=0.008), a 20% lower risk of cardiovascular death, MI or stroke of (HR 0.80 [0.68-0.93]; P=0.003), and a 23% lower risk of cardiovascular death (HR 0.77 [0.60-0.99]; P=0.04).
Conclusions
Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for over >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation.



Circulation: 29 Aug 2022; epub ahead of print
O'Donoghue ML, Giugliano RP, Wiviott SD, Atar D, ... Abbasi S, Sabatine MS
Circulation: 29 Aug 2022; epub ahead of print | PMID: 36031810
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Impact:
Abstract

Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients with COVID-19: COVID-PACT.

Bohula EA, Berg DD, Lopes MS, Connors JM, ... Sabatine MS, Morrow DA
Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically-ill COVID-19 patients remains uncertain.
Methods:
COVID-PACT was a multicenter, 2x2 factorial, open-label, randomized-controlled trial with blinded endpoint adjudication in ICU-level patients with COVID-19. Patients were randomized to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death due to venous or arterial thrombosis, pulmonary embolism, clinically-evident deep venous thrombosis (DVT), type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically-silent DVT, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win-ratio and time-to-first event analysis while patients were on-treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was GUSTO moderate/severe bleeding. Recruitment was stopped early in 03/2022 (∼50% planned recruitment) due to waning ICU-level COVID-19 rates.
Results:
At 34 centers in the United States, 390 patients were randomized between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio 1.95, 95%CI 1.08-3.55, p=0.028). Results were consistent in time-to-event analysis for the primary efficacy endpoint (full-dose versus standard-dose incidence 19/191 [9.9%] vs 29/191 [15.2%]; HR 0.56, 95%CI 0.32-0.99, p=0.046). The primary safety endpoint occurred in 4 (2.1%) on full-dose and in 1 (0.5%) on standard-dose (p=0.19); the secondary safety endpoint occurred in 15 (7.9%) versus 1 (0.5%; p=0.002). There was no difference in all-cause mortality (HR 0.91, 95%CI 0.56-1.48; p=0.70). There were no differences in the primary efficacy or safety endpoints with clopidogrel versus no antiplatelet therapy. Conclusions: In critically-ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality.




Circulation: 29 Aug 2022; epub ahead of print
Bohula EA, Berg DD, Lopes MS, Connors JM, ... Sabatine MS, Morrow DA
Circulation: 29 Aug 2022; epub ahead of print | PMID: 36036760
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Impact:
Abstract

Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure: A Prespecified Analysis of the DELIVER Trial.

Butt JH, Jhund PS, Belohlávek J, de Boer RA, ... Solomon SD, McMurray JJV
Background: Frailty is increasing in prevalence and because frail patients are often perceived to have a less favorable benefit/risk profile, they may be less likely to receive new pharmacological treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure and mildly reduced and preserved ejection fraction randomized in DELIVER.
Methods:
Frailty was measured using the Rockwood cumulative deficit approach. The primary endpoint was time to a first worsening heart failure event or cardiovascular death.
Results:
Of the 6263 patients randomized, a Frailty Index (FI) was calculable in 6258. In total, 2,354 (37.6%) patients had class 1 frailty (FI <0.210, i.e., not frail), 2,413 (38.6%) were in class 2 (FI 0.211-0.310, i.e., more frail), and 1,491 (23.8%) had class 3 frailty (FI >0.311, i.e., most frail). Greater frailty was associated with a higher rate of the primary endpoint (per 100 person years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7), P<0.001. The effect of dapagliflozin (as a hazard ratio) on the primary endpoint from FI class 1 to 3 was: 0.85 (95% CI, 0.68-1.06); 0.89 (0.74-1.08); and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although frailer patients had worse KCCQ scores at baseline, the improvement with dapagliflozin was greater than in less frail patients: placebo-corrected improvement in KCCQ-OSS at 4 months FI class 1, 0.3 (95% CI -0.9 to 1.4); class 2, 1.5 (0.3-2.7); and class 3, 3.4 (1.7-5.1) [Pinteraction=0.021]. Adverse reactions and treatment discontinuation, while more frequent in frailer patients, were not more common with dapagliflozin than placebo, irrespective of frailty class. Conclusions: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with greater frailty.




Circulation: 27 Aug 2022; epub ahead of print
Butt JH, Jhund PS, Belohlávek J, de Boer RA, ... Solomon SD, McMurray JJV
Circulation: 27 Aug 2022; epub ahead of print | PMID: 36029465
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Impact:
Abstract

A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes Following Acute Myocardial Infarction.

Rao SV, Kirsch B, Bhatt DL, Budaj A, ... Mundl H, Alexander JH
Background
Oral factor XIa (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without significantly increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI).
Methods
We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6-2 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on factor XIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo.
Results
The median age was 68 years, 23% were women, 51% had ST-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10, 20, 50 mg, and placebo (pooled asundexian vs. placebo: HR 0.98, 90% CI 0.71-1.35). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10, 20, 50 mg, and placebo (pooled asundexian 20 and 50 mg vs. placebo: HR 1.05, 90% CI 0.69-1.61).
Conclusions
In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients following acute MI.



Circulation: 27 Aug 2022; epub ahead of print
Rao SV, Kirsch B, Bhatt DL, Budaj A, ... Mundl H, Alexander JH
Circulation: 27 Aug 2022; epub ahead of print | PMID: 36030390
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Impact:
Abstract

Plasma Cell-Free DNA Predicts Survival and Maps Specific Sources of Injury in Pulmonary Arterial Hypertension.

Brusca SB, Elinoff JM, Zou Y, Jang MK, ... Agbor-Enoh S, Solomon MA
Background
Cell-free DNA (cfDNA) is a noninvasive marker of cellular injury. Its significance in pulmonary arterial hypertension (PAH) is unknown.
Methods
Plasma cfDNA was measured in 2 PAH cohorts (A, n=48; B, n=161) and controls (n=48). Data were collected for REVEAL 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) scores and outcome determinations. Patients were divided into the following REVEAL risk groups: low (≤6), medium (7-8), and high (≥9). Total cfDNA concentrations were compared among controls and PAH risk groups by 1-way analysis of variance. Log-rank tests compared survival between cfDNA tertiles and REVEAL risk groups. Areas under the receiver operating characteristic curve were estimated from logistic regression models. A sample subset from cohort B (n=96) and controls (n=16) underwent bisulfite sequencing followed by a deconvolution algorithm to map cell-specific cfDNA methylation patterns, with concentrations compared using t tests.
Results
In cohort A, median (interquartile range) age was 62 years (47-71), 75% female, versus 6 (4-9) in REVEAL 2.0. In cohort B, median (interquartile range) age was 59 years (49-71), 69% female, versus 7 (6-9) in REVEAL 2.0. In both cohorts, cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls (analysis of variance P≤0.002) and were greater in the high-risk compared with the low-risk category (P≤0.002). In cohort B, death or lung transplant occurred in 14 of 54, 23 of 53, and 35 of 54 patients in the lowest, middle, and highest cfDNA tertiles, respectively. cfDNA levels stratified as tertiles (log-rank: P=0.0001) and REVEAL risk groups (log-rank: P<0.0001) each predicted transplant-free survival. The addition of cfDNA to REVEAL improved discrimination (area under the receiver operating characteristic curve, 0.72-0.78; P=0.02). Compared with controls, methylation analysis in patients with PAH revealed increased cfDNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes (Bonferroni adjusted P<0.05). cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium were greater in patients with PAH with high-risk versus low-risk REVEAL scores (P≤0.02).
Conclusions
Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival. Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis.



Circulation: 25 Aug 2022:101161CIRCULATIONAHA121056719; epub ahead of print
Brusca SB, Elinoff JM, Zou Y, Jang MK, ... Agbor-Enoh S, Solomon MA
Circulation: 25 Aug 2022:101161CIRCULATIONAHA121056719; epub ahead of print | PMID: 36004627
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Impact:
Abstract

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension.

Cao N, Lan C, Chen C, Xu Z, ... Yu J, Zeng C
Background
Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known.
Methods
Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential prevention and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation.
Results
Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS-exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 (Rac1) gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of Rac1. Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension.
Conclusions
These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.



Circulation: 25 Aug 2022:CIRCULATIONAHA122059891; epub ahead of print
Cao N, Lan C, Chen C, Xu Z, ... Yu J, Zeng C
Circulation: 25 Aug 2022:CIRCULATIONAHA122059891; epub ahead of print | PMID: 36004643
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Impact:
Abstract

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

Tabák AG, Brunner EJ, Lindbohm JV, Singh-Manoux A, ... Sattar N, Kivimäki M
Background
It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease.
Methods
Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min-1·1.73 m-2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants.
Results
Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population.
Conclusions
More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.



