Topic: Basic Research

Abstract

Delayed prolongation of the QRS interval in patients with left ventricular dysfunction.

Rav-Acha M, Nujidat A, Farkash R, Medina A, ... Glikson M, Hasin T
Aims
Patients with left ventricular dysfunction (LVD) and prolonged QRS on surface electrocardiogram are at increased risk for heart failure and death and may benefit from resynchronization therapy. Patients with initial narrow QRS may prolong their QRS during the disease course. The occurrence of delayed QRS prolongation, its predictors and associated risk of heart failure hospitalizations (HFH) or death are currently unknown and the subject of this investigation.
Methods & results
Patients with LVD, QRS < 120 ms and available follow-up ECGs were retrospectively evaluated for persistent unprovoked QRS prolongation >130 ms. Impact on mortality or HFH was assessed using Cox regression with QRS > 130 ms as a time dependent covariate. Following 178 patients for 30 (10;59) median (IQR) months, 28 (16%) patients prolonged their QRS to >130 ms, reaching a QRS duration of 154 ± 29 ms; LBBB pattern was diagnosed among 14 (50%) patients. Patients with delayed QRS prolongation were older (71.9 ± 11.8 vs 64.4 ± 15.1 years p = 0.014), had larger left ventricle and left atrial diameters (6.3 ± 0.9 vs 5.7 ± 0.9 cm p = 0.010; 4.9 ± 0.6 vs 4.5 ± 0.7 cm p = 0.006, respectively) and wider baseline QRS (104.8 ± 12.6 vs 91.4 ± 14.5 ms p < 0.001) which was linearly associated with late QRS prolongation (p for trend<0.0001). In a multivariable model, age, baseline QRS width and left atrial diameter were significantly associated with delayed QRS prolongation. QRS prolongation at follow-up was independently associated with risk of death or HFH (HR 7.426, 95% CI3.017-18.280, p < 0.0001).
Conclusion
QRS prolongation occurs in a significant proportion of patients with LVD and portends adverse outcome. Advanced age, prolonged QRS and larger left atria are potential predictors. Routine monitoring is justified and physicians may choose to plan ahead for resynchronization therapy in patients at risk for QRS prolongation.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 30 Nov 2019; 296:71-75
Rav-Acha M, Nujidat A, Farkash R, Medina A, ... Glikson M, Hasin T
Int J Cardiol: 30 Nov 2019; 296:71-75 | PMID: 31327517
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Abstract

Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats.

Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y

Patients with pulmonary arterial hypertension (PAH) and right ventricular (RV) failure have a poor clinical outcome, but the mechanisms of PAH and RV failure development are not totally clear. PAH is associated with reduced NO bioavailability and increased endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays a critical role in ADMA degradation. Here we generated a novel DDAH1 deficiency rat strain using the CRISPR-Cas9 technique, and studied the effect of DDAH1 dysfunction on monocrotaline-induced PAH, lung vascular remodeling and RV hypertrophy. DDAH1 knockout resulted in abolished DDAH1 expression in various tissues, and significant increases of plasma and lung ADMA content. DDAH1 knockout has no detectable effect on cardiac and lung structure, and LV function under control conditions in rats. However, DDAH1 knockout significantly aggravated monocrotaline-induced lung and RV oxidative stress, lung vascular remodeling and fibrosis, pulmonary hypertension and RV hypertrophy in rats. DDAH1 KO resulted in significantly greater increases of plasma and lung ADMA content under control conditions. In the wild type rats monocrotaline resulted in significant increases of plasma and lung ADMA contents and reduction of lung eNOS protein content and these changes were more marked in DDAH1 KO rats. Together, our results demonstrated that DDAH1 plays an important role in attenuating monocrotaline-induced lung oxidative stress, pulmonary hypertension and RV hypertrophy in rats.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 14 Nov 2019; 295:14-20
Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y
Int J Cardiol: 14 Nov 2019; 295:14-20 | PMID: 31402164
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Abstract

Lipid levels achieved after a first myocardial infarction and the prediction of recurrent atherosclerotic cardiovascular disease.

Ohm J, Hjemdahl P, Skoglund PH, Discacciati A, ... Jernberg T, Svensson P
Background
Low density lipoprotein cholesterol (LDL-C) goals post-myocardial infarction (MI) are debated, and the significance of achieved blood lipid levels for predicting a first recurrent atherosclerotic cardiovascular disease (rASCVD) event post-MI is unclear.
Methods
This was a cohort study on first-ever MI survivors aged ≤76 years attending 4-14 week revisits throughout Sweden 2005-2013. Personal-level data was collected from SWEDEHEART and linked national registries. Exposures were quintiles of LDL-C, high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TGs) at the revisit. Group level associations with rASCVD (nonfatal MI or coronary heart disease death or fatal or nonfatal ischemic stroke) were estimated in Cox regression models. Predictive capacity was estimated by differences in C-statistic, integrated discriminatory improvement, and net reclassification improvement when adding each blood lipid to a validated risk prediction model.
Results
25,643 patients, 96.9% on statin therapy, were followed during a mean of 4.1 years. rASCVD occurred in 2173 patients (8.5%). For LDL-C and TC, moderate associations with rASCVD were observed only in the 5th vs. the lowest (referent) quintiles. For TGs and HDL-C increased risks were observed in quintiles 3-5 vs. the lowest. Minor predictive improvements were observed when lipid fractions were added to the risk model but the discrimination overall was poor (C-statistics <0.6).
Conclusions
Our data question the importance of LDL-C levels achieved at first revisit post-MI for decisions on continued treatment intensity considering the weak association with rASCVD observed in this post-MI cohort.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:1-7
Ohm J, Hjemdahl P, Skoglund PH, Discacciati A, ... Jernberg T, Svensson P
Int J Cardiol: 30 Nov 2019; 296:1-7 | PMID: 31303394
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Abstract

Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality.

Liu X, Zhang S, An L, Wu J, ... He L, Zhu H
Background
The therapeutic potential of doxorubicin (DOX) is limited by cardiotoxicity. Rubicon is an inhibitory interacting partner of autophagy protein UVRAG. Currently, the role of Rubicon in DOX-induced cardiotoxicity is unknown. In this study, we test the hypothesis that loss of Rubicon attenuates DOX-induced cardiotoxicity.
Methods
A mouse model of acute DOX-induced cardiotoxicity was established by a single intraperitoneal injection of DOX at a dose of 20 mg/kg. Rubicon expression was detected by Western blot. Cardiac damage was determined by measuring activities of lactate dehydrogenase and myocardial muscle creatine kinase in the serum, cytoplasmic vacuolization, collagen deposition, ROS levels, ATP content and mitochondrial damage in the heart. Cardiac morphometry and function were assessed by echocardiography. Markers for autophagy, mitophagy and mitochondrial dynamics were evaluated by Western blot and real time reverse transcription polymerase chain reaction.
Results
Rubicon expression was reduced in the heart 16 h after DOX treatment. DOX induced accumulation of cytoplasmic vacuolization and collagen, increased serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, enhanced ROS levels, reduced ATP content, pronounced mitochondrial damage and greater left ventricular wall thickness in wild type mice, which were mitigated by Rubicon deficiency. Mechanistically, loss of Rubicon improved DOX-induced impairment of autophagic flux, Parkin-mediated mitophagy and mitochondrial fission and fusion in the heart.
Conclusions
Loss of Rubicon ameliorates DOX-induced cardiotoxicity through enhancement of mitochondrial quality by improving autophagic flux, mitophagy and mitochondrial dynamics. Rubicon is a potential molecular target for prevention and therapy of DOX cardiotoxicity.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:129-135
Liu X, Zhang S, An L, Wu J, ... He L, Zhu H
Int J Cardiol: 30 Nov 2019; 296:129-135 | PMID: 31439425
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Abstract

Cardiovascular Disease and hospital admissions in African immigrants and former Soviet Union immigrants: A retrospective cohort study.

Reuven Y, Shvartzman P, Dreiher J
Background
Previous studies reported low prevalence of cardiovascular disease (CVD) despite an increasing prevalence of metabolic abnormalities in immigrants who moved from low CVD-risk regions to Western countries. Nevertheless, little is known about hospital admissions due to CVD in immigrants.
Methods
A retrospective cohort study of East Africa immigrants (EAI), Former Soviet Union immigrants (FSUI) and native-born Israelis (NBI) over 11-year period. Associations between ethnicity, age, sex, CVD, and hospital admission were assessed using logistic and Poisson regression models. Incidence density rates per person-years were calculated.
Results
The age-adjusted prevalence rates of ischemic heart disease in EAI, FSUI and NBI, respectively, were 1.8%, 8.2%, and 5.8%, respectively (p < 0.001). The corresponding rates for stroke were 2.6%, 3.5%, and 2.5%, respectively. Multivariate odds ratios for all CVD were found to be significantly lower in EAI for both sexes. Hospitalizations rate due to CVD were 9, 17, and 6 per 1000 person-years in EAI, FSUI and NBI, respectively (p < 0.001). EAI were more likely to be hospitalized due to hypertensive disease, cerebral vascular diseases and heart disease, in comparison to NBI and FSUI. However, when controlling for CVD risk factors profile, EAI had similar admission rates to NBI. EAI were more likely to be hospitalized in internal medicine, geriatrics, and neurology departments, and less likely to be admitted to intensive care units or surgical department.
Conclusions
EAI had low rates of all types of CVD, and low risk of hospitalization after controlling for CVD risk factors profile.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:172-176
Reuven Y, Shvartzman P, Dreiher J
Int J Cardiol: 30 Nov 2019; 296:172-176 | PMID: 31477314
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Abstract

The age-related blood pressure trajectories from young-old adults to centenarians: A cohort study.

Wang R, Vetrano DL, Liang Y, Qiu C
Background
Blood pressure (BP) trajectories among older adults, especially among the oldest-old, are still poorly characterized.
Objective
To investigate the longitudinal trajectories of four BP components with age and their potential influential factors.
Methods
This population-based prospective cohort study included 3315 participants (age 60-105 years, 64.6% women) who were regularly examined from 2001 to 2004 through 2013-2016. The longitudinal trajectories of systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) with age were estimated using linear mixed-effects models.
Results
Overall, SBP and PP increased with age until ∼80 years and then declined, whereas DBP and MAP decreased constantly after 60 years of age. The age-related BP trajectories varied by survival time, birth cohort, use of antihypertensive drugs, and heart disease. Specifically, people who survived <2 years after the last visit showed higher levels of BP components before ∼80 years, followed by steeper declines in SBP and PP. At the same age, people who were born earlier showed higher BP than those who were born later. People who used antihypertensive drugs had higher BP than those who did not until ∼80-90 years old, thereafter BP showed no significant difference. After ∼80 years old, people with heart disease showed steeper declines in SBP and PP than those without.
Conclusions
The late-life longitudinal BP trajectories with age vary with demographics, clinical conditions, and contextual factors. These findings may help better understand the age-dependent relationship of BP with health outcomes as well as help achieve optimal BP control in older people.
Perspectives
Competency in medical knowledge: Understanding the age-related blood pressure trajectories and potential influential factors may help improve blood pressure management in older people. Translational outlook 1: Blood pressure trajectories with age in older adults vary by birth cohort, survival time, antihypertensive therapy, and heart disease. The age-related blood pressure trajectories by birth cohorts are featured with lower blood pressure levels at the same age in more recent birth cohorts, which may partially reflect the improvement of blood pressure control over time. Translational outlook 2: The age-related blood pressure trajectories in the oldest old (e.g., age ≥ 85 years) are characterized by steeper and faster blood pressure declines associated with heart disease and short survival (e.g., <2 years). This may have implications for the optimal management of blood pressure as well as for the interpretation of the relationships between blood pressure and health outcomes (e.g., death) among the oldest old.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:141-148
Wang R, Vetrano DL, Liang Y, Qiu C
Int J Cardiol: 30 Nov 2019; 296:141-148 | PMID: 31443986
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Abstract

Heart failure risk predictions in adult patients with congenital heart disease: a systematic review.

Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ

To summarise existing heart failure (HF) risk prediction models and describe the risk factors for HF-related adverse outcomes in adult patients with congenital heart disease (CHD). We performed a systematic search of MEDLINE, EMBASE and Cochrane databases from January 1996 to December 2018. Studies were eligible if they developed multivariable models for risk prediction of decompensated HF in adult patients with CHD (ACHD), death in patients with ACHD-HF or both, or if they reported corresponding predictors. A standardised form was used to extract information from selected studies. Twenty-five studies met the inclusion criteria and all studies were at moderate to high risk of bias. One study derived a model to predict the risk of a composite outcome (HF, death or arrhythmia) with a c-statistic of 0.85. Two studies applied an existing general HF model to patients with ACHD but did not report model performance. Twenty studies presented predictors of decompensated HF, and four examined patient characteristics associated with mortality (two reported predictors of both). A wide variation in population characteristics, outcome of interest and candidate risk factors was observed between studies. Although there were substantial inconsistencies regarding which patient characteristics were predictive of HF-related adverse outcomes, brain natriuretic peptide, New York Heart Association class and CHD lesion characteristics were shown to be important predictors. To date, evidence in the published literature is insufficient to accurately profile patients with ACHD. High-quality studies are required to develop a unique ACHD-HF prediction model and confirm the predictive roles of potential risk factors.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1661-1669
Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ
Heart: 30 Oct 2019; 105:1661-1669 | PMID: 31350277
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Abstract

Individualizing Revascularization Strategy for Diabetic Patients With Multivessel Coronary Disease.

Qintar M, Humphries KH, Park JE, Arnold SV, ... Cohen DJ, Spertus JA
Background
In patients with diabetes and multivessel coronary artery disease (CAD), the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that, on average, coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) for major acute cardiovascular events (MACE) and angina reduction. Nonetheless, multivessel PCI remains a common revascularization strategy in the real world.
Objectives
To translate the results of FREEDOM to individual patients in clinical practice, risk models of the heterogeneity of treatment benefit were built.
Methods
Using patient-level data from 1,900 FREEDOM patients, the authors developed models to predict 5-year MACE (all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke) and 1-year angina after CABG and PCI using baseline covariates and treatment interactions. Parsimonious models were created to support clinical use. The models were internally validated using bootstrap resampling, and the MACE model was externally validated in a large real-world registry.
Results
The 5-year MACE occurred in 346 (18.2%) patients, and 310 (16.3%) had angina at 1 year. The MACE model included 8 variables and treatment interactions with smoking status (c = 0.67). External validation in stable CAD (c = 0.65) and ACS (c = 0.68) demonstrated comparable performance. The 6-variable angina model included a treatment interaction with SYNTAX score (c = 0.67). PCI was never superior to CABG, and CABG was superior to PCI for MACE in 54.5% of patients and in 100% of patients with history of smoking.
Conclusions
To help disseminate the results of FREEDOM, the authors created a personalized risk prediction tool for patients with diabetes and multivessel CAD that could be used in shared decision-making for CABG versus PCI by estimating each patient\'s personal outcomes with both treatments.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Oct 2019; 74:2074-2084
Qintar M, Humphries KH, Park JE, Arnold SV, ... Cohen DJ, Spertus JA
J Am Coll Cardiol: 21 Oct 2019; 74:2074-2084 | PMID: 31623766
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Abstract

Bedside mental status and outcome in elderly patients admitted for acute coronary syndromes.

