Topic: Imaging

Abstract

Impact of heart rate on coronary computed tomographic angiography interpretability with a third-generation dual-source scanner.

Miller RJH, Eisenberg E, Friedman J, Cheng V, ... Thomson L, Berman DS
Background
Guidelines suggest coronary computed tomography angiography (CCTA) should be performed with a heart rate (HR) below 60. Third-generation dual-source CT (DSCT) scanners, with improved temporal resolution, and end-systolic acquisition may facilitate imaging at higher HRs. We determined the influence of HR and end-systolic acquisition on image interpretability and quality with a third-generation DSCT.
Methods
Patients who underwent CCTA between July 2017 and December 2018 were retrospectively identified. All images were acquired using a SOMATOM Force scanner (Siemens Healthcare). The primary outcome was the presence of any uninterpretable coronary segment. The association between HR and CCTA with uninterpretable segments was assessed with multivariable logistic regression, correcting for demographics and imaging variables.
Results
In total, 2620 patients were included, mean age 61.4 ± 12.9 years and 61.2% male, with uninterpretable segments present in 229 (8.7%) scans. In multivariable analysis, HR 80-89 was associated with an increased likelihood of having a scan with uninterpretable segments (adjusted odds ratio [OR] 4.53, p < 0.001). However, no significant association was present with end-systolic acquisition (HR 80-89, adjusted OR 2.32, p = 0.125). HR ≥ 90 was associated with a decreased likelihood of good or excellent image quality (adjusted OR 0.26, 95% CI 0.11-0.63, p = 0.003).
Conclusions
With third-generation dual-source CT scanners, patients with HR 60-80 can be imaged without impacting image interpretability. End-systolic image acquisition facilitates imaging at HRs > 80 without increasing non-diagnostic scans. Routine use of systolic gating could omit the need for strict HR control and pre-test beta blockade currently required for CCTA.

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

Int J Cardiol: 14 Nov 2019; 295:42-47
Miller RJH, Eisenberg E, Friedman J, Cheng V, ... Thomson L, Berman DS
Int J Cardiol: 14 Nov 2019; 295:42-47 | PMID: 31427117
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Abstract

Prognostic value of cardiac metaiodobenzylguanidine imaging and QRS duration in implantable cardioverter defibrillator patients with and without heart failure.

Kawasaki M, Yamada T, Morita T, Furukawa Y, ... Sakata Y, Fukunami M
Background
Cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with heart failure (HF). Recent studies showed that the highest rate of ventricular tachyarrhythmias (VTs) is seen in HF patients with an intermediate decrease in MIBG uptake, rather than in those with the lowest values. However, prolonged QRS duration (QRSd) has been shown to be associated with VTs in HF patients. This study assessed the prognostic value of the combination of an intermediate decrease in MIBG uptake and prolonged QRSd for predicting VTs in patients with implantable cardioverter defibrillators (ICDs) in relation to the presence of heart failure (HF).
Methods and results
A total of 196 outpatients with ICDs (age: 64 ± 14 years, male: 81%, left ventricular ejection fraction [LVEF]: 49% ± 16%) were prospectively enrolled; 135 had HF (NYHA class: 2.0 ± 0.6). At entry, cardiac MIBG imaging was performed, and QRSd was measured on standard 12‑lead electrocardiography. An intermediate decrease in the heart-to-mediastinum ratio on the delayed planar image (ID-H/M) was defined as 1.40-1.89. During the 3.3 ± 2.2-year follow-up, 59 patients had appropriate ICD discharges (ATx) for VTs. On multivariate Cox analysis, ID-H/M and prolonged QRSd (≥147 ms) were significantly and independently associated with ATx. In both patients with and without HF, ATx were significantly more frequent in patients with ID-H/M and/or prolonged QRSd than in those with neither (with HF: 40% vs. 14%, p = 0.020; without HF: 43% vs. 10%, p = 0.0028).
Conclusions
The combination of ID-H/M and prolonged QRSd provided more prognostic information for predicting VTs in ICD patients, with and without HF.