Circulation: 25 Aug 2022:101161CIRCULATIONAHA122059430; epub ahead of print
Tabák AG, Brunner EJ, Lindbohm JV, Singh-Manoux A, ... Sattar N, Kivimäki M
Circulation: 25 Aug 2022:101161CIRCULATIONAHA122059430; epub ahead of print | PMID: 36004644
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Impact:
Abstract

Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator.

Nordenswan HK, Pöyhönen P, Lehtonen J, Ekström K, ... Pietilä-Effati P, Kupari M
Background
Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown.
Methods
We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up.
Results
Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (χ2=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; χ2=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; χ2=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation.
Conclusions
Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.



Circulation: 24 Aug 2022:101161CIRCULATIONAHA121058120; epub ahead of print
Nordenswan HK, Pöyhönen P, Lehtonen J, Ekström K, ... Pietilä-Effati P, Kupari M
Circulation: 24 Aug 2022:101161CIRCULATIONAHA121058120; epub ahead of print | PMID: 36000392
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Impact:
Abstract

Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages.

Yaku A, Inagaki T, Asano R, Okazawa M, ... Nakaoka Y, Takeuchi O
Background
Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension (PH) characterized by obliterative pulmonary vascular remodeling, resulting in right-sided heart failure. Although the pathogenesis of PAH is not fully understood, inflammatory responses and cytokines have been shown to be associated with PAH, in particular, with connective tissue disease-PAH. In this sense, Regnase-1, an RNase that regulates mRNAs encoding genes related to immune reactions, was investigated in relation to the pathogenesis of PH.
Methods
We first examined the expression levels of ZC3H12A (encoding Regnase-1) in peripheral blood mononuclear cells from patients with PH classified under various types of PH, searching for an association between the ZC3H12A expression and clinical features. We then generated mice lacking Regnase-1 in myeloid cells, including alveolar macrophages, and examined right ventricular systolic pressures and histological changes in the lung. We further performed a comprehensive analysis of the transcriptome of alveolar macrophages and pulmonary arteries to identify genes regulated by Regnase-1 in alveolar macrophages.
Results
ZC3H12A expression in peripheral blood mononuclear cells was inversely correlated with the prognosis and severity of disease in patients with PH, in particular, in connective tissue disease-PAH. The critical role of Regnase-1 in controlling PAH was also reinforced by the analysis of mice lacking Regnase-1 in alveolar macrophages. These mice spontaneously developed severe PAH, characterized by the elevated right ventricular systolic pressures and irreversible pulmonary vascular remodeling, which recapitulated the pathology of patients with PAH. Transcriptomic analysis of alveolar macrophages and pulmonary arteries of these PAH mice revealed that Il6, Il1b, and Pdgfa/b are potential targets of Regnase-1 in alveolar macrophages in the regulation of PAH. The inhibition of IL-6 (interleukin-6) by an anti-IL-6 receptor antibody or platelet-derived growth factor by imatinib but not IL-1β (interleukin-1β) by anakinra, ameliorated the pathogenesis of PAH.
Conclusions
Regnase-1 maintains lung innate immune homeostasis through the control of IL-6 and platelet-derived growth factor in alveolar macrophages, thereby suppressing the development of PAH in mice. Furthermore, the decreased expression of Regnase-1 in various types of PH implies its involvement in PH pathogenesis and may serve as a disease biomarker, and a therapeutic target for PH as well.



Circulation: 23 Aug 2022:101161CIRCULATIONAHA122059435; epub ahead of print
Yaku A, Inagaki T, Asano R, Okazawa M, ... Nakaoka Y, Takeuchi O
Circulation: 23 Aug 2022:101161CIRCULATIONAHA122059435; epub ahead of print | PMID: 35997026
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Abstract

Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

Patone M, Mei XW, Handunnetthi L, Dixon S, ... Sheikh A, Hippisley-Cox J
Background
Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain.
Methods
A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test.
Results
In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09-1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24-1.85]; 1.57 [95% CI, 1.28-1.92], and 1.72 [95% CI, 1.33-2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64-14.36] and 5.97 [95% CI, 4.54-7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25-19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25-5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91-99] versus 16 [95% CI, 12-18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1-9] versus 8 [95% CI, 6-8]).
Conclusions
Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.



Circulation: 22 Aug 2022; epub ahead of print
Patone M, Mei XW, Handunnetthi L, Dixon S, ... Sheikh A, Hippisley-Cox J
Circulation: 22 Aug 2022; epub ahead of print | PMID: 35993236
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Abstract

HNRNPA2B1: RNA-Binding Protein That Orchestrates Smooth Muscle Cell Phenotype in Pulmonary Arterial Hypertension.

Ruffenach G, Medzikovic L, Aryan L, Li M, Eghbali M
Background
RNA-binding proteins are master orchestrators of gene expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs. Thus, characterizing RNA-binding proteins targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RNA-binding protein targets, limiting our understanding of their function. In cancer, the RNA-binding protein HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1; A2B1) promotes the pro-proliferative/anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMCs) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH.
Method
Through the integration of computational and experimental biology, the authors investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA sequencing allowed them to investigate the transcriptome-wide function of A2B1, and RNA immunoprecipitation and A2B1 silencing experiments allowed them to decipher the intricate molecular mechanism at play. In addition, they performed a preclinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity.
Results
They found that A2B1 expression and its nuclear localization are increased in human PAH-PASMC. Using bioinformatics, they identified 3 known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, they demonstrated the complementary nonredundant function of A2B1 motifs because all motifs are implicated in different aspects of the cell cycle. In addition, they showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC led to a decrease of all tested mRNAs carrying an A2B1 motif and a concomitant decrease in proliferation and resistance to apoptosis. Last, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats.
Conclusions
Through the integration of computational and experimental biology, the study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.



Circulation: 22 Aug 2022:101161CIRCULATIONAHA122059591; epub ahead of print
Ruffenach G, Medzikovic L, Aryan L, Li M, Eghbali M
Circulation: 22 Aug 2022:101161CIRCULATIONAHA122059591; epub ahead of print | PMID: 35993245
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Abstract

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.

Dhingra R, Rabinovich-Nikitin I, Rothman S, Guberman M, ... Javaheri A, Kirshenbaum LA
Background
Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (tumor necrosis factor activating factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα-TRAF2-NF-κB signaling in the pathogenesis of DOX cardiotoxicity.
Methods
Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg-1·wk-1) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability.
Results
In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific protein 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1(H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX.
Conclusions
Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.



Circulation: 19 Aug 2022:101161CIRCULATIONAHA121058411; epub ahead of print
Dhingra R, Rabinovich-Nikitin I, Rothman S, Guberman M, ... Javaheri A, Kirshenbaum LA
Circulation: 19 Aug 2022:101161CIRCULATIONAHA121058411; epub ahead of print | PMID: 35983756
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Abstract

State of the Science: The Relevance of Symptoms in Cardiovascular Disease and Research: A Scientific Statement From the American Heart Association.

Jurgens CY, Lee CS, Aycock DM, Masterson Creber R, ... Konstam MA, American Heart Association Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Stroke Council
Symptoms of cardiovascular disease drive health care use and are a major contributor to quality of life. Symptoms are of fundamental significance not only to the diagnosis of cardiovascular disease and appraisal of response to medical therapy but also directly to patients\' daily lives. The primary purpose of this scientific statement is to present the state of the science and relevance of symptoms associated with cardiovascular disease. Symptoms as patient-reported outcomes are reviewed in terms of the genesis, manifestation, and similarities or differences between diagnoses. Specifically, symptoms associated with acute coronary syndrome, heart failure, valvular disorders, stroke, rhythm disorders, and peripheral vascular disease are reviewed. Secondary aims include (1) describing symptom measurement methods in research and application in clinical practice and (2) describing the importance of cardiovascular disease symptoms in terms of clinical events and other patient-reported outcomes as applicable.



Circulation: 18 Aug 2022:101161CIR0000000000001089; epub ahead of print
Jurgens CY, Lee CS, Aycock DM, Masterson Creber R, ... Konstam MA, American Heart Association Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Stroke Council
Circulation: 18 Aug 2022:101161CIR0000000000001089; epub ahead of print | PMID: 35979825
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Abstract

Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA-HF.

Docherty KF, Welsh P, Verma S, De Boer RA, ... McMurray JJV, DAPA-HF Investigators and Committees
Background
Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline.
Methods
Iron deficiency was defined as a ferritin level <100 ng/mL or a transferrin saturation <20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.
Results
Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P<0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron-replete patients (hazard ratio, 0.74 [95% CI, 0.58-0.92] versus 0.81 [95% CI, 0.63-1.03]; P-interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo.
Conclusions
Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03036124.