Briet C, Blanchart K, Lemaître A, Roux I, ... Roule V, Beygui F
Objective
We investigated whether mental status assessed by simple bedside tests in elderly patients admitted for acute coronary syndromes (ACS) was associated with higher risk of mortality.
Methods
We used the data from a prospective, open, ongoing cohort of patients≥75 years old admitted for ACS to a tertiary centre. Cognitive impairment (CogI) was defined by delirium detected by the Confusion Assessment Method or an abnormal Mini Mental State Examination score. A Cox model adjusted on predefined correlates of mortality was used to assess the relationship between CogI and 1-year mortality.
Results
Six-hundred consecutive patients with mental status assessment within 48 hours after admission were included. CogI was identified in 172 (29%) patients among whom 153 (25.5%) had an abnormal Mini Mental State Evaluation and 19 (3.2%) delirium. Death occurred in 49 (28.6%) patients with and 43 (10.5%) patients without CogI at 1 year. There was a significant association between CogI and 1-year mortality (adjusted-HR 2.4, 95% CI 1.53 to 3.62), p<0.001) independent of other covariables. CogI was also independently associated with higher rates of in-hospital bleeding and mortality as well as 3-month rates of all-cause, cardiovascular-related and heart failure-related rehospitalisation.
Conclusions
CogI detected by simple bedside tests in patients≥75 admitted for ACS is associated with an increased risk of 1-year mortality and 3 month rehospitalisation independent of other correlates of poor outcome.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1635-1641
Briet C, Blanchart K, Lemaître A, Roux I, ... Roule V, Beygui F
Heart: 30 Oct 2019; 105:1635-1641 | PMID: 31142593
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Abstract

Climate changes and ST-elevation myocardial infarction treated with primary percutaneous coronary angioplasty.

Versaci F, Biondi-Zoccai G, Giudici AD, Mariano E, ... Federici M, Romeo F
Background
The impact of seasonal changes on the incidence of acute myocardial infarction has been incompletely appraised, especially in the modern era of primary percutaneous coronary intervention (PPCI). We aimed to appraise the overall and season-specific impact of climate changes on the daily rate of PCCI.
Methods
Details on PPCI and climate changes were retrospectively collected in three high-volume Italian institutions with different geographical features. The association between rate of PPCI and temperature, atmospheric pressure (ATM), humidity and rainfall was appraised with Poisson models, with overall analyses and according to season of the year.
Results
Details on 6880 days with a total of 4132 PPCI were collected. Overall adjusted analysis showed that higher minimum atmospheric pressure 3 days before PPCI were associated with lower risk (regression coefficient = 0.999 [95% confidence interval 0.998-1.000], p = 0.030). Focusing on season, in Winter PPCI rates were increased by lower same day mean temperature (0.973 [0.956-0.990], p = 0.002) and lower rainfall (0.980 [0.960-1.000], p = 0.049). Conversely, in Spring greater changes in atmospheric pressure 3 days before PPCI were associated with increased risk (1.023 [1.002-1.045], p = 0.032), with similar effects in Summer for minimum temperature on the same day (1.022 [1.001-1.044], p = 0.040).
Conclusions
Climate has a significant impact on the risk of PPCI in the current era, with a complex interplay according to season. Higher risk risk is expected with lower minimum atmospheric pressure in the preceding days, lower rainfall in Winter, greater changes in atmospheric pressure in Spring, and higher temperatures in Summer. These findings have important implications for prevention strategies.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2019; 294:1-5
Versaci F, Biondi-Zoccai G, Giudici AD, Mariano E, ... Federici M, Romeo F
Int J Cardiol: 31 Oct 2019; 294:1-5 | PMID: 31301864
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Abstract

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling.

Naruse G, Kanamori H, Yoshida A, Minatoguchi S, ... Nishigaki K, Minatoguchi S
Aims
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production.
Methods and results
Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out.
Conclusions
Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1873-1885
Naruse G, Kanamori H, Yoshida A, Minatoguchi S, ... Nishigaki K, Minatoguchi S
Cardiovasc Res: 31 Oct 2019; 115:1873-1885 | PMID: 30629149
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Abstract

Inhibition of heat shock protein 70 blocks the development of cardiac hypertrophy by modulating the phosphorylation of histone deacetylase 2.

Yoon S, Kim M, Min HK, Lee YU, ... Eom GH, Kook H
Aims
Previously, we reported that phosphorylation of histone deacetylase 2 (HDAC2) and the resulting activation causes cardiac hypertrophy. Through further study of the specific binding partners of phosphorylated HDAC2 and their mechanism of regulation, we can better understand how cardiac hypertrophy develops. Thus, in the present study, we aimed to elucidate the function of one such binding partner, heat shock protein 70 (HSP70).
Methods and results
Primary cultures of rat neonatal ventricular cardiomyocytes and H9c2 cardiomyoblasts were used for in vitro cellular experiments. HSP70 knockout (KO) mice and transgenic (Tg) mice that overexpress HSP70 in the heart were used for in vivo analysis. Peptide-precipitation and immunoprecipitation assay revealed that HSP70 preferentially binds to phosphorylated HDAC2 S394. Forced expression of HSP70 increased phosphorylation of HDAC2 S394 and its activation, but not that of S422/424, whereas knocking down of HSP70 reduced it. However, HSP70 failed to phosphorylate HDAC2 in the cell-free condition. Phosphorylation of HDAC2 S394 by casein kinase 2α1 enhanced the binding of HSP70 to HDAC2, whereas dephosphorylation induced by the catalytic subunit of protein phosphatase 2A (PP2CA) had the opposite effect. HSP70 prevented HDAC2 dephosphorylation by reducing the binding of HDAC2 to PP2CA. HSP70 KO mouse hearts failed to phosphorylate S394 HDAC2 in response to isoproterenol infusion, whereas Tg overexpression of HSP70 increased the phosphorylation and activation of HDAC2. 2-Phenylethynesulfonamide (PES), an HSP70 inhibitor, attenuated cardiac hypertrophy induced either by phenylephrine in neonatal ventricular cardiomyocytes or by aortic banding in mice. PES reduced HDAC2 S394 phosphorylation and its activation by interfering with the binding of HSP70 to HDAC2.
Conclusion
These results demonstrate that HSP70 specifically binds to S394-phosphorylated HDAC2 and maintains its phosphorylation status, which results in HDAC2 activation and the development of cardiac hypertrophy. Inhibition of HSP70 has possible application as a therapeutic.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1850-1860
Yoon S, Kim M, Min HK, Lee YU, ... Eom GH, Kook H
Cardiovasc Res: 31 Oct 2019; 115:1850-1860 | PMID: 30596969
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Abstract

A sequential interferon gamma directed chemotactic cellular immune response determines survival and cardiac function post-myocardial infarction.

Finger S, Knorr M, Molitor M, Schüler R, ... Karbach S, Wenzel P
Aims
Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI.
Methods and results
MI was induced in 8- to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumour necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post-MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI.
Conclusion
IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1907-1917
Finger S, Knorr M, Molitor M, Schüler R, ... Karbach S, Wenzel P
Cardiovasc Res: 31 Oct 2019; 115:1907-1917 | PMID: 30949687
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Abstract

Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients.

Gast M, Rauch BH, Haghikia A, Nakagawa S, ... Zeller T, Poller W
Aims
Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.
Methods and results
Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1-/- mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1-/- splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1-/- spleen displayed anomalous Treg and TH cell differentiation. NEAT1-/- bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1-/- BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1-/- bone marrow and blood. NEAT1-/- mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals.
Conclusion
The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1-/- mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1886-1906
Gast M, Rauch BH, Haghikia A, Nakagawa S, ... Zeller T, Poller W
Cardiovasc Res: 31 Oct 2019; 115:1886-1906 | PMID: 30924864
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Impact:
Abstract

Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.

Bonacina F, Moregola A, Porte R, Baragetti A, ... Garlanda C, Norata GD
Aims
Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity.
Methods and results
PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers.
Conclusion
Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1861-1872
Bonacina F, Moregola A, Porte R, Baragetti A, ... Garlanda C, Norata GD
Cardiovasc Res: 31 Oct 2019; 115:1861-1872 | PMID: 30859179
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Abstract

A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor.

Rimbert A, Dalila N, Wolters JC, Huijkman N, ... van de Sluis B, Kuivenhoven JA
Aims
Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR).
Methods and results
Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10-6 to 8.0 × 10-9), with lower risk of MI (P-trend 0.04-0.002) and lower risk of cardiovascular mortality (P-trend 0.005-0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane.
Conclusion
This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 18 Oct 2019; epub ahead of print
Rimbert A, Dalila N, Wolters JC, Huijkman N, ... van de Sluis B, Kuivenhoven JA
Eur Heart J: 18 Oct 2019; epub ahead of print | PMID: 31630160
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Abstract

Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells.

Kavanagh DPJ, Lokman AB, Neag G, Colley A, Kalia N
Aims
Adequate microcirculatory perfusion, and not just opening of occluded arteries, is critical to salvage heart tissue following myocardial infarction. However, the degree of microvascular perfusion taking place is not known, limited primarily by an inability to directly image coronary microcirculation in a beating heart in vivo. Haematopoietic stem/progenitor cells (HSPCs) offer a potential therapy but little is known about their homing dynamics at a cellular level and whether they protect coronary microvessels. This study used intravital microscopy to image the anaesthetized mouse beating heart microcirculation following stabilization.
Methods and results
A 3D-printed stabilizer was attached to the ischaemia-reperfusion injured (IRI) beating heart. The kinetics of neutrophil, platelet and HSPC recruitment, as well as functional capillary density (FCD), was imaged post-reperfusion. Laser speckle contrast imaging (LSCI) was used for the first time to monitor ventricular blood flow in beating hearts. Sustained hyperaemic responses were measured throughout reperfusion, initially indicating adequate flow resumption. Intravital microscopy confirmed large vessel perfusion but demonstrated poor transmission of flow to downstream coronary microvessels. Significant neutrophil adhesion and microthrombus formation occurred within capillaries with the latter occluding them, resulting in patchy perfusion and reduced FCD. Interestingly, \'patrolling\' neutrophils were also observed in capillaries. Haematopoietic stem/progenitor cells readily trafficked through the heart but local retention was poor. Despite this, remarkable anti-thromboinflammatory effects were observed, consequently improving microvascular perfusion.
Conclusion
We present a novel approach for imaging multiple microcirculatory perturbations in the beating heart with LSCI assessment of blood flow. Despite deceptive hyperaemic responses, increased microcirculatory flow heterogeneity was seen, with non-perfused areas interspersed with perfused areas. Microthrombi, rather than neutrophils, appeared to be the major causative factor. We further applied this technique to demonstrate local stem cell presence is not a pre-requisite to confer vasculoprotection. This is the first detailed in vivo characterization of coronary microcirculatory responses post-reperfusion injury.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 31 Oct 2019; 115:1918-1932
Kavanagh DPJ, Lokman AB, Neag G, Colley A, Kalia N
Cardiovasc Res: 31 Oct 2019; 115:1918-1932 | PMID: 31062860
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Abstract

Discrimination, Abuse, Harassment, and Burnout in Surgical Residency Training.

Hu YY, Ellis RJ, Hewitt DB, Yang AD, ... Nasca TR, Bilimoria KY
Background
Physicians, particularly trainees and those in surgical subspecialties, are at risk for burnout. Mistreatment (i.e., discrimination, verbal or physical abuse, and sexual harassment) may contribute to burnout and suicidal thoughts.
Methods
A cross-sectional national survey of general surgery residents administered with the 2018 American Board of Surgery In-Training Examination assessed mistreatment, burnout (evaluated with the use of the modified Maslach Burnout Inventory), and suicidal thoughts during the past year. We used multivariable logistic-regression models to assess the association of mistreatment with burnout and suicidal thoughts. The survey asked residents to report their gender.
Results
Among 7409 residents (99.3% of the eligible residents) from all 262 surgical residency programs, 31.9% reported discrimination based on their self-identified gender, 16.6% reported racial discrimination, 30.3% reported verbal or physical abuse (or both), and 10.3% reported sexual harassment. Rates of all mistreatment measures were higher among women; 65.1% of the women reported gender discrimination and 19.9% reported sexual harassment. Patients and patients\' families were the most frequent sources of gender discrimination (as reported by 43.6% of residents) and racial discrimination (47.4%), whereas attending surgeons were the most frequent sources of sexual harassment (27.2%) and abuse (51.9%). Proportion of residents reporting mistreatment varied considerably among residency programs (e.g., ranging from 0 to 66.7% for verbal abuse). Weekly burnout symptoms were reported by 38.5% of residents, and 4.5% reported having had suicidal thoughts during the past year. Residents who reported exposure to discrimination, abuse, or harassment at least a few times per month were more likely than residents with no reported mistreatment exposures to have symptoms of burnout (odds ratio, 2.94; 95% confidence interval [CI], 2.58 to 3.36) and suicidal thoughts (odds ratio, 3.07; 95% CI, 2.25 to 4.19). Although models that were not adjusted for mistreatment showed that women were more likely than men to report burnout symptoms (42.4% vs. 35.9%; odds ratio, 1.33; 95% CI, 1.20 to 1.48), the difference was no longer evident after the models were adjusted for mistreatment (odds ratio, 0.90; 95% CI, 0.80 to 1.00).
Conclusions
Mistreatment occurs frequently among general surgery residents, especially women, and is associated with burnout and suicidal thoughts.

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Oct 2019; epub ahead of print
Hu YY, Ellis RJ, Hewitt DB, Yang AD, ... Nasca TR, Bilimoria KY
N Engl J Med: 27 Oct 2019; epub ahead of print | PMID: 31657887
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Abstract

Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry.

Björklund E, Nielsen SJ, Hansson EC, Karlsson M, ... Pivodic A, Jeppsson A
Aims
To evaluate the long-term use of secondary prevention medications [statins, β-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and platelet inhibitors] after coronary artery bypass grafting (CABG) and the association between medication use and mortality.
Methods and results
All patients who underwent isolated CABG in Sweden from 2006 to 2015 and survived at least 6 months after discharge were included (n = 28 812). Individual patient data from SWEDEHEART and other mandatory nationwide registries were merged. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between medication use and long-term mortality. Statins were dispensed to 93.9% of the patients 6 months after discharge and to 77.3% 8 years later. Corresponding figures for β-blockers were 91.0% and 76.4%, for RAAS inhibitors 72.9% and 65.9%, and for platelet inhibitors 93.0% and 79.8%. All medications were dispensed less often to patients ≥75 years. Treatment with statins [hazard ratio (HR) 0.56, 95% confidence interval (95% CI) 0.52-0.60], RAAS inhibitors (HR 0.78, 95% CI 0.73-0.84), and platelet inhibitors (HR 0.74, 95% CI 0.69-0.81) were individually associated with lower mortality risk after adjustment for age, gender, comorbidities, and use of other secondary preventive drugs (all P < 0.001). There was no association between β-blockers and mortality risk (HR 0.97, 95% CI 0.90-1.06; P = 0.54).
Conclusion
The use of secondary prevention medications after CABG was high early after surgery but decreased significantly over time. The results of this observational study, with inherent risk of selection bias, suggest that treatment with statins, RAAS inhibitors, and platelet inhibitors is essential after CABG whereas the routine use of β-blockers may be questioned.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 21 Oct 2019; epub ahead of print
Björklund E, Nielsen SJ, Hansson EC, Karlsson M, ... Pivodic A, Jeppsson A
Eur Heart J: 21 Oct 2019; epub ahead of print | PMID: 31638654
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Impact:
Abstract

Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.

Aung N, Vargas JD, Yang C, Cabrera CP, ... Munroe PB, Petersen SE
Background
The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.
Methods
The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.
Results
The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent <1×10. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (, and ) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).
Conclusions
We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.



Circulation: 14 Oct 2019; 140:1318-1330
Aung N, Vargas JD, Yang C, Cabrera CP, ... Munroe PB, Petersen SE
Circulation: 14 Oct 2019; 140:1318-1330 | PMID: 31554410
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Abstract

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Marston NA, Giugliano RP, Im K, Silverman MG, ... Ference BA, Sabatine MS
Background
Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.
Methods
We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters.
Results
A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; <0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; <0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; =0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; <0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; =0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; <0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]).
Conclusions
In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.