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

Int J Cardiol: 30 Nov 2019; 296:164-171
Kawasaki M, Yamada T, Morita T, Furukawa Y, ... Sakata Y, Fukunami M
Int J Cardiol: 30 Nov 2019; 296:164-171 | PMID: 31371118
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Abstract

False-positive stress echocardiograms: Predictors and prognostic relevance.

Rachwan RJ, Mshelbwala FS, Dardari Z, Batal O
Background
Recent studies indicate that the pretest likelihood of significant coronary artery disease (CAD) (≥50% luminal stenosis) is over-estimated and that the frequency and severity of positive stress tests have been decreasing. This suggests an increased prevalence of false-positive (FP) stress tests. The aims of this retrospective study were to investigate the predictors of FP stress echocardiography (SE) and to compare the outcomes of patients with FP results to those with true-positive (TP) results.
Methods
Patients who underwent SE between 2013 and 2017 in a tertiary-care center were reviewed. Included were patients aged ≥40years who had cardiac catheterization (CC) within 1year of the index stress test. SE was considered FP if a new or worsening wall motion abnormality was present in the absence of significant corresponding CAD.
Results
Of the 5100 patients with SE, 1069 satisfied inclusion criteria. A total of 305 patients had positive SE results; of which 162 (53%) were FP. Logistic regression revealed that female gender (p=0.009), the absence of diabetes (p=0.03), the absence of a personal history of CAD (p=0.004), and lower stress WMSI (p=0.03) were independently associated with FP results. Patients with FP results on SE had similar all-cause mortality to those with TP results.
Conclusions
Accounting for predictors of FP findings on SE could improve the interpretation of SE results and limit the use of unnecessary CC. Furthermore, patients with FP results on SE could benefit from aggressive risk factor control and careful clinical follow-up.

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

Int J Cardiol: 30 Nov 2019; 296:157-163
Rachwan RJ, Mshelbwala FS, Dardari Z, Batal O
Int J Cardiol: 30 Nov 2019; 296:157-163 | PMID: 31477317
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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

Usefulness of dual imaging stress echocardiography for the diagnosis of coronary allograft vasculopathy in heart transplant recipients.

Pichel IÁ, Fernández Cimadevilla OC, de la Hera Galarza JM, Pasanisi E, ... Sicari R, Fernández MM
Background
Coronary allograft vasculopathy (CAV) is the main factor limiting long-term survival after cardiac transplantation. Dual imaging stress echocardiography with wall motion and Doppler-derived coronary flow reserve (CRF) of the left anterior descending artery (LAD) is a state-of-the-art methodology during dipyridamole stress echocardiography (DiSE). This study involving 74 heart transplanted patients has the purpose to assess the diagnostic value of dipyridamole stress echocardiography with evaluation of wall motion (WM) and Doppler-derived coronary flow reserve for the diagnosis of coronary allograft vasculopathy.
Methods and results
All patients underwent DiSE and coronary angiography. Moderate-severe CAV was defined according to International Society of Heart and Lung Transplant (ISHLT) recommended nomenclature for CAV, and CFR < 2 was considered to be impaired. Moderate-severe CAV was present in 11 patients. WM analysis revealed four patients (5%) with rest WM abnormalities. CFR analysis revealed that 40 (54%) individuals had an abnormal result. The combined evaluation of WM analysis and CFR resulted in a sensitivity of 72.7% (95% CI: 39.3 to 92.6%), a specificity of 49.2% (95% CI: 36.5 to 61.9%), a positive predictive value of 20% (95% CI: 9.6 to 36.1%), and negative predictive value of 91.1% (95% CI: 75.1 to 97.6%) for the diagnosis of CAV.
Conclusions
Our results support the inclusion of DiSE performance in Heart transplant follow up protocol. The addition of CFR evaluation offers valuable information to the angiography findings in the detection of CAV and could be helpful in selected patients to adjust the time and indications of coronary angiography.