Circulation: 16 Aug 2022:101161CIRCULATIONAHA122060511; epub ahead of print
Docherty KF, Welsh P, Verma S, De Boer RA, ... McMurray JJV, DAPA-HF Investigators and Committees
Circulation: 16 Aug 2022:101161CIRCULATIONAHA122060511; epub ahead of print | PMID: 35971840
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Abstract

Patients With Bicuspid Aortic Stenosis Demonstrate Adverse Left Ventricular Remodeling and Impaired Cardiac Function Before Surgery With Increased Risk of Postoperative Heart Failure.

Wedin JO, Vedin O, Rodin S, Simonson OE, ... Ståhle E, Grinnemo KH
Background
Differences in adverse cardiac remodeling between patients who have bicuspid (BAV) and tricuspid aortic valve (TAV) with severe isolated aortic stenosis (AS) and its prognostic impact after surgical aortic valve replacement remains unclear. We sought to investigate differences in preoperative diastolic and systolic function in patients with BAV and TAV who have severe isolated AS and the incidence of postoperative heart failure hospitalization and mortality.
Methods
Two hundred seventy-one patients with BAV (n=152) or TAV (n=119) and severe isolated AS without coronary artery disease or other valvular heart disease, scheduled for surgical aortic valve replacement, were prospectively included. Comprehensive preoperative echocardiographic assessment of left ventricular (LV) diastolic and systolic function was performed. The heart failure events were registered during a mean prospective follow-up of 1260 days versus 1441 days for patients with BAV or TAV, respectively.
Results
Patients with BAV had a more pronounced LV hypertrophy with significantly higher indexed LV mass ([LVMi] 134 g/m2 versus 104 g/m2, P<0.001), higher prevalence of LV diastolic dysfunction (72% versus 44%, P<0.001), reduced LV ejection fraction (55% versus 60%, P<0.001), significantly impaired global longitudinal strain (P<0.001), significantly higher NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P=0.007), and a higher prevalence of preoperative levosimendan treatment (P<0.001) than patients with TAV. LVMi was associated with diastolic dysfunction in both patients with BAV and TAV. There was a significant interaction between aortic valve morphology and LVMi on LV ejection fraction, which indicated a pronounced association between LVMi and LV ejection fraction for patients with BAV and lack of association between LVMi and LV ejection fraction for patients with TAV. Postoperatively, the patients with BAV required significantly more inotropic support (P<0.001). The patients with BAV had a higher cumulative incidence of postoperative heart failure admissions compared with patients with TAV (28.2% versus 10.6% at 6 years after aortic valve replacement, log-rank P=0.004). Survival was not different between patients with BAV and TAV (log-rank P=0.165).
Conclusions
Although they were significantly younger, patients with BAV who had isolated severe AS had worse preoperative LV function and an increased risk of postoperative heart failure hospitalization compared with patients who had TAV. Our findings suggest that patients who have BAV with AS might benefit from closer surveillance and possibly earlier intervention.



Circulation: 16 Aug 2022:101161CIRCULATIONAHA122060125; epub ahead of print
Wedin JO, Vedin O, Rodin S, Simonson OE, ... Ståhle E, Grinnemo KH
Circulation: 16 Aug 2022:101161CIRCULATIONAHA122060125; epub ahead of print | PMID: 35971843
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Abstract

Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden.

Rillig A, Borof K, Breithardt G, Camm AJ, ... Zapf A, Kirchhof P
Background
The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known.
Methods
These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA2DS2-VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA2DS2-VA score).
Results
EAST-AFNET4 randomized 1093 patients with CHA2DS2-VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA2DS2-VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA2DS2-VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA2DS2-VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P=0.56, Pinteraction=0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA2DS2-VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P=0.175), but occurred more often in patients with CHA2DS2-VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P=0.019, Pinteraction=0.008). Life-threatening events or death were not different between groups (CHA2DS2-VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA2DS2-VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA2DS2-VA score), the Pinteraction was not significant for the primary efficacy outcome (P=0.25), but remained significant (P=0.044) for the primary safety outcome.
Conclusions
Patients with recently diagnosed atrial fibrillation and CHA2DS2-VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT01288352; URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20; URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.



Circulation: 15 Aug 2022:101161CIRCULATIONAHA122060274; epub ahead of print
Rillig A, Borof K, Breithardt G, Camm AJ, ... Zapf A, Kirchhof P
Circulation: 15 Aug 2022:101161CIRCULATIONAHA122060274; epub ahead of print | PMID: 35968706
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Impact:
Abstract

Cardiovascular Effects of Home Dialysis Therapies: A Scientific Statement From the American Heart Association.

Sarnak MJ, Auguste BL, Brown E, Chang AR, ... American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Hypertension; and Council on Lifestyle and Cardiometabolic Health
Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage kidney disease. Currently, thrice-weekly in-center hemodialysis for 3 to 5 hours per session is the most common therapy worldwide for patients with treated kidney failure. Outcomes with thrice-weekly in-center hemodialysis are poor. Emerging evidence supports the overarching hypothesis that a more physiological approach to administering dialysis therapy, including in the home through home hemodialysis or peritoneal dialysis, may lead to improvement in several cardiovascular risk factors and cardiovascular outcomes compared with thrice-weekly in-center hemodialysis. The Advancing American Kidney Health Initiative, which has a goal of increasing the use of home dialysis, is aligned with the American Heart Association\'s 2024 mission to champion a full and healthy life and health equity. We conclude that incorporation of interdisciplinary care models to increase the use of home dialysis therapies in an equitable manner will contribute to the ultimate goal of improving outcomes for patients with kidney failure and cardiovascular disease.



Circulation: 15 Aug 2022:101161CIR0000000000001088; epub ahead of print
Sarnak MJ, Auguste BL, Brown E, Chang AR, ... American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Hypertension; and Council on Lifestyle and Cardiometabolic Health
Circulation: 15 Aug 2022:101161CIR0000000000001088; epub ahead of print | PMID: 35968722
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Impact:
Abstract

Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC.

Pérez-Hernández M, van Opbergen CJM, Bagwan N, Rasmus Vissing C, ... Delmar M, Lundby A
Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by high propensity to life-threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to ARVC reside in the PKP2 gene, which encodes the PKP2 protein (plakophilin-2).
Methods
We describe a comprehensive characterization of the ARVC molecular landscape as determined by high-resolution mass spectrometry, RNA sequencing, and transmission electron microscopy of right ventricular biopsy samples obtained from patients with ARVC with PKP2 mutations and left ventricular ejection fraction >45%. Samples from healthy relatives served as controls. The observations led to experimental work using multiple imaging and biochemical techniques in mice with a cardiac-specific deletion of Pkp2 studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell-derived PKP2-deficient myocytes.
Results
Samples from patients with ARVC present a loss of nuclear envelope integrity, molecular signatures indicative of increased DNA damage, and a deficit in transcripts coding for proteins in the electron transport chain. Mice with a cardiac-specific deletion of Pkp2 also present a loss of nuclear envelope integrity, which leads to DNA damage and subsequent excess oxidant production (O2.- and H2O2), the latter increased further under mechanical stress (isoproterenol or exercise). Increased oxidant production and DNA damage is recapitulated in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Furthermore, PKP2-deficient cells release H2O2 into the extracellular environment, causing DNA damage and increased oxidant production in neighboring myocytes in a paracrine manner. Treatment with honokiol increases mitochondrial nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT3 (sirtuin 3) activity, reduces oxidant levels and DNA damage in vitro and in vivo, reduces collagen abundance in the right ventricular free wall, and has a protective effect on right ventricular function.
Conclusions
Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of ARVC. We show transcriptional downregulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease (before loss of left ventricular ejection fraction <45%), which associates with increased oxidant production (O2.- and H2O2). We propose therapies that limit oxidant formation as a possible intervention to restrict DNA damage in ARVC.



Circulation: 12 Aug 2022:101161CIRCULATIONAHA122060454; epub ahead of print
Pérez-Hernández M, van Opbergen CJM, Bagwan N, Rasmus Vissing C, ... Delmar M, Lundby A
Circulation: 12 Aug 2022:101161CIRCULATIONAHA122060454; epub ahead of print | PMID: 35959657
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Impact:
Abstract

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations.

Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.



Circulation: 11 Aug 2022:101161CIRCULATIONAHA121054602; epub ahead of print
Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
Circulation: 11 Aug 2022:101161CIRCULATIONAHA121054602; epub ahead of print | PMID: 35950927
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Impact:
Abstract

Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial.