Circulation: 14 Oct 2019; 140:1308-1317
Marston NA, Giugliano RP, Im K, Silverman MG, ... Ference BA, Sabatine MS
Circulation: 14 Oct 2019; 140:1308-1317 | PMID: 31530008
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Abstract

Outcomes of Second Arterial Conduits in Patients Undergoing Multivessel Coronary Artery Bypass Graft Surgery.

Chikwe J, Sun E, Hannan EL, Itagaki S, ... Adams DH, Egorova NN
Background
Benefits of multiarterial versus single-arterial coronary bypass grafting (CABG) are debated.
Objectives
This study sought to compare long-term survival, morbidity, and graft patency after multiarterial versus single-arterial CABG.
Methods
Mandatory clinical registries linked with discharge databases were used to identify baseline and operative characteristics and outcomes of 42,714 patients undergoing CABG from 2005 through 2012. Patients with single-vessel disease, without arterial conduits, or undergoing emergency, reoperative, or concomitant procedures were excluded. Survival, stroke, myocardial infarction, and repeat revascularization rates were compared using Cox modeling, and patients were matched by propensity score. Median follow-up was 7.8 years (interquartile range: 5 to 10 years); last follow-up was December 31, 2016.
Results
Of the 26,124 patients, 3,647 (14.0%) underwent multiarterial CABG. Single-arterial CABG patients were older (mean 68 vs. 61 years; p < 0.001), had more comorbidities, and received fewer bypass grafts (3.4 vs. 3.6; p < 0.001). After adjusting for baseline differences, multiarterial CABG was associated with lower 10-year mortality compared with single-arterial CABG in 3,588 propensity-matched pairs (15.1% vs. 17.3%; p = 0.01). Multiarterial CABG was associated with lower 10-year myocardial infarction (hazard ratio: 0.81; 95% confidence interval: 0.69 to 0.95) and lower 10-year reintervention rate (hazard ratio: 0.81; 95% confidence interval: 0.67 to 0.99).
Conclusions
In contemporary practice, single-arterial CABG is used in 85% of patients and is associated with increased long-term mortality, myocardial infarction, and reintervention compared with multiarterial CABG. Multiarterial CABG is underused in contemporary surgical revascularization, and targeted referral of younger patients for multiarterial revascularization may address this practice gap.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 04 Nov 2019; 74:2238-2248
Chikwe J, Sun E, Hannan EL, Itagaki S, ... Adams DH, Egorova NN
J Am Coll Cardiol: 04 Nov 2019; 74:2238-2248 | PMID: 31672179
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Impact:
Abstract

Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

Chen Y, Yang M, Huang W, Chen W, ... Sahoo D, Silverstein RL

A hallmark of chronic inflammatory disorders is persistence of pro-inflammatory macrophages in diseased tissues. In atherosclerosis this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood.To investigate mechanisms linking dyslipidemia, oxidative stress and macrophage activation through modulation of immunemetabolism, and to explore therapeutic potential targeting specific metabolic pathways.Using a combination of biochemical, immunological, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxLDL. Mitochondrial-specific inhibition of superoxide inhibited oxLDL-induced NF-κB activation and inflammatory cytokine generation. RNAseq, flow cytometry, H-labeled palmitic acid uptake, lipidomic analysis, confocal and EM imaging, and functional energetics revealed that oxLDL upregulated effectors of long-chain fatty acid (FA) uptake and mitochondrial import, while downregulating FA oxidation and inhibiting ATP5A, an electron transport chain (ETC) component. The combined effect is long-chain FA accumulation, alteration of mitochondrial structure and function, repurposing of the ETC to superoxide production, and NF-κB activation. Apoe null mice challenged with high fat diet showed similar metabolic changes in circulating Ly6C monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial ROS was positively correlated with CD36 expression in aortic lesional macrophages.These findings reveal that oxLDL/CD36 signaling in macrophages links dys-regulated FA metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.



Circ Res: 17 Oct 2019; epub ahead of print
Chen Y, Yang M, Huang W, Chen W, ... Sahoo D, Silverstein RL
Circ Res: 17 Oct 2019; epub ahead of print | PMID: 31625810
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Abstract

Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass.

Pireaux V, Tassignon J, Demoulin S, Derochette S, ... Guyaux M, Godfroid E
Background
Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I. ricinus ticks, which specifically inhibits both factors XIIa and XIa, 2 factors contributing to thrombotic disease while playing a limited role in hemostasis.
Objectives
This study assessed the antithrombotic activity of Ir-CPI in animal contact phase-initiated thrombosis models, including CPB. The safety of Ir-CPI also was evaluated.
Methods
The authors evaluated the antithrombotic activity of Ir-CPI by using in vitro catheter-induced clotting assays and rabbit experimental models of catheter occlusion and arteriovenous shunt. During CPB with cardiac surgery in sheep, the clinical applicability of Ir-CPI was investigated and its efficacy compared to that of UFH using an uncoated system suitable for adult therapy. Taking advantage of the similar hemostatic properties of pigs and humans, the authors performed pig liver bleeding assays to evaluate the safety of Ir-CPI.
Results
Ir-CPI prevented clotting in catheter and arteriovenous shunt rabbit models. During CPB, Ir-CPI was as efficient as UFH in preventing clot formation within the extracorporeal circuit and maintained physiological parameters during and post-surgery. Unlike UFH, Ir-CPI did not promote bleeding.
Conclusions
Preclinical animal models used in this study showed that Ir-CPI is an effective and safe antithrombotic agent that provides a clinically relevant approach to thrombosis prevention in bypass systems, including highly thrombogenic CPB.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 28 Oct 2019; 74:2178-2189
Pireaux V, Tassignon J, Demoulin S, Derochette S, ... Guyaux M, Godfroid E
J Am Coll Cardiol: 28 Oct 2019; 74:2178-2189 | PMID: 31648711
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Impact:
Abstract

Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.

Neubauer S, Kolm P, Ho CY, Kwong RY, ... Kramer CM,
Background
The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.
Objectives
The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.
Methods
Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.
Results
A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.
Conclusions
The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Nov 2019; 74:2333-2345
Neubauer S, Kolm P, Ho CY, Kwong RY, ... Kramer CM,
J Am Coll Cardiol: 11 Nov 2019; 74:2333-2345 | PMID: 31699273
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Impact:
Abstract

Sex-Related Differences in Heart Failure After ST-Segment Elevation Myocardial Infarction.

Cenko E, van der Schaar M, Yoon J, Manfrini O, ... Badimon L, Bugiardini R
Background
ST-segment elevation myocardial infarction (STEMI) complicated by symptoms of acute de novo heart failure is associated with excess mortality. Whether development of heart failure and its outcomes differ by sex is unknown.
Objectives
This study sought to examine the relationships among sex, acute heart failure, and related outcomes after STEMI in patients with no prior history of heart failure recorded at baseline.
Methods
Patients were recruited from a network of hospitals in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) registry (NCT01218776). Main outcome measures were incidence of Killip class ≥II at hospital presentation and risk-adjusted 30-day mortality rates were estimated using inverse probability of weighting and logistic regression models.
Results
This study included 10,443 patients (3,112 women). After covariate adjustment and matching for age, cardiovascular risk factors, comorbidities, disease severity, and delay to hospital presentation, the incidence of de novo heart failure at hospital presentation was significantly higher for women than for men (25.1% vs. 20.0%, odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.21 to 1.48). Women with de novo heart failure had higher 30-day mortality than did their male counterparts (25.1% vs. 20.6%; OR: 1.29; 95% CI: 1.05 to 1.58). The sex-related difference in mortality rates was still apparent in patients with de novo heart failure undergoing reperfusion therapy after hospital presentation (21.3% vs. 15.7%; OR: 1.45; 95% CI: 1.07 to 1.96).
Conclusions
Women are at higher risk to develop de novo heart failure after STEMI and women with de novo heart failure have worse survival than do their male counterparts. Therefore, de novo heart failure is a key feature to explain mortality gap after STEMI among women and men.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 11 Nov 2019; 74:2379-2389
Cenko E, van der Schaar M, Yoon J, Manfrini O, ... Badimon L, Bugiardini R
J Am Coll Cardiol: 11 Nov 2019; 74:2379-2389 | PMID: 31699278
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Impact:
Abstract

ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons.

Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.



Hypertension: 30 Oct 2019; 74:1181-1191
Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E
Hypertension: 30 Oct 2019; 74:1181-1191 | PMID: 31564162
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Abstract

Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart.

Li H, Fan J, Zhao Y, Zhang X, ... Chen C, Wang DW

Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among diabetes patients, but little is known about the mechanism that connects diabetes to the development of cardiovascular dysfunction.We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes and diabetic complications that lead to heart failure.We first profiled the expression of miRNAs by microarray and qRT-PCR on db/db mice, and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the up-regulation of the same miRNA in the failing heart of diabetes patients. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA (saRNA) in the nucleus at the level of transcription. By ChIP-seq and ChIP-qPCR analysis of Ago2 and RNA Pol II in response to miR-320 induction, we identified CD36 as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart.These findings uncover a novel mechanism for diabetes-triggered cardiac dysfunction, provide an endogenous case for saRNA that has been demonstrated so far only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes-associated cardiovascular complications.



Circ Res: 21 Oct 2019; epub ahead of print
Li H, Fan J, Zhao Y, Zhang X, ... Chen C, Wang DW
Circ Res: 21 Oct 2019; epub ahead of print | PMID: 31638474
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Abstract

Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications.

Zhang Z, Luo X, Lv Y, Yan L, ... Pan Y, Du L

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension-like pathophysiological features in adulthood.



Hypertension: 30 Oct 2019; 74:1160-1171
Zhang Z, Luo X, Lv Y, Yan L, ... Pan Y, Du L
Hypertension: 30 Oct 2019; 74:1160-1171 | PMID: 31596625
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Abstract

NaHCO Dilates Mouse Afferent Arteriole Via Na/HCO Cotransporters NBCs.

Jiang S, Wang X, Wei J, Zhang G, ... Lai EY, Liu R

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na/HCO cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, <0.05) in response to NaHCO (44 mmol/L). Whereas, NaCl solution containing the same Na concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2\',7\'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; <0.05) in the presence of NaHCO, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 μM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; <0.005) and increases NO generation by 22±3% (n=7; <0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO increased NO generation in Af-Art by 19±4% (n=5; <0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; <0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.



Hypertension: 30 Oct 2019; 74:1104-1112
Jiang S, Wang X, Wei J, Zhang G, ... Lai EY, Liu R
Hypertension: 30 Oct 2019; 74:1104-1112 | PMID: 31522618
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Impact:
Abstract

SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for endothelial to mesenchymal transition.

Qin W, Zhang L, Li Z, Xiao D, ... Yang B, Zhang Y
Background
Vascular aging has profound effects on cardiovascular diseases. Endothelial to mesenchymal transition (EndMT) is defined as the acquisition of mesenchymal characteristics by endothelial cells (ECs) and has been found induced in a model of ECs aging. However, whether EndMT occurs during aging in vivo, the functional significance of EndMT on vascular biology and the underlying mechanisms remain unknown.
Methods and results
In this study, we examined the vascular ECs from young (2 months old) and old (18 months old) mice, and demonstrated that aged ECs underwent EndMT. Moreover, the transwell assay showed that EndMT process was accompanied by increased endothelial permeability. It was found that sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, was down-regulated during ECs aging. Knockdown of SIRT6 in young ECs could induce EndMT. Next, we identified five long non-coding RNAs that are enriched in ECs for downstream effector of SIRT6; only metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was significantly up-regulated in aged ECs. Knockdown of SIRT6 could increase MALAT1 levels. Furthermore, the ChIP assay and luciferase reporter gene assay confirmed that SIRT6 bound directly to the promoter region of MALAT1 and suppressed MALAT1 expression. Finally, we demonstrated that MALAT1 mediated aging-induced EndMT through increasing Snail expression.
Conclusion
Our study provides in vivo evidence that ECs undergo EndMT during vascular aging, which increases endothelial permeability. SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for EndMT. Manipulating EndMT may be considered as a new therapeutic strategy for retarding aging-associated vascular diseases.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:7-13
Qin W, Zhang L, Li Z, Xiao D, ... Yang B, Zhang Y
Int J Cardiol: 14 Nov 2019; 295:7-13 | PMID: 31399301
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Abstract

Nonproportional Hazards for Time-to-Event Outcomes in Clinical Trials: JACC Review Topic of the Week.

Gregson J, Sharples L, Stone GW, Burman CF, Öhrn F, Pocock S

Most major clinical trials in cardiology report time-to-event outcomes using the Cox proportional hazards model so that a treatment effect is estimated as the hazard ratio between groups, accompanied by its 95% confidence interval and a log-rank p value. But nonproportionality of hazards (non-PH) over time occurs quite often, making alternative analysis strategies appropriate. This review presents real examples of cardiology trials with different types of non-PH: an early treatment effect, a late treatment effect, and a diminishing treatment effect. In such scenarios, the relative merits of a Cox model, an accelerated failure time model, a milestone analysis, and restricted mean survival time are examined. Some post hoc analyses for exploring any specific pattern of non-PH are also presented. Recommendations are made, particularly regarding how to handle non-PH in pre-defined Statistical Analysis Plans, trial publications, and regulatory submissions.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Oct 2019; 74:2102-2112
Gregson J, Sharples L, Stone GW, Burman CF, Öhrn F, Pocock S
J Am Coll Cardiol: 21 Oct 2019; 74:2102-2112 | PMID: 31623769
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Abstract

Rapamycin-Loaded Leukosomes Reverse Vascular Inflammation.

Boada C, Zinger A, Tsao CJ, Zhao P, ... Cooke JP, Tasciotti E

Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation, and thus the progression of vascular disease.Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in-vivo model of atherosclerosis after a short dosing schedule.Biomimetic nanoparticles (\"leukosomes\") were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108 +/- 2.3 nm, a surface charge of -15.4 +/- 14.4 mV and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either phosphate-buffered saline, free rapamycin (5mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa) (5mg/kg) once daily for seven days. In mice treated with Leuko-Rapa flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6 +/- 9.79 %) compared to untreated mice (30.2 +/- 13.34 %) and rapamycin alone (26.8 +/- 9.87 %). Decreased macrophage proliferation correlated with decreased levels of monocyte chemoattractant protein (MCP-1) and Il-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa treated mice also displayed significantly decreased MMP activity in the aorta (Mean Difference 2554 {plus minus} 363.9, p= 9.95122E-06). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa treated mice.We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key pro-inflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (seven days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.



Circ Res: 23 Oct 2019; epub ahead of print
Boada C, Zinger A, Tsao CJ, Zhao P, ... Cooke JP, Tasciotti E
Circ Res: 23 Oct 2019; epub ahead of print | PMID: 31647755
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Abstract

Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis.

Fulmer D, Toomer K, Guo L, Moore K, ... Norris RA, Lipschutz JH
Background
Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities.
Methods
We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based onvalue and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.
Results
Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.
Conclusions
These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.



Circulation: 14 Oct 2019; 140:1331-1341
Fulmer D, Toomer K, Guo L, Moore K, ... Norris RA, Lipschutz JH
Circulation: 14 Oct 2019; 140:1331-1341 | PMID: 31387361
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Abstract

Heightened Risk of Intensive Rate Control in Patients With Atrial Fibrillation Who Are Obese or Have Type 2 Diabetes: A Critical Review and Re-Evaluation.