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

Int J Cardiol: 30 Nov 2019; 296:109-112
Pichel IÁ, Fernández Cimadevilla OC, de la Hera Galarza JM, Pasanisi E, ... Sicari R, Fernández MM
Int J Cardiol: 30 Nov 2019; 296:109-112 | PMID: 31324395
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Abstract

The prognostic value of biventricular long axis strain using standard cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

Yang F, Wang J, Li Y, Li W, ... Han Y, Chen Y
Background
Long axis strain (LAS) is a parameter derived from standard cardiovascular magnetic resonance imaging. However, the prognostic value of biventricular LAS in hypertrophic cardiomyopathy (HCM) is unknown.
Methods
Patients with HCM (n = 384) and healthy volunteers (n = 150) were included in the study. Left ventricular (LV)-LAS was defined as the percentage change in the length measured from the epicardial border of the LV apex to the midpoint of a line connecting the mitral annulus at end-systole and end-diastole. Right ventricular (RV)-LAS represented the percentage change of length between epicardial border of the LV apex to the midpoint of a line connecting the tricuspid annulus at end-systole and end-diastole. The primary endpoint was a combination of all-cause death and sudden cardiac death aborted by appropriate implantable cardioverter-defibrillator discharge and cardiopulmonary resuscitation after syncope. The secondary endpoint was a combination of the primary endpoint and hospitalization for congestive heart failure.
Results
Twenty-nine patients (7.6%) achieved the primary endpoint, and the secondary endpoint occurred in 66 (17.2%) patients. In multivariate Cox regression analysis, RV-LAS was an independent prognostic factor for the primary (hazard ratio (HR), 1.13) and secondary (HR, 1.11) endpoints. In the subgroup of patients with a normal RV ejection fraction (EF) (>45.0%, n = 345), impaired RV-LAS was associated with adverse outcomes and might add incremental prognostic value to RVEF and tricuspid annular plane systolic excursion (TAPSE) (p < 0.01).
Conclusions
RV-LAS is an independent predictor of adverse prognosis in HCM in addition to RVEF and TAPSE.

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

Int J Cardiol: 31 Oct 2019; 294:43-49
Yang F, Wang J, Li Y, Li W, ... Han Y, Chen Y
Int J Cardiol: 31 Oct 2019; 294:43-49 | PMID: 31405582
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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

Functional, Anatomical, and Prognostic Correlates of Coronary Flow Velocity Reserve During Stress Echocardiography.

Ciampi Q, Zagatina A, Cortigiani L, Gaibazzi N, ... Picano E,
Background
The assessment of coronary flow velocity reserve (CFVR) in left anterior descending coronary artery (LAD) expands the risk stratification potential of stress echocardiography (SE) based on stress-induced regional wall motion abnormalities (RWMA).
Objectives
The purpose of this study was to assess the feasibility and functional correlates of CFVR.
Methods
This prospective, observational, multicenter study initially screened 3,410 patients (2,061 [60%] male; age 63 ± 11 years; ejection fraction 61 ± 9%) with known or suspected coronary artery disease and/or heart failure. All patients underwent SE (exercise, n = 1,288; vasodilator, n = 1,860; dobutamine, n = 262) based on new or worsening RWMA in 20 accredited laboratories of 8 countries. CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed-Doppler assessment of LAD flow. A subset of 1,867 patients was followed up.
Results
The success rate for CFVR on LAD was 3,002 of 3,410 (feasibility = 88%). Reduced (≤2.0) CFVR was found in 896 of 3,002 (30%) patients. At multivariable logistic regression analysis, inducible RWMA (odds ratio [OR]: 6.5; 95% confidence interval [CI]: 4.9 to 8.5; p < 0.01), abnormal left ventricular contractile reserve (OR: 3.4; 95% CI: 2.7 to 4.2; p < 0.01), and B-lines (OR: 1.5; 95% CI: 1.1 to 1.9; p = 0.01) were associated with reduced CFVR. During a median follow-up time of 16 months, 218 events occurred. RWMA (hazard ratio: 3.8; 95% CI: 2.3 to 6.3; p < 0.001) and reduced CFVR (hazard ratio: 1.5; 95% CI: 1.1 to 2.2; p = 0.009) were independently associated with adverse outcome.
Conclusions
CFVR is feasible with all SE protocols. Reduced CFVR is often accompanied by RWMA, abnormal LVCR, and pulmonary congestion during stress, and shows independent value over RWMA in predicting an adverse outcome.