Stables RH, Mullen LJ, Elguindy M, Nicholas Z, ... De Bruyne B, Curzen N
Background
Measurement of fractional flow reserve (FFR) has an established role in guiding percutaneous coronary intervention. We tested the hypothesis that, at the stage of diagnostic invasive coronary angiography, systematic FFR-guided assessment of coronary artery disease would be superior, in terms of resource use and quality of life, to assessment by angiography alone.
Methods
We performed an open-label, randomized, controlled trial in 17 UK centers, recruiting 1100 patients undergoing invasive coronary angiography for the investigation of stable angina or non-ST-segment-elevation myocardial infarction. Patients were randomized to either angiography alone (angiography) or angiography with systematic pressure wire assessment of all epicardial vessels >2.25 mm in diameter (angiography+FFR). The coprimary outcomes assessed at 1 year were National Health Service hospital costs and quality of life. Prespecified secondary outcomes included clinical events.
Results
In the angiography+FFR arm, the median number of vessels examined was 4 (interquartile range, 3-5). The median hospital costs were similar: angiography, £4136 (interquartile range, £2613-£7015); and angiography+FFR, £4510 (£2721-£7415; P=0.137). There was no difference in median quality of life using the visual analog scale of the EuroQol EQ-5D-5L: angiography, 75 (interquartile range, 60-87); and angiography+FFR, 75 (interquartile range, 60-90; P=0.88). The number of clinical events was as follows: deaths, 5 versus 8; strokes, 3 versus 4; myocardial infarctions, 23 versus 22; and unplanned revascularizations, 26 versus 33, with a composite hierarchical event rate of 8.7% (48 of 552) for angiography versus 9.5% (52 of 548) for angiography+FFR (P=0.64).
Conclusions
A strategy of systematic FFR assessment compared with angiography alone did not result in a significant reduction in cost or improvement in quality of life.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier NCT01070771.



Circulation: 10 Aug 2022:101161CIRCULATIONAHA121057793; epub ahead of print
Stables RH, Mullen LJ, Elguindy M, Nicholas Z, ... De Bruyne B, Curzen N
Circulation: 10 Aug 2022:101161CIRCULATIONAHA121057793; epub ahead of print | PMID: 35946404
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Impact:
Abstract

Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell-Derived Cardiac Progenitors.

Zhu L, Choudhary K, Gonzalez-Teran B, Ang YS, ... Pollard KS, Srivastava D
Background
GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors.
Methods
We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4\'s novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors.
Results
We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms.
Conclusions
This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.



Circulation: 08 Aug 2022:CIRCULATIONAHA121057620; epub ahead of print
Zhu L, Choudhary K, Gonzalez-Teran B, Ang YS, ... Pollard KS, Srivastava D
Circulation: 08 Aug 2022:CIRCULATIONAHA121057620; epub ahead of print | PMID: 35938400
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Abstract

Multinational Federated Learning Approach to Train ECG and Echocardiogram Models for Hypertrophic Cardiomyopathy Detection.

Goto S, Solanki D, John JE, Yagi R, ... MacRae CA, Deo RC
Background
Novel targeted treatments increase the need for prompt hypertrophic cardiomyopathy (HCM) detection. However, its low prevalence (0.5%) and resemblance to common diseases present challenges that may benefit from automated machine learning-based approaches. We aimed to develop machine learning models to detect HCM and to differentiate it from other cardiac conditions using ECGs and echocardiograms, with robust generalizability across multiple cohorts.
Methods
Single-institution HCM ECG models were trained and validated on external data. Multi-institution models for ECG and echocardiogram were trained on data from 3 academic medical centers in the United States and Japan using a federated learning approach, which enables training on distributed data without data sharing. Models were validated on held-out test sets for each institution and from a fourth academic medical center and were further evaluated for discrimination of HCM from aortic stenosis, hypertension, and cardiac amyloidosis. Last, automated detection was compared with manual interpretation by 3 cardiologists on a data set with a realistic HCM prevalence.
Results
We identified 74 376 ECGs for 56 129 patients and 8392 echocardiograms for 6825 patients at the 4 academic medical centers. Although ECG models trained on data from each institution displayed excellent discrimination of HCM on internal test data (C statistics, 0.88-0.93), the generalizability was limited, most notably for a model trained in Japan and tested in the United States (C statistic, 0.79-0.82). When trained in a federated manner, discrimination of HCM was excellent across all institutions (C statistics, 0.90-0.96 and 0.90-0.96 for ECG and echocardiogram model, respectively), including for phenotypic subgroups. The models further discriminated HCM from hypertension, aortic stenosis, and cardiac amyloidosis (C statistics, 0.84, 0.83, and 0.88, respectively, for ECG and 0.93, 0.94, 0.85, respectively, for echocardiogram). Analysis of electrocardiography-echocardiography paired data from 11 823 patients from an external institution indicated a higher sensitivity of automated HCM detection at a given positive predictive value compared with cardiologists (0.98 versus 0.81 at a positive predictive value of 0.01 for ECG and 0.78 versus 0.59 at a positive predictive value of 0.24 for echocardiogram).
Conclusions
Federated learning improved the generalizability of models that use ECGs and echocardiograms to detect and differentiate HCM from other causes of hypertrophy compared with training within a single institution.



Circulation: 02 Aug 2022:CIRCULATIONAHA121058696; epub ahead of print
Goto S, Solanki D, John JE, Yagi R, ... MacRae CA, Deo RC
Circulation: 02 Aug 2022:CIRCULATIONAHA121058696; epub ahead of print | PMID: 35916132
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Abstract

Sleep-Disordered Breathing and Cardiac Arrhythmias in Adults: Mechanistic Insights and Clinical Implications: A Scientific Statement From the American Heart Association.

Mehra R, Chung MK, Olshansky B, Dobrev D, ... Somers VK, American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology; and Stroke Council
Sleep-disordered breathing (SDB), characterized by specific underlying physiological mechanisms, comprises obstructive and central pathophysiology, affects nearly 1 billion individuals worldwide, and is associated with excessive cardiopulmonary morbidity. Strong evidence implicates SDB in cardiac arrhythmogenesis. Immediate consequences of SDB include autonomic nervous system fluctuations, recurrent hypoxia, alterations in carbon dioxide/acid-base status, disrupted sleep architecture, and accompanying increases in negative intrathoracic pressures directly affecting cardiac function. Day-night patterning and circadian biology of SDB-induced pathophysiological sequelae collectively influence the structural and electrophysiological cardiac substrate, thereby creating an ideal milieu for arrhythmogenic propensity. Cohort studies support strong associations of SDB and cardiac arrhythmia, with evidence that discrete respiratory events trigger atrial and ventricular arrhythmic events. Observational studies suggest that SDB treatment reduces atrial fibrillation recurrence after rhythm control interventions. However, high-level evidence from clinical trials that supports a role for SDB intervention on rhythm control is not available. The goals of this scientific statement are to increase knowledge and awareness of the existing science relating SDB to cardiac arrhythmias (atrial fibrillation, ventricular tachyarrhythmias, sudden cardiac death, and bradyarrhythmias), synthesizing data relevant for clinical practice and identifying current knowledge gaps, presenting best practice consensus statements, and prioritizing future scientific directions. Key opportunities identified that are specific to cardiac arrhythmia include optimizing SDB screening, characterizing SDB predictive metrics and underlying pathophysiology, elucidating sex-specific and background-related influences in SDB, assessing the role of mobile health innovations, and prioritizing the conduct of rigorous and adequately powered clinical trials.



Circulation: 01 Aug 2022:CIR0000000000001082; epub ahead of print
Mehra R, Chung MK, Olshansky B, Dobrev D, ... Somers VK, American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology; and Stroke Council
Circulation: 01 Aug 2022:CIR0000000000001082; epub ahead of print | PMID: 35912643
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Impact:
Abstract

Identification of a Gain-of-Function Variant as a Novel Cause of Familial Combined Hypocholesterolemia.

Dijk W, Di Filippo M, Kooijman S, van Eenige R, ... Moulin P, Cariou B
Background
Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family.
Methods
Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance-based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC-E97G overexpression.
Results
Family members carrying the LIPC-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver.
Conclusions
We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.



Circulation: 28 Jul 2022:101161CIRCULATIONAHA121057978; epub ahead of print
Dijk W, Di Filippo M, Kooijman S, van Eenige R, ... Moulin P, Cariou B
Circulation: 28 Jul 2022:101161CIRCULATIONAHA121057978; epub ahead of print | PMID: 35899625
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Impact:
Abstract

Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2.

Sun LY, Lyu YY, Zhang HY, Shen Z, ... Qian K, Pu J
Background
Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear hormone receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown.
Methods
We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)-specific, endothelial cell-specific, and myeloid cell-specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)- and CaPO4-induced AAA models.
Results
Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO4-induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs.
Conclusions
Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.