Packer M

Atrial fibrillation (AF) is common in patients with obesity and diabetes; the arrhythmia (if long-standing) is typically managed by rate-control and anticoagulation. However, the coexistence of these two metabolic disorders complicates therapeutic options for rate-control. The likely pathogenesis of AF in these patients is an expansion of epicardial adipose tissue, whose inflammation is transmitted to the left atrium causing electromechanical remodeling. However, this same process is also transmitted to the left ventricle, impairing its distensibility and its ability to tolerate volume, leading to heart failure with preserved ejection fraction. Unfortunately, the latter diagnosis (although commonly present in patients with AF and a coexistent metabolic disorder) is often ignored. To achieve rate control, physicians prescribe intensive treatment with atrioventricular (AV)-nodal blocking drugs, often at doses that are titrated to blunt exercise as well as resting heart rate responses. However, strict rate control (target rate <80/min) is associated with somewhat worse outcomes than lenient rate control (target rate <110/min). Furthermore, any rate slowing that facilitates diastolic filling may aggravate filling pressures that are already disproportionately increased because the left ventricle is stiff and overfilled as a result of cardiac inflammation. Rate slowing in AF with beta-blockers may not achieve the benefit expected from the blockade of adrenergically-mediated cardiotoxicity, and some AV-nodal blocking drugs (digoxin and dronedarone) can increase the risk of death in patients with AF. Finally, cardiac fibrosis in obesity and diabetes may affect the conduction system, which can predispose to serious bradyarrhythmias if patients are prescribed AV-nodal blocking drugs. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print
Packer M
J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print | PMID: 31626365
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Abstract

Alteration of Cardiac Performance and Serum B-Type Natriuretic Peptide Level in Healthy Aging.

Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, ... Homma S, Komuro I
Background
The impact of aging on cardiac function is not fully elucidated. Speckle-tracking echocardiography can unmask subclinical cardiac dysfunction.
Objectives
This study investigated the impact of healthy aging on left ventricular (LV), right ventricular (RV), and left atrial (LA) performance and their relationship with serum B-type natriuretic peptide (BNP) levels in a sample of the general population without prevalent cardiovascular risk factors and structural heart disease.
Methods
Speckle-tracking echocardiography was performed to assess LV global longitudinal strain (LVGLS), RV free wall strain, and LA phasic strain in 481 normal weight healthy participants who underwent extensive cardiovascular examination. Elevated BNP was defined as BNP >37.82 pg/ml for men and >50.86 pg/ml for women, which was the 90th percentile of BNP value distribution in the study population.
Results
Mean age was 60 ± 12 years (range: 24 to 86 years), and 46% of the participants were men. The earliest alteration of age-related cardiac performance was observed in LA reservoir and conduit strain starting from decade 5, followed by elevated E/e\' from decade 6. LVGLS decreased starting from decade 7, whereas there were no significant differences in RV strain, LV ejection fraction, or LV mass index across the decades. In the multivariable linear regression analyses, age was an independent predictor of decreased LVGLS (standardized β = 0.21; p < 0.001) and decreased LA phasic strain (standardized β = -0.40 and -0.61 for reservoir and conduit strain; both p < 0.001). Age and LA strain were significantly associated with elevated BNP values (adjusted odds ratios: 1.10 and 0.93; both p < 0.05, respectively), independent of ventricular morphology and function.
Conclusions
Decreases in LA reservoir and conduit strain are the earliest markers of age-related cardiac remodeling, and LA reservoir strain is an independent predictor of elevated serum BNP level, with both possibly being markers of increased risk of heart failure in older adults.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Oct 2019; 74:1789-1800
Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, ... Homma S, Komuro I
J Am Coll Cardiol: 08 Oct 2019; 74:1789-1800 | PMID: 31582139
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Abstract

Ascending Aortic Length and Risk of Aortic Adverse Events: The Neglected Dimension.

Wu J, Zafar MA, Li Y, Saeyeldin A, ... Yu C, Elefteriades JA
Background
Little information is available regarding the longitudinal changes of the aneurysmal ascending aorta.
Objectives
This study sought to outline the natural history of ascending thoracic aortic aneurysm (ATAA) based on ascending aortic length (AAL) and develop novel predictive tools to better aid risk stratification.
Methods
The ascending aortic diameters and lengths, and long-term aortic adverse events (AAEs) (rupture, dissection, and death) of 522 ATAA patients were evaluated using comprehensive statistical approaches.
Results
An AAL of ≥13 cm was associated with an almost 5-fold higher average yearly rate of AAEs compared with an AAL of <9 cm. Two AAL \"hinge points\" with a sharp increase in the estimated probability of AAEs were detected between 11.5 and 12.0 cm, and between 12.5 and 13.0 cm. The mean estimated annual aortic elongation rate was 0.18 cm/year, and aortic elongation was age dependent. Aortic diameter increased 18% due to dissection while AAL only increased by 2.7%. There was a noticeable improvement in the discrimination of the logistic regression model (area under the receiver-operating characteristic curve: 0.810) due to the introduction of aortic height index (AHI) (diameter height index + length height index). The AHIs <9.33, 9.38 to 10.81, 10.86 to 12.50, and ≥12.57 cm/m were associated with a ∼4%, ∼7%, ∼12%, and ∼18% average yearly risk of AAEs, respectively.
Conclusions
An aortic elongation of 11 cm serves as a potential intervention criterion for ATAA, which is even more reliable than diameter due to its relative immunity to dissection. AHI (including both length and diameter) is more powerful than any single parameter in this study.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1883-1894
Wu J, Zafar MA, Li Y, Saeyeldin A, ... Yu C, Elefteriades JA
J Am Coll Cardiol: 15 Oct 2019; 74:1883-1894 | PMID: 31526537
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Impact:
Abstract

Long-Term Dabigatran Treatment Delays Alzheimer\'s Disease Pathogenesis in the TgCRND8 Mouse Model.

Cortes-Canteli M, Kruyer A, Fernandez-Nueda I, Marcos-Diaz A, ... Strickland S, Fuster V
Background
Alzheimer\'s disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment.
Objectives
This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD.
Methods
TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity.
Results
Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB.
Conclusions
Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1910-1923
Cortes-Canteli M, Kruyer A, Fernandez-Nueda I, Marcos-Diaz A, ... Strickland S, Fuster V
J Am Coll Cardiol: 15 Oct 2019; 74:1910-1923 | PMID: 31601371
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Abstract

Community Health Workers Improve Linkage to Hypertension Care in Western Kenya.

Vedanthan R, Kamano JH, DeLong AK, Naanyu V, ... Kimaiyo S, Fuster V
Background
Elevated blood pressure (BP) is the leading global risk factor for mortality. Delay in seeking hypertension care is associated with increased mortality.
Objectives
This study investigated whether community health workers, equipped with behavioral communication strategies and smartphone technology, can increase linkage of individuals with elevated BP to a hypertension care program in western Kenya and significantly reduce BP.
Methods
The study was a cluster randomized trial with 3 arms: 1) usual care (standard training); 2) \"paper-based\" (tailored behavioral communication, using paper-based tools); and 3) \"smartphone\" (tailored behavioral communication, using smartphone technology). The co-primary outcomes were: 1) linkage to care; and 2) change in systolic BP (SBP). A covariate-adjusted mixed-effects model was used, adjusting for differential time to follow-up. Bootstrap and multiple imputation were used to handle missing data.
Results
A total of 1,460 individuals (58% women) were enrolled (491 usual care, 500 paper-based, 469 smartphone). Average baseline SBP was 159.4 mm Hg. Follow-up measures of linkage were available for 1,128 (77%) and BP for 1,106 (76%). Linkage to care was 49% overall, with significantly greater linkage in the usual care and smartphone arms of the trial. Average overall follow-up SBP was 149.9 mm Hg. Participants in the smartphone arm experienced a modestly greater reduction in SBP versus usual care (-13.1 mm Hg vs. -9.7 mm Hg), but this difference was not statistically significant. Mediation analysis revealed that linkage to care contributed to SBP change.
Conclusions
A strategy combining tailored behavioral communication and mobile health (mHealth) for community health workers led to improved linkage to care, but not statistically significant improvement in SBP reduction. Further innovations to improve hypertension control are needed. (Optimizing Linkage and Retention to Hypertension Care in Rural Kenya [LARK]; NCT01844596).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1897-1906
Vedanthan R, Kamano JH, DeLong AK, Naanyu V, ... Kimaiyo S, Fuster V
J Am Coll Cardiol: 15 Oct 2019; 74:1897-1906 | PMID: 31487546
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Impact:
Abstract

Cardiac Magnetic Resonance Stress Perfusion Imaging for Evaluation of Patients With Chest Pain.

Kwong RY, Ge Y, Steel K, Bingham S, ... Stuber M, Simonetti OP
Background
Stress cardiac magnetic resonance imaging (CMR) has demonstrated excellent diagnostic and prognostic value in single-center studies.
Objectives
This study sought to investigate the prognostic value of stress CMR and downstream costs from subsequent cardiac testing in a retrospective multicenter study in the United States.
Methods
In this retrospective study, consecutive patients from 13 centers across 11 states who presented with a chest pain syndrome and were referred for stress CMR were followed for a target period of 4 years. The authors associated CMR findings with a primary outcome of cardiovascular death or nonfatal myocardial infarction using competing risk-adjusted regression models and downstream costs of ischemia testing using published Medicare national payment rates.
Results
In this study, 2,349 patients (63 ± 11 years of age, 47% female) were followed for a median of 5.4 years. Patients with no ischemia or late gadolinium enhancement (LGE) by CMR, observed in 1,583 patients (67%), experienced low annualized rates of primary outcome (<1%) and coronary revascularization (1% to 3%), across all years of study follow-up. In contrast, patients with ischemia+/LGE+ experienced a >4-fold higher annual primary outcome rate and a >10-fold higher rate of coronary revascularization during the first year after CMR. Patients with ischemia and LGE both negative had low average annual cost spent on ischemia testing across all years of follow-up, and this pattern was similar across the 4 practice environments of the participating centers.
Conclusions
In a multicenter U.S. cohort with stable chest pain syndromes, stress CMR performed at experienced centers offers effective cardiac prognostication. Patients without CMR ischemia or LGE experienced a low incidence of cardiac events, little need for coronary revascularization, and low spending on subsequent ischemia testing. (Stress CMR Perfusion Imaging in the United States [SPINS]: A Society for Cardiovascular Resonance Registry Study; NCT03192891).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Oct 2019; 74:1741-1755
Kwong RY, Ge Y, Steel K, Bingham S, ... Stuber M, Simonetti OP
J Am Coll Cardiol: 08 Oct 2019; 74:1741-1755 | PMID: 31582133
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Impact:
Abstract

KLF15-Wnt-Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart.

Noack C, Iyer LM, Liaw NY, Schoger E, ... Zimmermann WH, Zelarayán LC
Background
The combination of cardiomyocyte (CM) and vascular cell (VC) fetal reprogramming upon stress culminates in end-stage heart failure (HF) by mechanisms that are not fully understood. Previous studies suggest KLF15 as a key regulator of CM hypertrophy.
Objectives
This study aimed to characterize the impact of KLF15-dependent cardiac transcriptional networks leading to HF progression, amenable to therapeutic intervention in the adult heart.
Methods
Transcriptomic bioinformatics, phenotyping of Klf15 knockout mice, Wnt-signaling-modulated hearts, and pressure overload and myocardial ischemia models were applied. Human KLF15 knockout embryonic stem cells and engineered human myocardium, and human samples were used to validate the relevance of the identified mechanisms.
Results
The authors identified a sequential, postnatal transcriptional repression mediated by KLF15 of pathways implicated in pathological tissue remodeling, including distinct Wnt-pathways that control CM fetal reprogramming and VC remodeling. The authors further uncovered a vascular program induced by a cellular crosstalk initiated by CM, characterized by a reduction of KLF15 and a concomitant activation of Wnt-dependent transcriptional signaling. Within this program, a so-far uncharacterized cardiac player, SHISA3, primarily expressed in VCs in fetal hearts and pathological remodeling was identified. Importantly, the KLF15 and Wnt codependent SHISA3 regulation was demonstrated to be conserved in mouse and human models.
Conclusions
The authors unraveled a network interplay defined by KLF15-Wnt dynamics controlling CM and VC homeostasis in the postnatal heart and demonstrated its potential as a cardiac-specific therapeutic target in HF. Within this network, they identified SHISA3 as a novel, evolutionarily conserved VC marker involved in pathological remodeling in HF.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Oct 2019; 74:1804-1819
Noack C, Iyer LM, Liaw NY, Schoger E, ... Zimmermann WH, Zelarayán LC
J Am Coll Cardiol: 08 Oct 2019; 74:1804-1819 | PMID: 31582141
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Impact:
Abstract

Impaired Autophagy in CD11b Dendritic Cells Expands CD4 Regulatory T Cells And Limits Atherosclerosis in Mice.

Clément M, Raffort J, Lareyre F, Tsiantoulas D, ... Kaser A, Mallat Z

Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit.Dendritic cells (DCs) are at the crossroad of innate and adaptive immune responses and profoundly modulate the development of atherosclerosis. Intriguingly, the role of autophagy in DC function during atherosclerosis and how the autophagy process would impact disease development has not been addressed.Here, we show that the autophagic flux in atherosclerosis-susceptible low-density lipoprotein receptor deficient () mice is substantially higher in splenic and aortic DCs compared to macrophages, and is further activated under hypercholesterolemic conditions. RNA sequencing and functional studies on selective cell populations reveal that disruption of autophagy through deletion ofdifferentially affects the biology and functions of DC subsets inmice under high fat diet.deficient CD11b DCs develop a TGF-beta-dependent tolerogenic phenotype and promote the expansion of regulatory T cells (Tregs), whereas no such effects are seen withdeficient CD8alpha DCs.deletion in DCs (all CD11c-expressing cells) expands aortic Tregs in vivo, limits the accumulation of T helper cells type 1 (Th1), and reduces the development of atherosclerosis inmice. In contrast, no such effects are seen whenis deleted selectively in conventional CD8alpha DCs and CD103 DCs. Total T cell or selective Treg cell depletion abrogates the atheroprotective effect ofdeficient DCs.In contrast to its pro-atherogenic role in macrophages, autophagy disruption in DCs induces a counter-regulatory response that maintains immune homeostasis inmice under high fat diet and limits atherogenesis. Selective modulation of autophagy in DCs could constitute an interesting therapeutic target in atherosclerosis.



Circ Res: 14 Oct 2019; epub ahead of print
Clément M, Raffort J, Lareyre F, Tsiantoulas D, ... Kaser A, Mallat Z
Circ Res: 14 Oct 2019; epub ahead of print | PMID: 31610723
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Abstract

Living myocardial slices: a novel multicellular model for cardiac translational research.

Perbellini F, Thum T

Heart function relies on the interplay of several specialized cell types and a precisely regulated network of chemical and mechanical stimuli. Over the last few decades, this complexity has often been undervalued and progress in translational cardiovascular research has been significantly hindered by the lack of appropriate research models. The data collected are often oversimplified and these make the translation of results from the laboratory to clinical trials challenging and occasionally misleading. Living myocardial slices are ultrathin (100-400μm) sections of living cardiac tissue that maintain the native multicellularity, architecture, and structure of the heart and can provide information at a cellular/subcellular level. They overcome most of the limitations that affect other in vitro models and they can be prepared from human specimens, proving a clinically relevant multicellular human model for translational cardiovascular research. The publication of a reproducible protocol, and the rapid progress in methodological and technological discoveries which prevent significant structural and functional changes associated with chronic in vitro culture, has overcome the last barrier for the in vitro use of this human multicellular preparations. This technology can bridge the gap between in vitro and in vivo human studies and has the potential to revolutionize translational research approaches.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 10 Nov 2019; epub ahead of print
Perbellini F, Thum T
Eur Heart J: 10 Nov 2019; epub ahead of print | PMID: 31711161
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Abstract

Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure.