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

J Am Coll Cardiol: 04 Nov 2019; 74:2278-2291
Ciampi Q, Zagatina A, Cortigiani L, Gaibazzi N, ... Picano E,
J Am Coll Cardiol: 04 Nov 2019; 74:2278-2291 | PMID: 31672185
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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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Abstract

Superiority of Out-of-Office Blood Pressure for Predicting Hypertensive Heart Disease in Non-Hispanic Black Adults.

Rader F, Franklin SS, Mirocha J, Vongpatanasin W, Haley RW, Victor RG

Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34-1.64 for out-of-office systolic BP and 1.15 [1.04-1.28] for clinic systolic BP; 1.71 [1.43-2.05] for out-of-office diastolic BP, and 1.03 [0.86-1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical trial registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00344903.



Hypertension: 30 Oct 2019; 74:1192-1199
Rader F, Franklin SS, Mirocha J, Vongpatanasin W, Haley RW, Victor RG
Hypertension: 30 Oct 2019; 74:1192-1199 | PMID: 31522619
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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

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

Hands On: How to approach patients undergoing lead extraction.

Lewis RK, Pokorney SD, Hegland DD, Piccini JP

Due to the growing number of patients treated with cardiac implantable electronic devices (CIEDs) there is an increased need for lead management, evaluation, and extraction. While CIED lead extraction has many indications, a consistent approach to pre-procedural planning should be applied in all cases, including a thorough consultation with careful review of the patient\'s medical and device history, as well as a discussion of informed consent and shared decision-making with the patient and their loved ones. The use of chest X-ray, echocardiography, and CT scan can further help with risk statification and procedural planning. Intra-procedural echocardiography (transesophageal or intracardiac) is recommended and allows early recognition of cardiothoracic injury. Establishing an extraction team with cardiology/electrophysiology, anesthesiology, and CT surgery is is crucial to a successful and safe CIED extraction practice, including immediately available surgical backup. This hands-on review will address how to approach patients who are undergoing lead extraction, as well as several innovations in pre-procedure and intra-procedural risk assessment. 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
Lewis RK, Pokorney SD, Hegland DD, Piccini JP
J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print | PMID: 31626390
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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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Abstract

The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction.

Reddy YNV, Obokata M, Wiley B, Koepp KE, ... Carter RE, Borlaug BA
Aims
Increases in extravascular lung water (EVLW) during exercise contribute to symptoms, morbidity, and mortality in patients with heart failure and preserved ejection fraction (HFpEF), but the mechanisms leading to pulmonary congestion during exercise are not well-understood.
Methods and results
Compensated, ambulatory patients with HFpEF (n = 61) underwent invasive haemodynamic exercise testing using high-fidelity micromanometers with simultaneous lung ultrasound, echocardiography, and expired gas analysis at rest and during submaximal exercise. The presence or absence of EVLW was determined by lung ultrasound to evaluate for sonographic B-line artefacts. An increase in EVLW during exercise was observed in 33 patients (HFpEFLW+, 54%), while 28 (46%) did not develop EVLW (HFpEFLW-). Resting left ventricular function was similar in the groups, but right ventricular (RV) dysfunction was two-fold more common in HFpEFLW+ (64 vs. 31%), with lower RV systolic velocity and RV fractional area change. As compared to HFpEFLW-, the HFpEFLW+ group displayed higher pulmonary capillary wedge pressure (PCWP), higher pulmonary artery (PA) pressures, worse RV-PA coupling, and higher right atrial (RA) pressures during exercise, with increased haemoconcentration indicating greater loss of water from the vascular space. The development of lung congestion during exercise was significantly associated with elevations in PCWP and RA pressure as well as impairments in RV-PA coupling (area under the curve values 0.76-0.84).
Conclusion
Over half of stable outpatients with HFpEF develop increases in interstitial lung water, even during submaximal exercise. The acute development of lung congestion is correlated with increases in pulmonary capillary hydrostatic pressure that favours fluid filtration, and systemic venous hypertension due to altered RV-PA coupling, which may interfere with fluid clearance.
Clinical trial registration
NCT02885636.