Circulation: 26 Jul 2022:101161CIRCULATIONAHA121057623; epub ahead of print
Sun LY, Lyu YY, Zhang HY, Shen Z, ... Qian K, Pu J
Circulation: 26 Jul 2022:101161CIRCULATIONAHA121057623; epub ahead of print | PMID: 35880522
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Abstract

Donor Macrophages Modulate Rejection After Heart Transplantation.

Kopecky BJ, Dun H, Amrute JM, Lin CY, ... Kreisel D, Lavine KJ
Background
Cellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge about donor immune cell types and functions in the setting of cardiac transplantation, and no current therapeutics exist for targeting these cell populations.
Methods
Using genetic lineage tracing, cell ablation, and conditional gene deletion, we examined donor mononuclear phagocyte diversity and macrophage function during acute cellular rejection of transplanted hearts in mice. We performed single-cell RNA sequencing on donor and recipient macrophages and monocytes at multiple time points after transplantation. On the basis of our imaging and single-cell RNA sequencing data, we evaluated the functional relevance of donor CCR2+ (C-C chemokine receptor 2) and CCR2- macrophages using selective cell ablation strategies in donor grafts before transplant. Last, we performed functional validation that donor macrophages signal through MYD88 (myeloid differentiation primary response protein 88) to facilitate cellular rejection.
Results
Donor macrophages persisted in the rejecting transplanted heart and coexisted with recipient monocyte-derived macrophages. Single-cell RNA sequencing identified donor CCR2+ and CCR2- macrophage populations and revealed remarkable diversity among recipient monocytes, macrophages, and dendritic cells. Temporal analysis demonstrated that donor CCR2+ and CCR2- macrophages were transcriptionally distinct, underwent significant morphologic changes, and displayed unique activation signatures after transplantation. Although selective depletion of donor CCR2- macrophages reduced allograft survival, depletion of donor CCR2+ macrophages prolonged allograft survival. Pathway analysis revealed that donor CCR2+ macrophages are activated through MYD88/NF-қB signaling. Deletion of MYD88 in donor macrophages resulted in reduced antigen-presenting cell recruitment, reduced ability of antigen-presenting cells to present antigen to T cells, decreased emergence of allograft-reactive T cells, and extended allograft survival.
Conclusions
Distinct populations of donor and recipient macrophages coexist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection, and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.



Circulation: 26 Jul 2022:101161CIRCULATIONAHA121057400; epub ahead of print
Kopecky BJ, Dun H, Amrute JM, Lin CY, ... Kreisel D, Lavine KJ
Circulation: 26 Jul 2022:101161CIRCULATIONAHA121057400; epub ahead of print | PMID: 35880523
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Impact:
Abstract

Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults.

Khan SS, Page C, Wojdyla DM, Schwartz YY, Greenland P, Pencina MJ
Background
Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies.
Methods
Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20-39 years [median, 30 years] of age), early midlife (FOS, 40-59 years [median, 43] years of age), and late midlife (ARIC, 45-59 years [median, 52 years] of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared with assess discrimination for each model individually and together with the optimism-corrected C index (95% CI).
Results
Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 [95% CI, 2.08-3.27], 2.09 [95% CI, 1.83-2.40], and 2.11 [95% CI, 1.96-2.28]) and the PRS (hazard ratio, 1.98 [95% CI, 1.70-2.30], 1.64 [95% CI, 1.47-1.84], and 1.22 [95% CI, 1.15-1.30]) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 [95% CI, 0.70-0.78], 0.70 [95% CI, 0.67-0.72], and 0.72 [95% CI, 0.70-0.73]) compared with an age- and sex-adjusted PRS (0.73 [95% CI, 0.69-0.78], 0.66 [95% CI, 0.62-0.69], and 0.66 [95% CI, 0.64-0.67]) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001-0.05), 0.02 (95% CI, -0.002 to 0.037), and 0.002 (95% CI, -0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively.
Conclusions
Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.



Circulation: 26 Jul 2022:101161CIRCULATIONAHA121058426; epub ahead of print
Khan SS, Page C, Wojdyla DM, Schwartz YY, Greenland P, Pencina MJ
Circulation: 26 Jul 2022:101161CIRCULATIONAHA121058426; epub ahead of print | PMID: 35880530
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Abstract

Management of Atrial Fibrillation Across the Spectrum of Heart Failure With Preserved and Reduced Ejection Fraction.

Reddy YNV, Borlaug BA, Gersh BJ
Atrial fibrillation (AF) is the most common arrhythmia among patients with heart failure (HF), and HF is the most common cause of death for patients presenting with clinical AF. AF is frequently associated with pathological atrial myocardial dysfunction and remodeling, a triad that has been called atrial myopathy. AF can be the cause or consequence of clinical HF, and the directionality varies between individual patients and across the spectrum of HF. Although initial trials suggested no advantage for a systematic rhythm control strategy in HF with reduced ejection fraction, recent data suggest that select patients may benefit from attempts to maintain sinus rhythm with catheter ablation. Preliminary data also show a close relationship among AF, left atrial myopathy, mitral regurgitation, and HF with preserved ejection, with potential clinical benefits to catheter ablation therapy. The modern management of AF in HF also requires consideration of the degree of atrial myopathy and chronicity of AF, in addition to the pathogenesis and phenotype of the underlying left ventricular HF. In this review, we summarize the contemporary management of AF and provide practical guidance and areas in need of future investigation.



Circulation: 26 Jul 2022; 146:339-357
Reddy YNV, Borlaug BA, Gersh BJ
Circulation: 26 Jul 2022; 146:339-357 | PMID: 35877831
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Impact:
Abstract

Long-Term Leisure-Time Physical Activity Intensity and All-Cause and Cause-Specific Mortality: A Prospective Cohort of US Adults.

Lee DH, Rezende LFM, Joh HK, Keum N, ... Tabung FK, Giovannucci EL
Background: The 2018 physical activity guidelines for Americans recommend a minimum of 150 to 300 min/wk of moderate physical activity (MPA), 75 to 150 min/wk of vigorous physical activity (VPA), or an equivalent combination of both. However, it remains unclear whether higher levels of long-term VPA and MPA are, independently and jointly, associated with lower mortality.
Methods:
A total of 116221 adults from 2 large prospective US cohorts (Nurses\' Health Study and Health Professionals Follow-up Study, 1988-2018) were analyzed. Detailed self-reported leisure-time physical activity was assessed with a validated questionnaire, repeated up to 15 times during the follow-up. Cox regression was used to estimate the hazard ratio and 95% CI of the association between long-term leisure-time physical activity intensity and all-cause and cause-specific mortality.
Results:
During 30 years of follow-up, we identified 47596 deaths. In analyses mutually adjusted for MPA and VPA, hazard ratios comparing individuals meeting the long-term leisure-time VPA guideline (75-149 min/wk) versus no VPA were 0.81 (95% CI, 0.76-0.87) for all-cause mortality, 0.69 (95% CI, 0.60-0.78) for cardiovascular disease (CVD) mortality, and 0.85 (95% CI, 0.79-0.92) for non-CVD mortality. Meeting the long-term leisure-time MPA guideline (150-299 min/wk) was similarly associated with lower mortality: 19% to 25% lower risk of all-cause, CVD, and non-CVD mortality. Compared with those meeting the long-term leisure-time physical activity guidelines, participants who reported 2 to 4 times above the recommended minimum of long-term leisure-time VPA (150-299 min/wk) or MPA (300-599 min/wk) showed 2% to 4% and 3% to 13% lower mortality, respectively. Higher levels of either long-term leisure-time VPA (≥300 min/wk) or MPA (≥600 min/wk) did not clearly show further lower all-cause, CVD, and non-CVD mortality or harm. In joint analyses, for individuals who reported <300 min/wk of long-term leisure-time MPA, additional leisure-time VPA was associated with lower mortality; however, among those who reported ≥300 min/wk of long-term leisure-time MPA, additional leisure-time VPA did not appear to be associated with lower mortality beyond MPA. Conclusions: The nearly maximum association with lower mortality was achieved by performing ≈150 to 300 min/wk of long-term leisure-time VPA, 300 to 600 min/wk of long-term leisure-time MPA, or an equivalent combination of both.




Circulation: 25 Jul 2022; epub ahead of print
Lee DH, Rezende LFM, Joh HK, Keum N, ... Tabung FK, Giovannucci EL
Circulation: 25 Jul 2022; epub ahead of print | PMID: 35876019
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Impact:
Abstract

Community-Based, Cluster-Randomized Pilot Trial of a Cardiovascular Mobile Health Intervention: Preliminary Findings of the FAITH! Trial.