Bilchick K, Kothari H, Narayan A, Garmey J, ... Capaldo B, McNamara C
Aims
In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure.
Methods and results
We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5 years, interquartile range 63.0-66.8 years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1β pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1β (1.80-fold decrease, P = 0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P = 0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P = 0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P = 0.03), and suppression was greater in responders vs. non-responders (P = 0.03 for IL-1β, P = 0.02 for FOS, P = 0.02 for DUSP1, and P = 0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P = 0.002; 2.60-fold higher, DUSP1, P = 0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P = 0.04) and DUSP1 (P = 0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P = 0.008).
Conclusion
Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 14 Oct 2019; epub ahead of print
Bilchick K, Kothari H, Narayan A, Garmey J, ... Capaldo B, McNamara C
Cardiovasc Res: 14 Oct 2019; epub ahead of print | PMID: 31612215
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Abstract

Extent of Myocardial Ischemia on Positron Emission Tomography and Survival Benefit With Early Revascularization.

Patel KK, Spertus JA, Chan PS, Sperry BW, ... McGhie AI, Bateman TM
Background
Prior studies with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) have shown a survival benefit with early revascularization in patients with >10% to 12.5% ischemic myocardium. The relationship among positron emission tomography (PET)-derived extent of ischemia, early revascularization, and survival is unknown.
Objectives
The purpose of this study was to evaluate the association among percent ischemia on PET MPI, revascularization, and survival.
Methods
A total of 16,029 unique consecutive patients who were undergoing Rubidium-82 rest-stress PET MPI from 2010 to 2016 were included. Patients with known cardiomyopathy and nondiagnostic perfusion results were excluded. Percent ischemic myocardium was estimated from a 17-segment model. Propensity scoring was used to account for nonrandomized referral to early revascularization (90 days of PET). A Cox model was developed, adjusting for propensity scores for early revascularization and percent ischemia, and an interaction between ischemia and early revascularization was tested.
Results
Median follow-up was 3.7 years. Overall, 1,277 (8%) patients underwent early revascularization and 2,493 (15.6%) died (738 cardiac). Nearly 37% of patients (n = 5,902) had ischemia, with 13.5% (n = 2,160) having ≥10%. In propensity-adjusted analyses, there was a significant interaction between ischemia and early revascularization (p < 0.001 for all-cause and cardiac death), such that patients with greater ischemia had improved survival with early revascularization, with a potential ischemia threshold at 5% (upper limit 95% confidence interval at 10%). There was no differential association between ischemia and early revascularization on death based on history of known coronary artery disease (interaction p = 0.72).
Conclusions
In a contemporary cohort of patients undergoing PET MPI, patients with greater ischemia had a survival benefit from early revascularization. On exploratory analyses, this threshold was lower than that previously reported for SPECT. These findings require future validation in prospective cohorts or trials.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Oct 2019; 74:1645-1654
Patel KK, Spertus JA, Chan PS, Sperry BW, ... McGhie AI, Bateman TM
J Am Coll Cardiol: 01 Oct 2019; 74:1645-1654 | PMID: 31558246
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Abstract

Noninvasive Stereotactic Radiotherapy for Renal Denervation in a Swine Model.

Cai X, Yang Y, Shen Y, Wang W, ... Jiang M, Li YG
Background
Catheter-based renal denervation (RDN) has achieved promising outcomes to treat hypertension in recent randomized controlled trials.
Objectives
The purpose of this study was to assess the feasibility, efficacy, and safety of noninvasive stereotactic body radiotherapy (SBRT) as an approach for RDN.
Methods
SBRT was performed in 24 renal arteries from 12 normotensive swine at doses of 25, 35, and 45 Gy (n = 4 each), and an additional 4 swine served as controls. Blood pressure (BP), renal function, and serum norepinephrine (NE) values were obtained at baseline and at 7 days, 1 month, and 3 months after SBRT. Abdominal contrast-enhanced computed tomography (CT) was performed after 3 months before euthanasia. Renal NE concentration was determined, and histological analysis and immunohistochemistry against tyrosine hydroxylase were performed.
Results
SBRT procedure was successful in all 12 swine. BP was comparable among groups. Serum and renal NE levels at 3 months were significantly lower in treatment groups compared with control group. Furthermore, SBRT resulted in significantly greater nerve injury score and lower tyrosine hydroxylase score compared with control subjects, whereas there were no statistical differences between SBRT groups. Circumferential lesions created with 35 and 45 Gy were significantly greater than with 25 Gy. CT and histology analysis revealed that animals receiving 35 and 45 Gy experienced more collateral damage, which was minimal in the 25-Gy group.
Conclusions
Noninvasive SBRT was feasible and effective for complete, circumferential RDN in a swine model, with dosage at 25 Gy providing the safest short-term profile.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Oct 2019; 74:1697-1709
Cai X, Yang Y, Shen Y, Wang W, ... Jiang M, Li YG
J Am Coll Cardiol: 01 Oct 2019; 74:1697-1709 | PMID: 31558254
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Abstract

Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study.

Liberale L, Gaul DS, Akhmedov A, Bonetti NR, ... Matter CM, Camici GG
Aims
Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.
Methods and results
SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.
Conclusion
Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 10 Oct 2019; epub ahead of print
Liberale L, Gaul DS, Akhmedov A, Bonetti NR, ... Matter CM, Camici GG
Eur Heart J: 10 Oct 2019; epub ahead of print | PMID: 31603194
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Abstract

Impact of renin-angiotensin system inhibitors on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: an analysis of from the PARTNER 2 trial and registries.

Chen S, Redfors B, Nazif T, Kirtane A, ... Kodali SK, Leon MB
Aims
Left ventricular pressure overload is associated with activation of the cardiac renin-angiotensin system, which may contribute to myocardial fibrosis and worse clinical outcomes. We sought to assess the association between treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) at baseline and clinical outcomes in patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) in the PARTNER 2 trial and registries.
Methods and results
A total of 3979 intermediate, high, or prohibitive risk patients who underwent TAVR in the PARTNER 2 trial and registries (excluding the valve in valve registry) were included in the study. Clinical outcomes at 2 years were compared according to baseline ACEI/ARB treatment status using Kaplan-Meier event rates and study-stratified multivariable Cox proportional hazards regression models. Sensitivity analysis was conducted using propensity score matching. Of 3979 patients who were included in the current analysis, 1736 (43.6%) were treated and 2243 (56.4%) were not treated with ACEI/ARB at baseline. Treatment with ACEI/ARB was associated with lower 2-year all-cause mortality (18.6% vs. 27.5%, P < 0.0001), cardiovascular mortality (12.3% vs. 17.9%, P < 0.0001), and non-cardiovascular mortality (7.2% vs. 11.7%, P < 0.0001). Angiotensin-converting enzyme inhibitor/ARB treatment at baseline remained independently associated with a lower hazard of 2-year all-cause and cardiovascular mortality after multivariable adjustment, and propensity score matching.
Conclusion
In a large cohort of patients with severe symptomatic AS from the PARTNER 2 trial and registries, ACEI/ARB treatment at baseline was independently associated with a lower risk of 2-year all-cause and cardiovascular mortality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 10 Nov 2019; epub ahead of print
Chen S, Redfors B, Nazif T, Kirtane A, ... Kodali SK, Leon MB
Eur Heart J: 10 Nov 2019; epub ahead of print | PMID: 31711153
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Abstract

From Detecting the Vulnerable Plaque to Managing the Vulnerable Patient: JACC State-of-the-Art Review.

Arbab-Zadeh A, Fuster V

The past decades have seen tremendous progress on elucidating mechanisms leading to acute coronary syndrome and sudden cardiac death. Pathology and imaging studies have identified features of coronary atherosclerosis that precede acute coronary events. However, many factors influence the risk of adverse events from coronary atherosclerotic disease and available data support our transition from focusing on individual \"vulnerable plaque,\" coronary arterial stenosis, and inducible myocardial ischemia to understanding coronary heart disease as multifactorial, chronic disease. The concept of the vulnerable patient has evolved, with the atheroma burden, its metabolic activity, and the disposition to vascular thrombosis building a platform for assessing central aspects of coronary heart disease. In turn, this model has directed us to a focus on controlling the activity of atherosclerotic disease and on modifying the susceptibility of vascular thrombosis which has led to reduced morbidity and mortality from coronary heart disease.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 Sep 2019; 74:1582-1593
Arbab-Zadeh A, Fuster V
J Am Coll Cardiol: 24 Sep 2019; 74:1582-1593 | PMID: 31537269
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Abstract

Changes in the Prevalence of Chronic Hypertension in Pregnancy, United States, 1970 to 2010.

Ananth CV, Duzyj CM, Yadava S, Schwebel M, Tita ATN, Joseph KS

We estimated changes in the prevalence of chronic hypertension among pregnant women and evaluated the extent to which changes in obesity and smoking were associated with these trends. We designed a population-based cross-sectional analysis of over 151 million women with delivery-related hospitalizations in the United States, 1970 to 2010. Maternal age, year of delivery (period), and maternal year of birth (birth cohort), as well as race, were examined as risk factors for chronic hypertension. Prevalence rates and rate ratios with 95% CIs of chronic hypertension in relation to age, period, and birth cohort were derived through age-period-cohort models. We also examined how changes in obesity and smoking rates influenced age-period-cohort effects. The overall prevalence of chronic hypertension was 0.63%, with black women (1.24%) having more than a 2-fold higher rate than white women (0.53%; rate ratio, 2.31; 95% CI, 2.30-2.32). In the age-period-cohort analysis, the rate of chronic hypertension increased sharply with advancing age and period from 0.11% in 1970 to 1.52% in 2010 (rate ratio, 13.41; 95% CI, 13.22-13.61). The rate of hypertension increased, on average, by 6% (95% CI, 5-6) per year, with the increase being slightly higher among white (7%; 95% CI, 6%-7%) than black (4%; 95% CI, 3%-4%) women. Adjustments for changes in rates of obesity and smoking were not associated with age and period effects. We observed a substantial increase in chronic hypertension rates by age and period and an over 2-fold race disparity in chronic hypertension rates.



Hypertension: 30 Oct 2019; 74:1089-1095
Ananth CV, Duzyj CM, Yadava S, Schwebel M, Tita ATN, Joseph KS
Hypertension: 30 Oct 2019; 74:1089-1095 | PMID: 31495278
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Abstract

Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients.

Kolte D, Vlahakes GJ, Palacios IF, Sakhuja R, ... Inglessis I, Elmariah S
Background
Transcatheter aortic valve replacement (TAVR) has emerged as a safe and effective therapeutic option for patients with severe aortic stenosis (AS) who are at prohibitive, high, or intermediate risk for surgical aortic valve replacement (SAVR). However, in low-risk patients, SAVR remains the standard therapy in current clinical practice.
Objectives
This study sought to perform a meta-analysis of randomized controlled trials (RCTs) comparing TAVR versus SAVR in low-risk patients.
Methods
Electronic databases were searched from inception to March 20, 2019. RCTs comparing TAVR versus SAVR in low-risk patients (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM] score <4%) were included. Primary outcome was all-cause death at 1 year. Random-effects models were used to calculate pooled risk ratio (RR) and corresponding 95% confidence interval (CI).
Results
The meta-analysis included 4 RCTs that randomized 2,887 patients (1,497 to TAVR and 1,390 to SAVR). The mean age of patients was 75.4 years, and the mean STS-PROM score was 2.3%. Compared with SAVR, TAVR was associated with significantly lower risk of all-cause death (2.1% vs. 3.5%; RR: 0.61; 95% CI: 0.39 to 0.96; p = 0.03; I = 0%) and cardiovascular death (1.6% vs. 2.9%; RR: 0.55; 95% CI: 0.33 to 0.90; p = 0.02; I = 0%) at 1 year. Rates of new/worsening atrial fibrillation, life-threatening/disabling bleeding, and acute kidney injury stage 2/3 were lower, whereas those of permanent pacemaker implantation and moderate/severe paravalvular leak were higher after TAVR versus SAVR. There were no significant differences between TAVR versus SAVR for major vascular complications, endocarditis, aortic valve re-intervention, and New York Heart Association functional class ≥II.
Conclusions
In this meta-analysis of RCTs comparing TAVR versus SAVR in low-risk patients, TAVR was associated with significantly lower risk of all-cause death and cardiovascular death at 1 year. These findings suggest that TAVR may be the preferred option over SAVR in low-risk patients with severe AS who are candidates for bioprosthetic AVR.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 Sep 2019; 74:1532-1540
Kolte D, Vlahakes GJ, Palacios IF, Sakhuja R, ... Inglessis I, Elmariah S
J Am Coll Cardiol: 24 Sep 2019; 74:1532-1540 | PMID: 31537261
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Abstract

Sex Differences in Circulating Biomarkers of Cardiovascular Disease.

Lau ES, Paniagua SM, Guseh JS, Bhambhani V, ... Levy D, Ho JE
Background
Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD).
Objectives
This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants.
Methods
The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD.
Results
Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (p <0.05 for all).
Conclusions
In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 24 Sep 2019; 74:1543-1553
Lau ES, Paniagua SM, Guseh JS, Bhambhani V, ... Levy D, Ho JE
J Am Coll Cardiol: 24 Sep 2019; 74:1543-1553 | PMID: 31537263
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Abstract

2-Year Outcomes After Complete or Staged Procedure for Tetralogy of Fallot in Neonates.

Savla JJ, Faerber JA, Huang YV, Zaoutis T, ... Kawut SM, Mercer-Rosa L
Background
There is ongoing debate about the best strategy to treat patients with tetralogy of Fallot who are symptomatic in the neonatal period.
Objectives
The aim of this study was to compare the outcomes of complete versus staged surgery (i.e., initial palliative procedure for possible later complete repair).
Methods
A retrospective cohort study was performed using the Pediatric Health Information System database, including patients who underwent complete or staged tetralogy of Fallot repair prior to 30 days of age. The primary outcome was death during 2-year follow-up after the initial procedure. Inverse probability-weighted Cox and logistic regression models were used to examine the association between surgical approach group and mortality while accounting for patient- and hospital-level factors. Causal mediation analyses examined the role of intermediate variables.
Results
A total of 2,363 patients were included (1,032 complete and 1,331 staged). There were 239 deaths. Complete neonatal repair was associated with a significantly higher risk for mortality during the 2-year follow-up period (hazard ratio: 1.51; 95% confidence interval: 1.05 to 2.06), between 7 and 30 days after the initial procedure (hazard ratio: 2.29; 95% confidence interval: 1.18 to 4.41), and during the initial hospital admission (odds ratio: 1.72; 95% confidence interval: 1.15 to 2.62). Post-operative cardiac complications were more common in the complete repair group and mediated the differences in 30-day and 2-year mortality.
Conclusions
Complete surgical repair for neonates with tetralogy of Fallot is associated with a significantly higher risk for early and 2-year mortality compared with the staged approach, after accounting for patient and hospital characteristics. Post-operative cardiac complications mediated these findings.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 Sep 2019; 74:1570-1579
Savla JJ, Faerber JA, Huang YV, Zaoutis T, ... Kawut SM, Mercer-Rosa L
J Am Coll Cardiol: 24 Sep 2019; 74:1570-1579 | PMID: 31537267
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Impact:
Abstract

In Silico Trial of Optimized Versus Actual Public Defibrillator Locations.