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: 13 Oct 2019; epub ahead of print
Reddy YNV, Obokata M, Wiley B, Koepp KE, ... Carter RE, Borlaug BA
Eur Heart J: 13 Oct 2019; epub ahead of print | PMID: 31609443
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Abstract

Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study.

Habib G, Erba PA, Iung B, Donal E, ... Lancellotti P,
Aims
The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE).
Methods and results
Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated.
Conclusion
Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

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: 13 Oct 2019; 40:3222-3232
Habib G, Erba PA, Iung B, Donal E, ... Lancellotti P,
Eur Heart J: 13 Oct 2019; 40:3222-3232 | PMID: 31504413
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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

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

Novel Transcatheter Mitral Valve Prosthesis for Patients With Severe Mitral Annular Calcification.

Sorajja P, Gössl M, Babaliaros V, Rizik D, ... Cavalcante JL, Sun B
Background
Treatment of mitral regurgitation (MR) in the setting of severe mitral annular calcification (MAC) is challenging due to the high risk for fatal atrioventricular groove disruption and significant paravalvular leak.
Objectives
The objective of this study was to evaluate the potential for transcatheter mitral valve replacement in patients with severe MAC using an anatomically designed mitral prosthesis.
Methods
Nine patients (77 ± 6 years of age; 5 men) were treated with the valve, using transapical delivery performed under general anesthesia and with guidance from transesophageal echocardiography and fluoroscopy.
Results
Device implantation was successful with relief of MR in all 9 patients. There were no procedural deaths. In 1 patient, left ventricular outflow tract obstruction occurred due to malrotation of the prosthesis, and successful alcohol septal ablation was performed. During a median follow-up of 12 months (range 1 to 28 months), there was 1 cardiac death, 1 noncardiac death, no other mortality, and no prosthetic dysfunction, and MR remained absent in all treated patients. Rehospitalization for heart failure occurred in 2 patients who did not die subsequently. Clinical improvement with mild or no symptoms occurred in all patients alive at the end of follow-up.
Conclusions
Transcatheter mitral valve replacement in severe mitral annular calcification with a dedicated prosthesis is feasible and can result in MR relief with symptom improvement. Further evaluation of this approach for these high-risk patients is warranted.

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

J Am Coll Cardiol: 17 Sep 2019; 74:1431-1440
Sorajja P, Gössl M, Babaliaros V, Rizik D, ... Cavalcante JL, Sun B
J Am Coll Cardiol: 17 Sep 2019; 74:1431-1440 | PMID: 31514943
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Abstract

Atrial fibrillation and cardiac fibrosis.

Sohns C, Marrouche NF

The understanding of atrial fibrillation (AF) evolved from a sole rhythm disturbance towards the complex concept of a cardiomyopathy based on arrhythmia substrates. There is evidence that atrial fibrosis can be visualized using late gadolinium enhancement cardiac magnetic resonance imaging and that it is a powerful predictor for the outcome of AF interventions. However, a strategy of an individual and fibrosis guided management of AF looks promising but results from prospective multicentre trials are pending. This review gives an overview about the relationship between cardiac fibrosis and AF focusing on translational aspects, clinical observations, and fibrosis imaging to emphasize the concept of personalized paths in AF management taking into account the individual amount and distribution of fibrosis.