Brewer LC, Jenkins S, Hayes SN, Kumbamu A, ... Cooper LA, Patten CA
Background
African Americans continue to have suboptimal cardiovascular health (CVH) based on the American Heart Association Life\'s Simple 7 (LS7), 7 health-promoting behaviors and biological risk factors (eg, physical activity, blood pressure). Innovative, community-level interventions in partnership with trusted institutions such as African American churches are potential means to improve CVH in this population.
Methods
Using a community-based participatory research approach, the FAITH! Trial (Fostering African American Improvement in Total Health) rigorously assessed the feasibility and preliminary efficacy of a refined, community-informed, mobile health intervention (FAITH! App) for promoting CVH among African Americans in faith communities using a cluster randomized controlled trial. Participants from 16 churches in Rochester and Minneapolis-St Paul, MN, were randomized to receive the FAITH! App (immediate intervention) or were assigned to a delayed intervention comparator group. The 10-week intervention core features included culturally relevant and LS7-focused education modules, diet/physical activity self-monitoring, and a group sharing board. Data were collected via electronic surveys and health assessments. Primary outcomes were average change in mean LS7 score (continuous measure of CVH ranging from poor to ideal [0-14 points]) from baseline to 6 months post-intervention (using generalized estimating equations) and app engagement/usability (by the Health Information Technology Usability Evaluation Scale; range, 0-5).
Results
Of 85 enrolled participants (randomized to immediate [N=41] and delayed [control] intervention [N=44] groups), 76 and 68 completed surveys/health assessments at baseline and 6 months post-intervention, respectively (80% retention rate with assessments at both baseline and 6-month time points); immediate intervention [N=30] and control [N=38] groups). At baseline, the majority of participants (mean age [SD], 54.2 [12.3] years, 71% female) had <4-year college education level (39/66, 59%) and poor CVH (44% in poor category; mean LS7 score [SD], 6.8 [1.9]). The mean LS7 score of the intervention group increased by 1.9 (SD 1.9) points compared with 0.7 (SD 1.7) point in the control group (both P<0.0001) at 6 months. The estimated difference of this increase between the groups was 1.1 (95% CI, 0.6-1.7; P<0.0001). App engagement/usability was overall high (100% connection to app; >75% completed weekly diet/physical activity tracking; Health Information Technology Usability Evaluation Scale, mean [SD], 4.2 [0.7]).
Conclusions
On the basis of preliminary findings, the refined FAITH! App appears to be an efficacious mobile health tool to promote ideal CVH among African Americans.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT03777709.



Circulation: 19 Jul 2022; 146:175-190
Brewer LC, Jenkins S, Hayes SN, Kumbamu A, ... Cooper LA, Patten CA
Circulation: 19 Jul 2022; 146:175-190 | PMID: 35861762
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Impact:
Abstract

Racial and Ethnic Differences in All-Cause and Cardiovascular Disease Mortality: The MESA Study.

Post WS, Watson KE, Hansen S, Folsom AR, ... Diez-Roux AV, McClelland RL
Background
Despite improvements in population health, marked racial and ethnic disparities in longevity and cardiovascular disease (CVD) mortality persist. This study aimed to describe risks for all-cause and CVD mortality by race and ethnicity, before and after accounting for socioeconomic status (SES) and other factors, in the MESA study (Multi-Ethnic Study of Atherosclerosis).
Methods
MESA recruited 6814 US adults, 45 to 84 years of age, free of clinical CVD at baseline, including Black, White, Hispanic, and Chinese individuals (2000-2002). Using Cox proportional hazards modeling with time-updated covariates, we evaluated the association of self-reported race and ethnicity with all-cause and adjudicated CVD mortality, with progressive adjustments for age and sex, SES (neighborhood SES, income, education, and health insurance), lifestyle and psychosocial risk factors, clinical risk factors, and immigration history.
Results
During a median of 15.8 years of follow-up, 22.8% of participants (n=1552) died, of which 5.3% (n=364) died of CVD. After adjusting for age and sex, Black participants had a 34% higher mortality hazard (hazard ratio [HR], 1.34 [95% CI, 1.19-1.51]), Chinese participants had a 21% lower mortality hazard (HR, 0.79 [95% CI, 0.66-0.95]), and there was no mortality difference in Hispanic participants (HR, 0.99 [95% CI, 0.86-1.14]) compared with White participants. After adjusting for SES, the mortality HR for Black participants compared with White participants was reduced (HR, 1.16 [95% CI, 1.01-1.34]) but still statistically significant. With adjustment for SES, the mortality hazards for Chinese and Hispanic participants also decreased in comparison with White participants. After further adjustment for additional risk factors and immigration history, Hispanic participants (HR, 0.77 [95% CI, 0.63-0.94]) had a lower mortality risk than White participants, and hazard ratios for Black participants (HR, 1.08 [95% CI, 0.92-1.26]) and Chinese participants (HR, 0.81 [95% CI, 0.60-1.08]) were not significantly different from those of White participants. Similar trends were seen for CVD mortality, although the age- and sex-adjusted HR for CVD mortality for Black participants compared with White participants was greater than all-cause mortality (HR, 1.72 [95% CI, 1.34-2.21] compared with HR, 1.34 [95% CI, 1.19-1.51]).
Conclusions
These results highlight persistent racial and ethnic differences in overall and CVD mortality, largely attributable to social determinants of health, and support the need to identify and act on systemic factors that shape differences in health across racial and ethnic groups.



Circulation: 19 Jul 2022; 146:229-239
Post WS, Watson KE, Hansen S, Folsom AR, ... Diez-Roux AV, McClelland RL
Circulation: 19 Jul 2022; 146:229-239 | PMID: 35861763
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Impact:
Abstract

Disparities in Cardiovascular Mortality Between Black and White Adults in the United States, 1999 to 2019.

Kyalwazi AN, Loccoh EC, Brewer LC, Ofili EO, ... Yeh RW, Wadhera RK
Background
Black adults experience a disproportionately higher burden of cardiovascular risk factors and disease in comparison with White adults in the United States. Less is known about how sex-based disparities in cardiovascular mortality between these groups have changed on a national scale over the past 20 years, particularly across geographic determinants of health and residential racial segregation.
Methods
We used CDC WONDER (Centers for Disease Control and Prevention\'s Wide-Ranging Online Data for Epidemiologic Research) to identify Black and White adults age ≥25 years in the United States from 1999 to 2019. We calculated annual age-adjusted cardiovascular mortality rates (per 100 000) for Black and White women and men, as well as absolute rate differences and rate ratios to compare the mortality gap between these groups. We also examined patterns by US census region, rural versus urban residence, and degree of neighborhood segregation.
Results
From 1999 to 2019, age-adjusted mortality rates declined overall for both Black and White adults. There was a decline in age-adjusted cardiovascular mortality among Black (602.1 to 351.8 per 100 000 population) and White women (447.0 to 267.5), and the absolute rate difference (ARD) between these groups decreased over time (1999: ARD, 155.1 [95% CI, 149.9-160.3]; 2019: ARD, 84.3 [95% CI, 81.2-87.4]). These patterns were similar for Black (824.1 to 526.3 per 100 000) and White men (637.5 to 396.0; 1999: ARD, 186.6 [95% CI, 178.6-194.6]; 2019: ARD, 130.3 [95% CI, 125.6-135.0]). Despite this progress, cardiovascular mortality in 2019 was higher for Black women (rate ratio, 1.32 [95% CI, 1.30-1.33])- especially in the younger (age <65 years) subgroup (rate ratio, 2.28 [95% CI, 2.23-2.32])-as well as for Black men (rate ratio, 1.33 [95% CI, 1.32-1.34]), compared with their respective White counterparts. There was regional variation in cardiovascular mortality patterns, and the Black-White gap differed across rural and urban areas. Cardiovascular mortality rates among Black women and men were consistently higher in communities with high levels of racial segregation compared with those with low to moderate levels.
Conclusions
During the past 2 decades, age-adjusted cardiovascular mortality declined significantly for Black and White adults in the United States, as did the absolute difference in death rates between these groups. Despite this progress, Black women and men continue to experience higher cardiovascular mortality rates than their White counterparts.



Circulation: 19 Jul 2022; 146:211-228
Kyalwazi AN, Loccoh EC, Brewer LC, Ofili EO, ... Yeh RW, Wadhera RK
Circulation: 19 Jul 2022; 146:211-228 | PMID: 35861764
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Impact:
Abstract

Cardiomyocyte-Specific Long Noncoding RNA Regulates Alternative Splicing of the Triadin Gene in the Heart.