Sun CLF, Karlsson L, Torp-Pedersen C, Morrison LJ, ... Folke F, Chan TCY
Background
Automated external defibrillators (AEDs) are often placed in areas of low risk and limited temporal availability. Mathematical optimization can improve AED accessibility but has not been compared with current practices.
Objectives
This study sought to determine whether, compared with real AED locations, optimized AED locations improve coverage of out-of-hospital cardiac arrests (OHCAs).
Methods
The authors conducted the first retrospective in silico trial of an AED placement intervention. This study identified all public OHCAs of presumed cardiac cause and real AED deployed (control group) from 2007 to 2016 in Copenhagen, Denmark. Optimization models trained on historical OHCAs (1994 to 2007) were used to optimize an equal number of AEDs to the control group in locations with availabilities based on building hours (intervention #1) or 24/7 access (intervention #2). The 2 interventions and control scenario were compared using the number of OHCAs that occurred within 100 m of an accessible AED (\"OHCA coverage\") during the 2007 to 2016 period. Change in bystander defibrillation and 30-day survival were estimated using multivariate logistic regression.
Results
There were 673 public OHCAs and 1,573 registered AEDs from 2007 to 2016. OHCA coverage of real AED placements was 22.0%. OHCA coverage of interventions #1 and #2 was significantly higher at 33.4% and 43.1%, respectively; relative gains of 52.0% to 95.9% (p < 0.001). Bystander defibrillation increased from 14.6% (control group) to 22.5% to 26.9% (intervention #1 to intervention #2); relative increase of 52.9% to 83.5% (p < 0.001). The 30-day survival rates increased from 31.3% (control group) to 34.7% to 35.4%, which is a relative increase of 11.0% to 13.3% (p < 0.001).
Conclusions
Optimized AED placements increased OHCA coverage by approximately 50% to 100% over real AED placements, leading to significant predicted increases in bystander defibrillation and 30-day survival.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 Sep 2019; 74:1557-1567
Sun CLF, Karlsson L, Torp-Pedersen C, Morrison LJ, ... Folke F, Chan TCY
J Am Coll Cardiol: 24 Sep 2019; 74:1557-1567 | PMID: 31537265
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Impact:
Abstract

Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2).

Kuntic M, Oelze M, Steven S, Kröller-Schön S, ... Daiber A, Münzel T
Aims
Electronic (e)-cigarettes have been marketed as a \'healthy\' alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms.
Methods and results
Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation.
Conclusions
E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 12 Nov 2019; epub ahead of print
Kuntic M, Oelze M, Steven S, Kröller-Schön S, ... Daiber A, Münzel T
Eur Heart J: 12 Nov 2019; epub ahead of print | PMID: 31715629
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Impact:
Abstract

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.

van der Wal HH, Grote Beverborg N, Dickstein K, Anker SD, ... Voors AA, van der Meer P
Aims
Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort.
Methods and results
We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007).
Conclusion
Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 25 Sep 2019; epub ahead of print
van der Wal HH, Grote Beverborg N, Dickstein K, Anker SD, ... Voors AA, van der Meer P
Eur Heart J: 25 Sep 2019; epub ahead of print | PMID: 31556953
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Abstract

Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores.

Tadros R, Tan HL, , El Mathari S, ... Wilde AA, Bezzina CR
Aims
Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).
Methods and results
In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).
Conclusion
We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 30 Sep 2019; 40:3097-3107
Tadros R, Tan HL, , El Mathari S, ... Wilde AA, Bezzina CR
Eur Heart J: 30 Sep 2019; 40:3097-3107 | PMID: 31504448
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Abstract

Right Atrial Mechanisms of Atrial Fibrillation in a Rat Model of Right Heart Disease.

Hiram R, Naud P, Xiong F, Al-U\'datt D, ... Tardif JC, Nattel S
Background
Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.
Objectives
This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.
Methods
PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.
Results
Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p < 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.
Conclusions
Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Sep 2019; 74:1332-1347
Hiram R, Naud P, Xiong F, Al-U'datt D, ... Tardif JC, Nattel S
J Am Coll Cardiol: 10 Sep 2019; 74:1332-1347 | PMID: 31488271
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Abstract

Operator Experience and Procedural Results of Transcatheter Mitral Valve Repair in the United States.

Chhatriwalla AK, Vemulapalli S, Szerlip M, Kodali S, ... Kosinski AS, Sorajja P
Background
Transcatheter mitral valve repair (TMVr) for the treatment of mitral regurgitation (MR) is a complex procedure that requires development of a unique skillset.
Objective
To examine the relationship between operator experience and procedural results of TMVr with MitraClip (Abbott Structural, Santa Clara, CA).
Methods
TMVr device procedures from the STS/ACC TVT Registry were analyzed with operator case number as a continuous and categorical (1-25, 26-50, and >50) variable. Outcomes of procedural success, procedural time, and in-hospital procedural complications were examined. The learning curve for the procedure was evaluated using generalized linear mixed models adjusting for baseline clinical variables.
Results
All TMVr device procedures (n=14,923) performed by 562 operators at 290 sites between November 2013 and March 2018 were analyzed. Optimal procedural success (≤ 1+ residual MR without death or cardiac surgery) increased across categories of operator experience (63.9%, 68.4%, and 75.1%; p<0.001), while procedural time and procedural complications decreased. Acceptable procedural success (≤ 2+ residual MR without death or cardiac surgery) also increased with operator experience, but the differences were smaller (91.4%, 92.4%, and 93.8%, p<0.001). These associations remained significant in adjusted, continuous variable analyses. Visual inflection points in the learning curves for procedural time, procedural success, and procedural complications were evident after approximately 50 cases, with continued improvements observed up to 200 cases.
Conclusions
For TMVr device proceedures, operator experience was associated with improvements in procedural success, procedure time, and procedural complications. The impact of operator experience was greater when considering the goal of achieving 1+ residual MR.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 19 Sep 2019; epub ahead of print
Chhatriwalla AK, Vemulapalli S, Szerlip M, Kodali S, ... Kosinski AS, Sorajja P
J Am Coll Cardiol: 19 Sep 2019; epub ahead of print | PMID: 31568867
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Abstract

Atrial Fibrillation and Diabetes Mellitus: JACC Review Topic of the Week.

Wang A, Green JB, Halperin JL, Piccini JP

Diabetes mellitus is one of the most common chronic medical conditions, and is a risk factor for the development of atrial fibrillation (AF). The presence of diabetes in patients with AF is associated with increased symptom burden and increased cardiovascular and cerebrovascular mortality. The pathophysiology of diabetes-related AF is not fully understood, but is related to structural, electrical, electromechanical, and autonomic remodeling. This paper reviews the complex interaction between diabetes and AF, and explores its effect on the prevention and treatment of AF.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Aug 2019; 74:1107-1115
Wang A, Green JB, Halperin JL, Piccini JP
J Am Coll Cardiol: 27 Aug 2019; 74:1107-1115 | PMID: 31439220
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Abstract

Large-Artery Stiffness in Health and Disease: JACC State-of-the-Art Review.

Chirinos JA, Segers P, Hughes T, Townsend R

A healthy aorta exerts a powerful cushioning function, which limits arterial pulsatility and protects the microvasculature from potentially harmful fluctuations in pressure and blood flow. Large-artery (aortic) stiffening, which occurs with aging and various pathologic states, impairs this cushioning function, and has important consequences on cardiovascular health, including isolated systolic hypertension, excessive penetration of pulsatile energy into the microvasculature of target organs that operate at low vascular resistance, and abnormal ventricular-arterial interactions that promote left ventricular remodeling, dysfunction, and failure. Large-artery stiffness independently predicts cardiovascular risk and represents a high-priority therapeutic target to ameliorate the global burden of cardiovascular disease. This paper provides an overview of key physiologic and biophysical principles related to arterial stiffness, the impact of aortic stiffening on target organs, noninvasive methods for the measurement of arterial stiffness, mechanisms leading to aortic stiffening, therapeutic approaches to reduce it, and clinical applications of arterial stiffness measurements.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Sep 2019; 74:1237-1263
Chirinos JA, Segers P, Hughes T, Townsend R
J Am Coll Cardiol: 03 Sep 2019; 74:1237-1263 | PMID: 31466622
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Abstract

In-Hospital Coronary Revascularization Rates and Post-Discharge Mortality Risk in Non-ST-Segment Elevation Acute Coronary Syndrome.

Bueno H, Rossello X, Pocock SJ, Van de Werf F, ... Medina J, Huo Y
Background
The relationship between in-hospital coronary revascularization rate (CRR) and post-discharge mortality rates in survivors of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at a system level is unclear.
Objectives
The purpose of this study was to evaluate CRR and 2-year post-discharge mortality rate (2YMR) in NSTE-ACS.
Methods
CRR and 2YMR were analyzed by hospital rate of CRR (in deciles), by country, and by world region in 11,931 patients with NSTE-ACS who survived to discharge and were enrolled in the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) and EPICOR Asia: twin multinational, observational, prospective cohort studies.
Results
Significant differences in patient baseline characteristics, medical therapies, CRR, and 2YMR were found. Mean CRR ranged from 0.0% to 96.8% in the first and tenth decile, respectively (p < 0.001); from 12.3% in Romania to 92.4% in Slovenia (p < 0.001); and from 53.9% in South East Asia (SEAsia) to 90.4% in South Korea-Singapore-Hong Kong. 2YMR varied significantly between hospital deciles of CRR (3.6% in tenth decile vs. 9.2% in first decile; p < 0.001), countries (lowest 1.5% in Slovenia, highest 19.4% in Malaysia; p < 0.001), and regions (lowest 3.8% in South Korea-Singapore-Hong Kong, highest 11.7% in SEAsia; p < 0.001). Poisson regression models, adjusted for 15 mortality predictors, showed a significant inverse association between CRR and 2YMR for hospitals (r = -0.90; p < 0.001), countries (r = -0.65; p < 0.001), and regions (r = -0.87; p = 0.005).
Conclusions
Higher CRRs at the hospital, country, and world region levels are strongly associated with higher post-discharge survival, suggesting CRR as a marker of higher system quality.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Sep 2019; 74:1454-1461
Bueno H, Rossello X, Pocock SJ, Van de Werf F, ... Medina J, Huo Y
J Am Coll Cardiol: 17 Sep 2019; 74:1454-1461 | PMID: 31514947
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Abstract

Health Status after Transcatheter vs. Surgical Aortic Valve Replacement in Low-Risk Patients with Aortic Stenosis.

Baron SJ, Magnuson EA, Lu M, Wang K, ... Cohen DJ,
Background
In patients with severe aortic stenosis (AS) at low surgical risk, treatment with transcatheter aortic valve replacement (TAVR) results in lower rates of death, stroke, and re-hospitalization at 1 year compared with surgical aortic valve replacement; however, the effect of treatment strategy on health status is unknown.
Objectives
This study sought to compare health status outcomes of TAVR vs. surgery in low-risk patients with severe AS.
Methods
Between 3/2016 and 10/2017, 1000 low-risk AS patients were randomized to transfemoral TAVR using a balloon-expandable valve or surgery in the PARTNER 3 Trial. Health status was assessed at baseline, 1, 6 and 12 months using the Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36 and EQ-5D. The primary endpoint was change in KCCQ-Overall Summary (KCCQ-OS) score over time. Longitudinal growth curve modeling was used to compare changes in health status between treatment groups over time.
Results
At 1 month, TAVR was associated with better health status than surgery (mean difference in KCCQ-OS 16.0 points; p<0.001). At 6 and 12 months, health status remained better with TAVR, although the effect was reduced (mean difference in KCCQ-OS 2.6 and 1.8 points respectively; p<0.04 for both). The proportion of patients with an excellent outcome (alive with KCCQ-OS ≥ 75 and no significant decline from baseline) was greater with TAVR than surgery at 6 months (90.3% vs. 85.3%; p=0.03) and 12 months (87.3% vs. 82.8%; p=0.07).
Conclusions
Among low-risk patients with severe AS, TAVR was associated with meaningful early and late health status benefits compared with surgery.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 18 Sep 2019; epub ahead of print
Baron SJ, Magnuson EA, Lu M, Wang K, ... Cohen DJ,
J Am Coll Cardiol: 18 Sep 2019; epub ahead of print | PMID: 31577923
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Abstract

Anticoagulation After Surgical or Transcatheter Bioprosthetic Aortic Valve Replacement.

Chakravarty T, Patel A, Kapadia S, Raschpichler M, ... Leon MB, Makkar RR
Background
There is paucity of evidence on the impact of anticoagulation (AC) after bioprosthetic aortic valve replacement (AVR) on valve hemodynamics and clinical outcomes.
Objectives
The study aimed to assess the impact of AC after bioprosthetic AVR on valve hemodynamics and clinical outcomes.
Methods
Data on antiplatelet and antithrombotic therapy were collected. Echocardiograms were performed at 30 days and 1 year post-AVR. Linear regression model and propensity-score adjusted cox proportional model were used to assess the impact of AC on valve hemodynamics and clinical outcomes, respectively.
Results
A total of 4,832 patients undergoing bioprosthetic AVR (transcatheter aortic valve replacement [TAVR], n = 3,889 and surgical AVR [SAVR], n = 943) in the pooled cohort of PARTNER2 (Placement of Aortic Transcatheter Valves) randomized trials and nonrandomized registries were studied. Following adjustment for valve size, annular diameter, atrial fibrillation, and ejection fraction at the time of assessment of hemodynamics, there was no significant difference in aortic valve mean gradients or aortic valve areas between patients discharged on AC vs. those not discharged on AC, for either TAVR or SAVR cohorts. A significantly greater proportion of patients not discharged on AC had an increase in mean gradient >10 mm Hg from 30 days to 1 year, compared with those discharged on AC (2.3% vs. 1.1%, p = 0.03). There was no independent association between AC after TAVR and adverse outcomes (death, p = 0.15; rehospitalization, p = 0.16), whereas AC after SAVR was associated with significantly fewer strokes (hazard ratio [HR]: 0.17; 95% confidence interval [CI]: 0.05-0.60; p = 0.006).
Conclusions
In the short term, early AC after bioprosthetic AVR did not result in adverse clinical events, did not significantly affect aortic valve hemodynamics (aortic valve gradients or area), and was associated with decreased rates of stroke after SAVR (but not after TAVR). Whether early AC after bioprosthetic AVR has impact on long-term outcomes remains to be determined. (Placement of AoRTic TraNscathetER Valves [PARTNERII A]; NCT01314313).

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 03 Sep 2019; 74:1190-1200
Chakravarty T, Patel A, Kapadia S, Raschpichler M, ... Leon MB, Makkar RR
J Am Coll Cardiol: 03 Sep 2019; 74:1190-1200 | PMID: 31466616
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Abstract

Fluorodeoxyglucose Accumulation in Arterial Tissues Determined by PET Signal Analysis.

Al-Mashhadi RH, Tolbod LP, Bloch LØ, Bjørklund MM, ... Falk E, Bentzon JF
Background
Arterial fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified.
Objectives
The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries.
Methods
Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography.
Results
Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries.
Conclusions
FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Sep 2019; 74:1220-1232
Al-Mashhadi RH, Tolbod LP, Bloch LØ, Bjørklund MM, ... Falk E, Bentzon JF
J Am Coll Cardiol: 03 Sep 2019; 74:1220-1232 | PMID: 31466620
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Abstract

Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature.

Oppi S, Nusser-Stein S, Blyszczuk P, Wang X, ... Lüscher TF, Stein S
Aims
Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown.
Methods and results
We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques.
Conclusions
Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 15 Sep 2019; epub ahead of print
Oppi S, Nusser-Stein S, Blyszczuk P, Wang X, ... Lüscher TF, Stein S
Eur Heart J: 15 Sep 2019; epub ahead of print | PMID: 31529020
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Abstract

Quality of life predicting long-term outcomes in cardiac resynchronization therapy patients.