Zhao Y, Riching AS, Knight WE, Chi C, ... Buttrick PM, Song K
Background
Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive.
Methods
We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart.
Results
We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA.
Conclusions
These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.



Circulation: 18 Jul 2022:101161CIRCULATIONAHA121058017; epub ahead of print
Zhao Y, Riching AS, Knight WE, Chi C, ... Buttrick PM, Song K
Circulation: 18 Jul 2022:101161CIRCULATIONAHA121058017; epub ahead of print | PMID: 35862102
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Impact:
Abstract

Effect of Patient-Reported Preprocedural Physical and Mental Health on 10-Year Mortality After Percutaneous or Surgical Coronary Revascularization.

Ono M, Serruys PW, Garg S, Kawashima H, ... Onuma Y, SYNTAX Extended Survival Investigators
Background
Clinical and anatomical characteristics are often considered key factors in deciding between percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with complex coronary artery disease (CAD) such as left-main CAD or 3-vessel disease. However, little is known about the interaction between self-reported preprocedural physical/mental health and clinical outcomes after revascularization.
Methods
This subgroup analysis of the SYNTAXES trial (SYNTAX Extended Survival), which is the extended follow-up of the randomized SYNTAX trial (Synergy Between PCI With Taxus and Cardiac Surgery) comparing PCI with CABG in patients with left-main CAD or 3-vessel disease, stratified patients by terciles of Physical (PCS) or Mental Component Summary (MCS) scores derived from the preprocedural 36-Item Short Form Health Survey, with higher PCS and MCS scores representing better physical and mental health, respectively. The primary end point was all-cause death at 10 years.
Results
A total of 1656 patients with preprocedural 36-Item Short Form Health Survey data were included in the present study. Both higher PCS and MCS were independently associated with lower 10-year mortality (10-point increase in PCS adjusted hazard ratio, 0.84 [95% CI, 0.73-0.97]; P=0.021; in MCS adjusted hazard ratio, 0.85 [95% CI, 0.76-0.95]; P=0.005). A significant survival benefit with CABG over PCI was observed in the highest PCS (>45.5) and MCS (>52.3) terciles with significant treatment-by-subgroup interactions (PCS Pinteraction=0.033, MCS Pinteraction=0.015). In patients with both high PCS (>45.5) and MCS (>52.3), 10-year mortality was significantly higher with PCI compared with CABG (30.5% versus 12.2%; hazard ratio, 2.87 [95% CI, 1.55-5.30]; P=0.001), whereas among those with low PCS (≤45.5) or low MCS (≤52.3), there were no significant differences in 10-year mortality between PCI and CABG, resulting in a significant treatment-by-subgroup interaction (Pinteraction=0.002).
Conclusions
Among patients with left-main CAD or 3-vessel disease, patient-reported preprocedural physical and mental health status was strongly associated with long-term mortality and modified the relative treatment effects of PCI versus CABG. Patients with the best physical and mental health had better 10-year survival with CABG compared with PCI. Assessment of self-reported physical and mental health is important when selecting the optimal revascularization strategy.
Registration
URL: https://www.
Clinicaltrials
gov; SYNTAXES Unique identifier: NCT03417050. URL: https://www.
Clinicaltrials
gov; SYNTAX Unique identifier: NCT00114972.



Circulation: 18 Jul 2022:101161CIRCULATIONAHA121057021; epub ahead of print
Ono M, Serruys PW, Garg S, Kawashima H, ... Onuma Y, SYNTAX Extended Survival Investigators
Circulation: 18 Jul 2022:101161CIRCULATIONAHA121057021; epub ahead of print | PMID: 35862109
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Impact:
Abstract

Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

O\'Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, ... American Heart Association Council on Genomic and Precision Medicine; Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation\' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.



Circulation: 18 Jul 2022:101161CIR0000000000001077; epub ahead of print
O'Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, ... American Heart Association Council on Genomic and Precision Medicine; Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Circulation: 18 Jul 2022:101161CIR0000000000001077; epub ahead of print | PMID: 35862132
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Impact:
Abstract

Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition.

Lytvyn Y, Kimura K, Peter N, Lai V, ... Soleymanlou N, Cherney DZI
Background
The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.
Methods
Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.
Results
Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.
Conclusions
Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure, and declines in total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.
Registration
URL: https://www.
Clinicaltrials
gov; Unique identifier: NCT02632747.



Circulation: 11 Jul 2022:101161CIRCULATIONAHA122059150; epub ahead of print
Lytvyn Y, Kimura K, Peter N, Lai V, ... Soleymanlou N, Cherney DZI
Circulation: 11 Jul 2022:101161CIRCULATIONAHA122059150; epub ahead of print | PMID: 35862082
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Impact:
Abstract

Effects of Cuisine-Based Chinese Heart-Healthy Diet in Lowering Blood Pressure Among Adults in China: Multicenter, Single-Blind, Randomized, Parallel Controlled Feeding Trial.

Wang Y, Feng L, Zeng G, Zhu H, ... Wu Y, DECIDE-Diet Study Group
Background: More than one-fifth of the world\'s population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation.
Methods:
A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mmHg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mmHg reduction in SBP was also calculated.
Results:
A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mmHg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mmHg and -2.8 (95% CI, -3.7 to -1.9) mmHg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mmHg and -3.8 (95% CI, -5.0 to -2.5) mmHg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mmHg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. Conclusions: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures.




Circulation: 11 Jul 2022; epub ahead of print
Wang Y, Feng L, Zeng G, Zhu H, ... Wu Y, DECIDE-Diet Study Group
Circulation: 11 Jul 2022; epub ahead of print | PMID: 35861850
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Impact:
Abstract

Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association.

Brittain EL, Thenappan T, Huston JH, Agrawal V, ... Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Stroke Council
This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.



Circulation: 11 Jul 2022:101161CIR0000000000001079; epub ahead of print
Brittain EL, Thenappan T, Huston JH, Agrawal V, ... Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; and Stroke Council
Circulation: 11 Jul 2022:101161CIR0000000000001079; epub ahead of print | PMID: 35862198
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Impact:
Abstract

Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Tremblay É, Gosselin C, Mai V, Lajoie AC, ... Lega JC, Provencher S
Background
Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients.
Methods
We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed.
Results
We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical.
Conclusions
PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable.
Registration
URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.



Circulation: 08 Jul 2022:101161CIRCULATIONAHA121058635; epub ahead of print
Tremblay É, Gosselin C, Mai V, Lajoie AC, ... Lega JC, Provencher S
Circulation: 08 Jul 2022:101161CIRCULATIONAHA121058635; epub ahead of print | PMID: 35862151
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Impact:
Abstract

Deformation of Transcatheter Aortic Valve Prostheses: Implications for Hypoattenuating Leaflet Thickening and Clinical Outcomes.

Fukui M, Bapat VN, Garcia S, Dworak MW, ... Cavalcante JL, Sorajja P
Background
Although transcatheter aortic valve replacement (TAVR) therapy continues to grow, there have been concerns about the occurrence of hypoattenuating leaflet thickening (HALT), which may affect prosthesis function or durability. This study aimed to examine prosthesis frame factors and correlate their extent to the frequency of HALT and clinical outcomes.
Methods
We prospectively examined 565 patients with cardiac computed tomography screening for HALT at 30 days after balloon-expandable SAPIEN3 and self-expanding EVOLUT TAVR. Deformation of the TAVR prostheses, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the postprocedural computed tomography. For descriptive purposes, an index of prosthesis deformation was calculated, with values >1.00 representing relative midsegment underexpansion. A time-to*event model was performed to evaluate the association of HALT with the clinical outcome.
Results
Overall, HALT was present in 21% of SAPIEN3 patients and in 16% of EVOLUT patients at 30 days after TAVR. The occurrence of HALT was directly associated with greater prosthesis frame deformation (P<0.001), worse asymmetry of the leaflets (P<0.001), and smaller TAVR neosinus volumes (P<0.001). These relations were present in both prosthetic types and in all of their size ranges (all P<0.05). In multivariable analyses that include clinical variables previously associated with HALT (eg, anticoagulant therapy), variables of TAVR prosthesis deformation remained predictive of HALT. Although HALT was not associated with changes in prosthetic hemodynamics, its presence was associated with the risk of mortality at 1 year, with respect to greater incidences of all-cause mortality (hazard ratio, 2.98 [95% CI, 1.57-5.63]; P=0.001), cardiac death (hazard ratio, 4.58 [95% CI, 1.81-11.6]; P=0.001), and a composite outcome of all-cause mortality and heart failure hospitalization (hazard ratio, 1.94 [95% CI, 1.14-3.30]; P=0.02) with adjustment for age, sex, and comorbidities.
Conclusions
Nonuniform expansion of TAVR prostheses resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume is related to occurrence of HALT in patients who undergo TAVR. These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes for these patients.