Nagy KV, Merkely B, Rosero S, Geller L, ... Zareba W, Kutyifa V
Aims
While improvement in quality of life (QoL) has been widely reported in cardiac resynchronization therapy (CRT) patients, its predictive value is not well-understood. We aimed to assess the predictive role of baseline QoL on long-term heart failure (HF) or death events in mild HF patients enrolled in Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
Methods and results
A total of 1791 of 1820 patients had their QoL evaluated at baseline, using the EuroQol-5 dimensions (EQ-5D) and the Kansas City Cardiomyopathy Questionnaires (KCCQ). Kaplan-Meier survival analyses and multivariate Cox models were utilized. Issues within any of the domains of the baseline EQ-5D questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were associated with long-term mortality (median follow-up 5.6 years) (all P < 0.05). Heart failure or death events were predicted by issues in baseline mobility [hazard ratio (HR) = 1.41, P < 0.001], usual activities (HR = 1.41, P < 0.001), and anxiety/depression (HR = 1.21, P = 0.035). The risk of HF events alone was significantly higher in patients with baseline mobility issues (HR = 1.42, P < 0.001) or usual activity (HR = 1.35, P = 0.003). Every 10% increase in the visual analogue scale (0-100) was associated with an 8% lower risk of all-cause mortality (P = 0.006), and a 6% lower risk of HF/death (P = 0.002). Mobility issues also predicted echocardiographic reverse remodelling (-33.08 mL vs. -31.17 mL, P = 0.043). Using the KCCQ, patients in the lower tertile of the clinical summary or physical limitations score had a significantly higher risk of long-term HF or death (P < 0.05).
Conclusion
In mild HF patients enrolled in MADIT-CRT, multiple baseline QoL questionnaire domains were predictors of echocardiographic remodelling, long-term all-cause mortality, and HF events.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Europace: 15 Oct 2019; epub ahead of print
Nagy KV, Merkely B, Rosero S, Geller L, ... Zareba W, Kutyifa V
Europace: 15 Oct 2019; epub ahead of print | PMID: 31617896
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Abstract

Machine learning of clinical variables and coronary artery calcium scoring for the prediction of obstructive coronary artery disease on coronary computed tomography angiography: analysis from the CONFIRM registry.

Al\'Aref SJ, Maliakal G, Singh G, van Rosendael AR, ... Min JK, Shaw LJ
Aims
Symptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA).
Methods and results
The study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P < 0.05 for all comparisons. CACS, age, and gender were the highest ranking features.
Conclusion
A ML model incorporating clinical features in addition to CACS can accurately estimate the pretest likelihood of obstructive CAD on CCTA. In clinical practice, the utilization of such an approach could improve risk stratification and help guide downstream management.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 11 Sep 2019; epub ahead of print
Al'Aref SJ, Maliakal G, Singh G, van Rosendael AR, ... Min JK, Shaw LJ
Eur Heart J: 11 Sep 2019; epub ahead of print | PMID: 31513271
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Impact:
Abstract

Cardiomyocyte HIPK2 Maintains Basal Cardiac Function via ERK Signaling.

Guo Y, Sui JY, Kim K, Zhang Z, ... Force T, Lal H

Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown.We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction-suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology.studies with neonatal rat ventricular cardiomyocytes corroborated thefindings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers,and , at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts.rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling.



Circulation: 03 Oct 2019; epub ahead of print
Guo Y, Sui JY, Kim K, Zhang Z, ... Force T, Lal H
Circulation: 03 Oct 2019; epub ahead of print | PMID: 31581792
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Impact:
Abstract

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography.

Oikonomou EK, Williams MC, Kotanidis CP, Desai MY, ... Newby DE, Antoniades C
Background
Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction.
Methods and results
We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI.
Conclusion
The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 02 Sep 2019; epub ahead of print
Oikonomou EK, Williams MC, Kotanidis CP, Desai MY, ... Newby DE, Antoniades C
Eur Heart J: 02 Sep 2019; epub ahead of print | PMID: 31504423
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Impact:
Abstract

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry.

Sorbets E, Fox KM, Elbez Y, Danchin N, ... Vidal-Petiot E, Steg PG
Aims
Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants.
Methods and results
Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7-8.3] overall [male 8.1% (7.8-8.5); female 7.6% (7.0-8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9-12.9) vs. 8.2% (95% CI 7.8-8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4-7.3)] or without angina [6.4% (95% CI 5.9-7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high.
Conclusion
This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment.
Clinical registry
ISRCTN43070564.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 02 Sep 2019; epub ahead of print
Sorbets E, Fox KM, Elbez Y, Danchin N, ... Vidal-Petiot E, Steg PG
Eur Heart J: 02 Sep 2019; epub ahead of print | PMID: 31504434
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Impact:
Abstract

Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial.

Fitchett D, Inzucchi SE, Wanner C, Mattheus M, ... Zinman B, Johansen OE
Aims
Hypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin.
Methods and results
About 7020 patients with T2D (HbA1c 7-10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia [HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia] was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad [hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25-2.93)] and HYPO-strict [1.72 (1.06-2.78)]. HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) [HR 1.56 (1.06-2.29)]. Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05).
Conclusion
In this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 30 Aug 2019; epub ahead of print
Fitchett D, Inzucchi SE, Wanner C, Mattheus M, ... Zinman B, Johansen OE
Eur Heart J: 30 Aug 2019; epub ahead of print | PMID: 31504427
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Impact:
Abstract

High penetrance and similar disease progression in probands and in family members with arrhythmogenic cardiomyopathy.

Chivulescu M, Lie ØH, Popescu BA, Skulstad H, ... Jurcut RO, Haugaa KH
Aims
We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study.
Methods and results
Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5-9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (-0.6%/year vs. -0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47-182.81, P < 0.01).
Conclusion
More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 31 Aug 2019; epub ahead of print
Chivulescu M, Lie ØH, Popescu BA, Skulstad H, ... Jurcut RO, Haugaa KH
Eur Heart J: 31 Aug 2019; epub ahead of print | PMID: 31504415
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Impact:
Abstract

The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study.

Van\'t Klooster CC, Ridker PM, Hjortnaes J, van der Graaf Y, ... Aerts JGJV, Visseren FLJ
Aims
Low-grade inflammation, measured by elevated plasma concentrations of high-sensitive C-reactive protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that low-grade inflammation is also related to a higher risk of cancer. The present prospective cohort study evaluates the relation between low-grade systemic inflammation and risk of cancer in patients with stable CVD.
Methods and results
In total, 7178 patients with stable CVD and plasma CRP levels ≤10 mg/L were included. Data were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident CVD and cancer. After a median follow-up time of 8.3 years (interquartile range 4.6-12.3) 1072 incident cancer diagnoses were observed. C-reactive protein concentration was related to total cancer [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.10-1.65] comparing last quintile to first quintile of CRP. Especially lung cancer, independent of histopathological subtype, was related to CRP (HR 3.39; 95% CI 2.02-5.69 comparing last to first quintile of CRP). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of anatomical location. Sensitivity analyses after excluding patients with a cancer diagnosis within 1, 2, and 5 years of follow-up showed similar results. No effect modification was observed by smoking status or time since smoking cessation (P-values for interaction > 0.05).
Conclusion
Chronic systemic low-grade inflammation, measured by CRP levels ≤10 mg/L, is a risk factor for incident cancer, markedly lung cancer, in patients with stable CVD. The relation between inflammation and incident cancer is seen in former and current smokers and is uncertain in never smokers.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 31 Aug 2019; epub ahead of print
Van't Klooster CC, Ridker PM, Hjortnaes J, van der Graaf Y, ... Aerts JGJV, Visseren FLJ
Eur Heart J: 31 Aug 2019; epub ahead of print | PMID: 31504409
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Impact:
Abstract

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of its Interaction with Actin.

Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, ... Kaibuchi K, Murohara T

Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear.To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line withandmice and applied a mouse model of transverse aortic constriction (TAC)- and angiotensin II (AngII)-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA.We demonstrated that RHOA activates two members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encodingand(cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and AngII-induced cardiac dysfunction. Further, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK . We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and AngII-induced cardiac dysfunction in wild type mice, while cmc-PKN1/2 DKO mice suppressed TAC- and AngII-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with G-actin by phosphorylating MRTFA, causing increased serum response factor (SRF)-mediated expression of cardiac hypertrophy- and fibrosis-associated genes.Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.



Circulation: 29 Sep 2019; epub ahead of print
Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, ... Kaibuchi K, Murohara T
Circulation: 29 Sep 2019; epub ahead of print | PMID: 31564129
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Impact:
Abstract

Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial.

de Vries TI, Eikelboom JW, Bosch J, Westerink J, ... Fox KAA, Visseren FLJ
Aims
Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease.
Methods and results
Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months).
Conclusion
There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 31 Aug 2019; epub ahead of print
de Vries TI, Eikelboom JW, Bosch J, Westerink J, ... Fox KAA, Visseren FLJ
Eur Heart J: 31 Aug 2019; epub ahead of print | PMID: 31504399
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Impact:
Abstract

miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders.

Du Y, Wang X, Li LY, Hao W, ... Wei YX, Ma XL

Obstructive sleep apnea (OSA), a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown.To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling.Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH prior to MI (CIH+MI) had no significant effect upon post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathologic remodeling and reduced survival rate. Mechanistically, CIH activated TGF-beta/Smad signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI),(a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Rt-PCR/Western analysis confirmed that cardiomyocyteexpression was significantly reduced in MI+CIH mice. RNA-seq, Rt-PCR, and dual-luciferase reporter assays identified that miR-214-3p is a noveltargeting miRNA. Its upregulation is responsible forgene suppression in MI+CIH. Finally, AAV9-mediated cardiac-specificoverexpression or rCTRP9 administration inhibited TGF-beta/Smad and Wnt/β-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals.This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in MI patients with OSA.



Circ Res: 06 Nov 2019; epub ahead of print
Du Y, Wang X, Li LY, Hao W, ... Wei YX, Ma XL
Circ Res: 06 Nov 2019; epub ahead of print | PMID: 31694459
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Impact:
Abstract

Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart.

Otani K, Tokudome T, Kamiya CA, Mao Y, ... Ikeda T, Kangawa K

The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial and brain natriuretic peptides (ANP and BNP, respectively) produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiological and pathophysiological roles of endogenous ANP/BNP in the perinatal period are not fully understood.To clarify the physiological and pathophysiological roles of the endogenous ANP/BNP-NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function.In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. In addition, Npr1-knockout mice showed a high mortality rate over consecutive pregnancy-lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin-nuclear factor of activated T cells pathway were observed. Pharmacological inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti-interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice.These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous ANP/BNP-NPR1 system plays an important role in protecting the maternal heart from interleukin-6-induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.



Circulation: 30 Oct 2019; epub ahead of print
Otani K, Tokudome T, Kamiya CA, Mao Y, ... Ikeda T, Kangawa K
Circulation: 30 Oct 2019; epub ahead of print | PMID: 31665900
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Abstract

Interventional Therapies for Acute Pulmonary Embolism: Current Status and Principles for the Development of Novel Evidence: A Scientific Statement From the American Heart Association.

Giri J, Sista AK, Weinberg I, Kearon C, ... Barnes GD,

Pulmonary embolism (PE) represents the third leading cause of cardiovascular mortality. The technological landscape for management of acute intermediate- and high-risk PE is rapidly evolving. Two interventional devices using pharmacomechanical means to recanalize the pulmonary arteries have recently been cleared by the US Food and Drug Administration for marketing, and several others are in various stages of development. The purpose of this document is to clarify the current state of endovascular interventional therapy for acute PE and to provide considerations for evidence development for new devices that will define which patients with PE would derive the greatest net benefit from their use in various clinical settings. First, definitions and limitations of commonly used risk stratification tools for PE are reviewed. An adjudication of risks and benefits of available interventional therapies for PE follows. Next, considerations for optimal future evidence development in this field are presented in the context of the current US regulatory framework. Finally, the document concludes with a discussion of the pros and cons of the rapidly expanding PE response team model of care delivery.



Circulation: 03 Oct 2019:CIR0000000000000707; epub ahead of print
Giri J, Sista AK, Weinberg I, Kearon C, ... Barnes GD,
Circulation: 03 Oct 2019:CIR0000000000000707; epub ahead of print | PMID: 31585051
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Impact:
Abstract

Mortality Assessment of Paclitaxel-Coated Balloons: Patient-Level Meta-Analysis of the ILLUMENATE Clinical Program at 3 Years.

Gray WA, Jaff MR, Parikh SA, Ansel GM, ... Adelman MA, Lyden SP
Background
A recent summary-level meta-analysis comprising randomized, controlled trials (RCTs) of femoropopliteal paclitaxel-coated balloon and stent intervention identified excess late mortality in the paclitaxel-treated patients.
Methods
We evaluated the safety of the Stellarex drug-coated balloon (DCB) for femoropopliteal artery disease with an independently performed meta-analysis of patient-level data from all patients in the Stellarex femoropopliteal clinical program. To compare mortality after DCB or uncoated percutaneous transluminal angioplasty (PTA), we aggregated data from 2 RCTs comprising 419 patients treated with DCB and 170 patients treated with PTA. In an additional analysis, data were aggregated from 6 poolable Stellarex DCB studies (2 RCTs, 3 single-arm studies, and 1 registry). All serious adverse events including deaths were adjudicated by a blinded, third-party, independent Clinical Events Committee. Kaplan-Meier estimates in the RCTs were compared with restricted mean survival time. Predictors of death were assessed with hazard ratios (HRs) and Cox proportional hazards modeling.
Results
Baseline characteristics were similar in the patients treated with DCB and PTA in the pooled RCT analysis, with the exception that the DCB cohort was younger (67.4±9.7 versus 69.4±9.4 years, =0.02), smoked more frequently (86.6% versus 78.8%, =0.02), and were less often treated for recurrent lesions (8.8% versus 14.7%, =0.04). In the RCTs, patients treated with DCB had all-cause mortality rates that were not different from those of patients treated with PTA (Kaplan-Meier estimates 1.8±0.7% versus 1.3±0.9%, 6.5±1.2% versus 5.9±1.9%, and 9.3±1.5% versus 9.9±2.4% at 1, 2, and 3 years, respectively, =0.86). All-cause mortality rates were similar in a 1906-patient pooled nonrandomized DCB data set (Kaplan-Meier estimates of 2.1%, 4.9%, and 7.0% at 1, 2, and 3 years, respectively). Clinical Events Committee-adjudicated causes of death were balanced between the DCB and PTA cohorts. Multivariable Cox modeling identified age (HR, 1.06; 95% CI, 1.04-1.08; <0.001), diabetes mellitus (HR, 1.42; 95% CI, 1.01-2.00; =0.04), congestive heart failure (HR, 1.88; 95% CI, 1.12-3.16; =0.02), and renal insufficiency (HR, 2.00; 95% CI, 1.33-3.01; <0.001) as predictors of mortality. Paclitaxel exposure was unrelated to mortality (HR, 1.04; 95% CI, 0.98-1.10; =0.23).
Conclusions
The mortality rates for patients treated with the DCB and uncoated PTA were indistinguishable over 3-year follow-up. Additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the generalizability of these findings.
Clinical trial registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110524, NCT01858363, NCT01858428, NCT03421561, NCT01912937, NCT01927068, and NCT02769273.



Circulation: 29 Sep 2019; 140:1145-1155
Gray WA, Jaff MR, Parikh SA, Ansel GM, ... Adelman MA, Lyden SP
Circulation: 29 Sep 2019; 140:1145-1155 | PMID: 31567024
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Impact:
Abstract

Supplementation with the Sialic Acid Precursor N-acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension.

Peng J, Vongpatanasin W, Sacharidou A, Kifer D, ... Mineo C, Shaul PW

Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory IgG receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension.Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells, and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high fat diet (HFD) and BP was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by SNAlectin blotting. Effects of IgG on endothelial NO synthase (eNOS) were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human subjects by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc).Mice deficient in B cells were protected from obesity-induced hypertension. Compared to IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase (NA)-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and NAtreated IgG inhibited VEGF activation of eNOS by altering eNOS phosphorylation. In humans obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension.Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesityinduced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.