Circulation: 08 Jul 2022:101161CIRCULATIONAHA121058339; epub ahead of print
Fukui M, Bapat VN, Garcia S, Dworak MW, ... Cavalcante JL, Sorajja P
Circulation: 08 Jul 2022:101161CIRCULATIONAHA121058339; epub ahead of print | PMID: 35862182
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Impact:
Abstract

Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction.

Rosch S, Kresoja KP, Besler C, Fengler K, ... Rommel KP, Lurz P
Background
Recent trial data suggest that stratification of patients with heart failure with preserved ejection fraction (HFpEF) according to left ventricular ejection fraction (LVEF) provides a means for dissecting different treatment responses. However, the differential pathophysiologic considerations have rarely been described.
Methods
This prospective, single-center study analyzed consecutive symptomatic patients with HFpEF diagnosed according to the 2016 European Society of Cardiology heart failure guidelines. Patients were grouped into LVEF 50% to 60% and LVEF >60% cohorts. All patients underwent cardiac magnetic resonance imaging. Transfemoral cardiac catheterization was performed to derive load-dependent and load-independent left ventricular (LV) properties on pressure-volume loop analyses.
Results
Fifty-six patients with HFpEF were enrolled and divided into LVEF 50% to 60% (n=21) and LVEF >60% (n=35) cohorts. On cardiac magnetic resonance imaging, the LVEF >60% cohort showed lower LV end-diastolic volumes (P=0.019) and end-systolic volumes (P=0.001) than the LVEF 50% to 60% cohort; stroke volume (P=0.821) did not differ between the cohorts. Extracellular volume fraction was higher in the LVEF 50% to 60% cohort than in the LVEF >60% cohort (0.332 versus 0.309; P=0.018). Pressure-volume loop analyses demonstrated higher baseline LV contractility (end-systolic elastance, 1.85 vs 1.33 mm Hg/mL; P<0.001) and passive diastolic stiffness (β constant, 0.032 versus 0.018; P=0.004) in the LVEF >60% cohort. Ventriculo-arterial coupling (end-systolic elastance/arterial elastance) at rest was in the range of optimized stroke work in the LVEF >60% cohort but was impaired in the LVEF 50% to 60% cohort (1.01 versus 0.80; P=0.005). During handgrip exercise, patients with LVEF >60% had higher increases in end-systolic elastance (1.85 versus 0.82 mm Hg/mL; P=0.023), attenuated increases in indexed end-systolic volume (-1 versus 7 mL/m²; P<0.004), and more exaggerated increases in LV filling pressures (8 vs 5 mm Hg; P=0.023). LV stroke volume decreased in the LVEF >60% cohort (P=0.007) under exertion.
Conclusions
Patients with HFpEF in whom LVEF ranged from 50% to 60% demonstrated reduced contractility, impaired ventriculo-arterial coupling, and higher extracellular volume fraction. In contrast, patients with HFpEF and a LVEF >60% demonstrated a hypercontractile state with excessive LV afterload and diminished preload reserve. A LVEF-based stratification of patients with HFpEF identified distinct morphologic and pathophysiologic subphenotypes.



Circulation: 08 Jul 2022:101161CIRCULATIONAHA122059280; epub ahead of print
Rosch S, Kresoja KP, Besler C, Fengler K, ... Rommel KP, Lurz P
Circulation: 08 Jul 2022:101161CIRCULATIONAHA122059280; epub ahead of print | PMID: 35862208
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Impact:
Abstract

Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles.

Hosen MR, Goody PR, Zietzer A, Xiang X, ... Nickenig G, Jansen F
Background
Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for high- and intermediate-risk patients with severe symptomatic aortic valve stenosis. A majority of patients exhibit improvements in left ventricular ejection fraction (LVEF) after TAVR in response to TAVR-associated afterload reduction. However, a specific role for circulating microRNAs (miRNAs) in the improvement of cardiac function for patients after TAVR has not yet been investigated. Here, we profiled the differential expression of miRNAs in circulating extracellular vesicles (EVs) in patients after TAVR and, in particular, the novel role of circulating miR-122-5p in cardiomyocytes.
Methods
Circulating EV-associated miRNAs were investigated by use of an unbiased Taqman-based human miRNA array. Several EV miRNAs (miR-122-5p, miR-26a, miR-192, miR-483-5p, miR-720, miR-885-5p, and miR-1274) were significantly deregulated in patients with aortic valve stenosis at day 7 after TAVR compared with the preprocedural levels in patients without LVEF improvement. The higher levels of miR-122-5p were negatively correlated with LVEF improvement at both day 7 (r=-0.264 and P=0.015) and 6 months (r=-0.328 and P=0.0018) after TAVR.
Results
Using of patient-derived samples and a murine aortic valve stenosis model, we observed that the expression of miR-122-5p correlates negatively with cardiac function, which is associated with LVEF. Mice with graded wire injury-induced aortic valve stenosis demonstrated a higher level of miR-122-5p, which was related to cardiomyocyte dysfunction. Murine ex vivo experiments revealed that miR-122-5p is highly enriched in endothelial cells compared with cardiomyocytes. Coculture experiments, copy-number analysis, and fluorescence microscopy with Cy3-labeled miR-122-5p demonstrated that miR-122-5p can be shuttled through large EVs from endothelial cells into cardiomyocytes. Gain- and loss-of-function experiments suggested that EV-mediated shuttling of miR-122-5p increases the level of miR-122-5p in recipient cardiomyocytes. Mechanistically, mass spectrometry, miRNA pulldown, electrophoretic mobility shift assay, and RNA immunoprecipitation experiments confirmed that miR-122-5p interacts with the RNA-binding protein hnRNPU (heterogeneous nuclear ribonucleoprotein U) in a sequence-specific manner to encapsulate miR-122-5p into large EVs. On shuttling, miR-122-5p reduces the expression of the antiapoptotic gene BCL2 by binding to its 3\' untranslated region to inhibit its translation, thereby decreasing the viability of target cardiomyocytes.
Conclusions
Increased levels of circulating proapoptotic EV-incorporated miR-122-5p are associated with reduced LVEF after TAVR. EV shuttling of miR-122-5p regulates the viability and apoptosis of cardiomyocytes in a BCL2-dependent manner.



Circulation: 08 Jul 2022:101161CIRCULATIONAHA122060258; epub ahead of print
Hosen MR, Goody PR, Zietzer A, Xiang X, ... Nickenig G, Jansen F
Circulation: 08 Jul 2022:101161CIRCULATIONAHA122060258; epub ahead of print | PMID: 35862223
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Impact:
Abstract

Escalating and De-escalating Temporary Mechanical Circulatory Support in Cardiogenic Shock: A Scientific Statement From the American Heart Association.

Geller BJ, Sinha SS, Kapur NK, Bakitas M, ... Critical Care, Perioperative and Resuscitation; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease; and Council on Cardiovascular Surgery and Anesthesia
The use of temporary mechanical circulatory support in cardiogenic shock has increased dramatically despite a lack of randomized controlled trials or evidence guiding clinical decision-making. Recommendations from professional societies on temporary mechanical circulatory support escalation and de-escalation are limited. This scientific statement provides pragmatic suggestions on temporary mechanical circulatory support device selection, escalation, and weaning strategies in patients with common cardiogenic shock causes such as acute decompensated heart failure and acute myocardial infarction. The goal of this scientific statement is to serve as a resource for clinicians making temporary mechanical circulatory support management decisions and to propose standardized approaches for their use until more robust randomized clinical data are available.



Circulation: 07 Jul 2022:101161CIR0000000000001076; epub ahead of print
Geller BJ, Sinha SS, Kapur NK, Bakitas M, ... Critical Care, Perioperative and Resuscitation; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease; and Council on Cardiovascular Surgery and Anesthesia
Circulation: 07 Jul 2022:101161CIR0000000000001076; epub ahead of print | PMID: 35862152
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Abstract

Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise.

Lerchenmüller C, Vujic A, Mittag S, Wang A, ... Rosenzweig A, Lee RT
Background
The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart.
Methods
Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts.
Results
Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes. No mononucleated/diploid 15N-thymidine-labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15N-thymidine-labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further.
Conclusions
Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.



Circulation: 06 Jul 2022:101161CIRCULATIONAHA121057276; epub ahead of print
Lerchenmüller C, Vujic A, Mittag S, Wang A, ... Rosenzweig A, Lee RT
Circulation: 06 Jul 2022:101161CIRCULATIONAHA121057276; epub ahead of print | PMID: 35862076
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