Circulation: 09 Oct 2019; epub ahead of print
Peng J, Vongpatanasin W, Sacharidou A, Kifer D, ... Mineo C, Shaul PW
Circulation: 09 Oct 2019; epub ahead of print | PMID: 31597453
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Impact:
Abstract

Human Immunodeficiency Virus Infection and Risk of Heart Failure Rehospitalizations.

Brouch D, Tashtish N, Di Felice C, Longenecker CT, Al-Kindi SG

Human Immunodeficiency Infection (HIV) is associated with increased risk for heart failure (HF). Outcomes of HF in patients living with HIV (PWH) are poorly understood. We sought to identify the risk of HF rehospitalizations (30 and 90 days) among PWH versus uninfected controls admitted with HF. Using the 2016 Nationwide Readmissions Database, we identified all patients (≥18 years) who were discharged alive with a primary diagnosis of HF (ICD10 I50.xx) with or without secondary diagnosis of HIV (ICD 10 Z21, B20, O98.7, or B97.35). Propensity score matching was used to match PWH with controls (1:1) based on 45 patient characteristics (demographics, hospitalization characteristics, and co-morbidities). Cox regression models were used to compare rates of HF rehospitalization (primary ICD10 I50.xx) within 30 and 90 days after discharge from the index HF hospitalization. A total of 312,264 patients with HF were identified, of whom 1,112 (0.4%) had HIV. After propensity score matching, 1,112 PWH were matched with 1,112 uninfected controls. The standard mean difference for each variable was <10% postmatching. Overall, HF rehospitalization rates were 11.2% and 19.2% at 30 and 90 days, respectively. The 2 groups (PWH and controls) were not different statistically with respect to all 45 covariates. Compared with controls, PWH had a higher risk of HF rehospitalization within 30 days (hazard ratio 1.45, 95% confidence interval 1.13 to 1.87, p = 0.004) and 90 days (hazard ratio 1.41, 95% CI 1.16 to 1.71, p <0.001). This risk was consistent across age groups, gender, types of HF, presence or absence of coronary artery disease, or chronic kidney disease. In conclusion, in this propensity-matched national cohort of patients admitted with HF, patients with HIV had increased risk of HF rehospitalizations compared with uninfected controls at 30 days and 90 days.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Oct 2019; 124:1232-1238
Brouch D, Tashtish N, Di Felice C, Longenecker CT, Al-Kindi SG
Am J Cardiol: 14 Oct 2019; 124:1232-1238 | PMID: 31537297
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Impact:
Abstract

Identification of Emetine as a Therapeutic Agent for Pulmonary Arterial Hypertension: Novel Effects of an Old Drug.

Siddique MAH, Satoh K, Kurosawa R, Kikuchi N, ... Tokuyama H, Shimokawa H
Objective
Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions.
Conclusions
Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.



Arterioscler Thromb Vasc Biol: 30 Oct 2019; 39:2367-2385
Siddique MAH, Satoh K, Kurosawa R, Kikuchi N, ... Tokuyama H, Shimokawa H
Arterioscler Thromb Vasc Biol: 30 Oct 2019; 39:2367-2385 | PMID: 31533472
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Abstract

Transcatheter aortic valve replacement versus surgical aortic valve replacement in low-surgical-risk patients: An updated meta-analysis.

Goel S, Pasam RT, Wats K, Patel J, ... Shani J, Gidwani U
Objective
The purpose of this meta-analysis is to compare the safety and efficacy of transcatheter aortic-valve replacement (TAVR) to surgical aortic valve replacement (SAVR) in low-surgical-risk patients.
Background
TAVR is proven to be safe and effective in patients with high- and intermediate-risk aortic stenosis. However, there is limited data on the safety and efficacy of TAVR in patients with low surgical risk.
Methods
We conducted an electronic database search of all published data for studies that compared TAVR to SAVR in low-surgical-risk patients (mean society for thoracic surgery [STS] score <4% and/or logistic EuroScore <10%) and reported on subsequent all-cause mortality, cardiac mortality, stroke rates, and other outcomes of interest. Event rates were compared with a forest plot of odds ratio using a random-effects model assuming interstudy heterogeneity.
Results
A total of seven studies (n = 6,293 patients; TAVR = 2,912; and SAVR = 3,381) were included in the final analysis. There was no significant difference between TAVR and SAVR in terms of all-cause mortality (OR 0.82; 95% CI 0.50-1.36, I = 51%), cardiac mortality (OR 0.57; 95% CI 0.32-1.02, I = 0%), new pacemaker implantation (OR = 3.11; 95% CI 0.58-16.60, I = 89%), moderate/severe paravalvular leak (PVL; OR 3.50; 95% CI 0.64-19.10, I = 54%) and rate of stroke (OR 0.63; 95% CI 0.34-1.15, I = 39%) at 1-year follow-up. TAVR was found to have a significantly lower incidence of atrial fibrillation (AF; OR 0.15, 95% CI 0.10-0.24, I = 38%) as compared to SAVR.
Conclusion
The results of our meta-analysis demonstrate similar rates of all-cause mortality, cardiac mortality, and stroke at 1-year follow-up in patients undergoing TAVR and SAVR. TAVR is associated with a lower incidence of AF relative to SAVR. However, there was a significantly higher incidence of PVL with TAVR compared to SAVR.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print
Goel S, Pasam RT, Wats K, Patel J, ... Shani J, Gidwani U
Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print | PMID: 31631514
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Abstract

Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study.

Bauer A, Klemm M, Rizas KD, Hamm W, ... Zabel M,
Background
A small proportion of patients undergoing primary prophylactic implantation of implantable cardioverter defibrillators (ICDs) experiences malignant arrhythmias. We postulated that periodic repolarisation dynamics, a novel marker of sympathetic-activity-associated repolarisation instability, could be used to identify electrically vulnerable patients who would benefit from prophylactic implantation of ICDs by way of a reduction in mortality.
Methods
We did a prespecified substudy of EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD), a prospective, investigator-initiated, non-randomised, controlled cohort study done at 44 centres in 15 EU countries. Patients aged 18 years or older with ischaemic or non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (≤35%) were eligible for inclusion if they met guideline-based criteria for primary prophylactic implantation of ICDs. Periodic repolarisation dynamics from 24-h Holter recordings were assessed blindly in patients the day before ICD implantation or on the day of study enrolment in patients who were conservatively managed. The primary endpoint was all-cause mortality. Propensity scoring and multivariable models were used to assess the interaction between periodic repolarisation dynamics and the treatment effect of ICDs on mortality.
Findings
Between May 12, 2014, and Sept 7, 2018, 1371 patients were enrolled in our study. 968 of these patients underwent ICD implantation, and 403 were treated conservatively. During follow-up (median 2·7 years [IQR 2·0-3·3] in the ICD group and 1·2 years [0·8-2·7] in the control group), 138 (14%) patients died in the ICD group and 64 (16%) patients died in the control group. We noted a 43% reduction in mortality in the ICD group compared with the control group (adjusted hazard ratio [HR] 0·57 [95% CI 0·41-0·79]; p=0·0008). Periodic repolarisation dynamics significantly predicted the treatment effect of ICDs on mortality (adjusted p=0·0307). The mortality benefits associated with ICD implantation were greater in patients with periodic repolarisation dynamics of 7·5 deg or higher (n=199; adjusted HR 0·25 [95% CI 0·13-0·47] for the ICD group vs the control group; p<0·0001) than in those with periodic repolarisation dynamics less than 7·5 deg (n=1166; adjusted HR 0·69 [95% CI 0·47-1·00]; p=0·0492; p=0·0056). The number needed to treat was 18·3 (95% CI 10·6-4895·3) in patients with periodic repolarisation dynamics less than 7·5 deg and 3·1 (2·6-4·8) in those with periodic repolarisation dynamics of 7·5 deg or higher.
Interpretation
Periodic repolarisation dynamics predict mortality reductions associated with prophylactic implantation of ICDs in contemporarily treated patients with ischaemic or non-ischaemic cardiomyopathy. Periodic repolarisation dynamics could help to guide treatment decisions about prophylactic ICD implantation.
Funding
The European Community\'s 7th Framework Programme.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 11 Oct 2019; 394:1344-1351
Bauer A, Klemm M, Rizas KD, Hamm W, ... Zabel M,
Lancet: 11 Oct 2019; 394:1344-1351 | PMID: 31488371
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Abstract

Cardiovascular risk of electronic cigarettes: a review of preclinical and clinical studies.

Buchanan ND, Grimmer JA, Tanwar V, Schwieterman N, Mohler PJ, Wold LE

Cigarette smoking is the most preventable risk factor related to cardiovascular morbidity and mortality. Tobacco usage has declined in recent years; however, the use of alternative nicotine delivery methods, particularly e-cigarettes, has increased exponentially despite limited data on their short- and long-term safety and efficacy. Due to their unique properties, the impact of e-cigarettes on cardiovascular physiology is not fully known. Here, we summarize both preclinical and clinical data extracted from short- and long-term studies on the cardiovascular effects of e-cigarette use. Current findings support that e-cigarettes are not a harm-free alternative to tobacco smoke. However, the data are primarily derived from acute studies. The impact of chronic e-cigarette exposure is essentially unstudied. To explore the uniqueness of e-cigarettes, we contemplate the cardiovascular effects of individual e-cigarette constituents. Overall, data suggest that exposure to e-cigarettes could be a potential cardiovascular health concern. Further preclinical research and randomized trials are needed to expand basic and clinical investigations before considering e-cigarettes safe alternatives to conventional cigarettes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 06 Nov 2019; epub ahead of print
Buchanan ND, Grimmer JA, Tanwar V, Schwieterman N, Mohler PJ, Wold LE
Cardiovasc Res: 06 Nov 2019; epub ahead of print | PMID: 31696222
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Abstract

Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation.

Barrett TJ, Distel E, Murphy AJ, Hu J, ... Goldberg IJ, Fisher EA
Background
Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering.
Methods
Aortic arches containing plaques developed inmice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined.
Results
Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus.
Conclusions
Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.



Circulation: 29 Sep 2019; 140:1170-1184
Barrett TJ, Distel E, Murphy AJ, Hu J, ... Goldberg IJ, Fisher EA
Circulation: 29 Sep 2019; 140:1170-1184 | PMID: 31567014
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Abstract

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

Padrón-Barthe L, Villalba-Orero M, Gómez-Salinero JM, Domínguez F, ... Garcia-Pavia P, Lara-Pezzi E
Background
Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.
Methods
We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.
Results
We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.
Conclusions
Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.



Circulation: 29 Sep 2019; 140:1188-1204
Padrón-Barthe L, Villalba-Orero M, Gómez-Salinero JM, Domínguez F, ... Garcia-Pavia P, Lara-Pezzi E
Circulation: 29 Sep 2019; 140:1188-1204 | PMID: 31567019
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Abstract

Different Lifestyle Interventions in Adults from Underserved Communities: The FAMILIA Trial.

Fernandez-Jimenez R, Jaslow R, Bansilal S, Diaz-Munoz R, ... Fayad ZA, Fuster V
Background
The current trends of unhealthy lifestyle behaviors in underserved communities are disturbing. Thus, effective health promotion strategies constitute an unmet need.
Objective
To assess the impact of two different lifestyle interventions on parents/caregivers of children attending preschools in a socioeconomically disadvantaged community.
Methods
The FAMILIA study is a cluster-randomized trial involving 15 Head Start preschools in Harlem, New York. Schools, and their children\'s parents/caregivers, were randomized to receive either an \"individual-focused\" or \"peer-to-peer based\" lifestyle intervention program for 12 months or control. The primary outcome was the change from baseline to 12 months in a composite health score related to Blood pressure, Exercise, Weight, Alimentation and Tobacco (Fuster-BEWAT Score, FBS), ranging from 0 to 15 (ideal health=15). To assess the sustainability of the intervention, we evaluated the change of FBS at 24 months. Main pre-specified secondary outcomes included changes in FBS subcomponents and the impact of the knowledge of presence of atherosclerosis as assessed by bilateral carotid/femoral vascular ultrasound. Mixed-effects models were used to test for intervention effects.
Results
We enrolled 635 parents/caregivers with a mean age of 38±11 years, 83% female, 57% Hispanic/Latino and 31% African American, and a baseline FBS of 9.3±2.4 points. The mean within-group change in FBS from baseline to 12 months was ∼0.20 points in all groups, with no overall between-group differences. However, high-adherence participants to the intervention exhibited a greater change in FBS than their low-adherence counterparts: 0.30 points (95% CI: 0.03 to 0.57; p-value = 0.025) vs. 0.00 points (95% CI: -0.43 to 0.43; p-value = 1.0), respectively. Furthermore, the knowledge by the participant of the presence of atherosclerosis significantly boosted the intervention effects. Similar results were sustained at 24 months.
Conclusions
Although we did not observe overall significant differences between intervention and control groups, the FAMILIA trial highlights that high adherence rates to lifestyle interventions may improve health outcomes. It also suggests a potential contributory role of the presentation of atherosclerosis pictures, providing helpful information to improve future lifestyle interventions in adults.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 05 Nov 2019; epub ahead of print
Fernandez-Jimenez R, Jaslow R, Bansilal S, Diaz-Munoz R, ... Fayad ZA, Fuster V
J Am Coll Cardiol: 05 Nov 2019; epub ahead of print | PMID: 31726193
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Abstract

Cost-Effectiveness of Transcatheter Mitral Valve Repair versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation: Results from the COAPT Trial.

Baron SJ, Wang K, Arnold SV, Magnuson EA, ... Cohen DJ,

The COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair (TMVr) using the MitraClip resulted in reduced mortality and heart-failure hospitalizations and improved quality of life when compared with maximally-tolerated guideline-directed medical therapy (GDMT) in heart-failure patients with 3-4+ secondary mitral regurgitation (SMR). Whether TMVr is cost-effective compared with GDMT in this population is unknown.We used data from the COAPT trial to perform a formal, patient-level economic analysis of TMVr + GDMT vs. GDMT alone for patients with heart failure and 3-4+ SMR from the perspective of the US health care system. Costs for the index TMVr hospitalization were assessed using a combination of resource-based accounting and hospital billing data (when available). Follow-up medical care costs were estimated based on medical resource use collected during the COAPT trial. Health utilities were estimated for all patients at baseline, 1, 6, 12 and 24 months using the SF-6D.Initial costs for the TMVr procedure and index hospitalization were $35,755 and $48,198, respectively. Although follow-up costs were significantly lower with TMVr compared with GDMT ($26,654 vs. $38,345; p=0.018), cumulative 2-year costs remained higher with TMVr due to the up-front cost of the index procedure ($73,416 vs. $38,345; p<0.001). When intrial survival, health utilities, and costs were modeled over a lifetime horizon, TMVr was projected to increase life-expectancy by 1.13 years and quality-adjusted life-years (QALYs) by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost-effectiveness ratio of $40,361/life-year gained and $55,600/QALY gained.For symptomatic heart-failure patients with 3-4+ SMR, TMVr increases lifeexpectancy and quality-adjusted life-expectancy compared with GDMT at an incremental cost per QALY gained that represents acceptable economic value based on current U.S. thresholds.URL: https://clinicaltrials.gov Unique Identifier: NCT01626079.



Circulation: 28 Sep 2019; epub ahead of print
Baron SJ, Wang K, Arnold SV, Magnuson EA, ... Cohen DJ,
Circulation: 28 Sep 2019; epub ahead of print | PMID: 31564137
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Older ...

This program is still in alpha version.