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 Nov 2019; epub ahead of print
Sohns C, Marrouche NF
Eur Heart J: 11 Nov 2019; epub ahead of print | PMID: 31713590
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Abstract

The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction.

Obokata M, Kane GC, Reddy YNV, Melenovsky V, ... Jarolim P, Borlaug BA
Aims
Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve.
Methods and results
Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s\' and e\' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e\', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001).
Conclusion
Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype.
Clinical trial registration
NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

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
Obokata M, Kane GC, Reddy YNV, Melenovsky V, ... Jarolim P, Borlaug BA
Eur Heart J: 11 Sep 2019; epub ahead of print | PMID: 31513270
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Abstract

Prognostic Value of F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Infective Endocarditis.

San S, Ravis E, Tessonier L, Philip M, ... Drancourt M, Habib G
Background
F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is commonly used for the diagnosis of infective endocarditis (IE), but its prognostic value remains unknown.
Objectives
This study sought to assess the prognostic value of F-FDG PET/CT in prosthetic valve endocarditis (PVE) and native valve endocarditis (NVE).
Methods
This study prospectively included 173 consecutive patients (109 PVE and 64 NVE) with definite left-sided IE who had an F-FDG PET/CT and were followed-up for 1 year. The primary endpoint was a composite of major cardiac events: death, recurrence of IE, acute cardiac failure, nonscheduled hospitalization for cardiovascular indication, and new embolic event.
Results
F-FDG PET/CT was positive in 100 (58%) patients, 83% (n = 90 of 109) in the PVE, and 16% (n = 10 of 64) in the NVE group. At a mean follow-up of 225 days (interquartile range: 199 to 251 days), the primary endpoint occurred in 94 (54%) patients: 63 (58%) in the PVE group and 31 (48%) in the NVE group. In the PVE group, positive F-FDG PET/CT was significantly associated with a higher rate of primary endpoint (hazard ratio [HR]: 2.7; 95% confidence interval [CI]: 1.1 to 6.7; p = 0.04). Moderate to intense F-FDG valvular uptake was also associated with worse outcome (HR: 2.3; 95% CI: 1.3 to 4.5; p = 0.03) and to new embolic events in PVE (HR: 7.5; 95% CI: 1.24 to 45.2; p = 0.03) and in NVE (HR: 8.8; 95% CI: 1.1 to 69.5; p = 0.02). In the NVE group, F-FDG PET/CT was not associated with occurrence of the primary endpoint Conclusions: In addition to its good diagnostic performance, F-FDG PET/CT is predictive of major cardiac events in PVE and new embolic events within the first year following IE.

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

J Am Coll Cardiol: 27 Aug 2019; 74:1031-1040
San S, Ravis E, Tessonier L, Philip M, ... Drancourt M, Habib G
J Am Coll Cardiol: 27 Aug 2019; 74:1031-1040 | PMID: 31439211
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Abstract

Long-Term Results of Mitral Valve Repair for Regurgitation Due to Leaflet Prolapse.

David TE, David CM, Tsang W, Lafreniere-Roula M, Manlhiot C
Background
Mitral valve (MV) repair has become the standard therapy for mitral regurgitation (MR) due to degenerative diseases, but information on late outcomes is limited.
Objectives
The purpose of this study was to examine the late results of MV repair for MR in a large cohort of patients.
Methods
A total of 1,234 consecutive patients (median age 59 years; 70.4% men) had MV repair for MR due to leaflet prolapse and were followed prospectively for a median of 13 years (interquartile range: 8 to 34 years) with periodical echocardiographic studies. There were 163 patients still at risk at 20 years. Cumulative incidences of adverse events and associated factors were examined with death as a competing outcome.
Results
At 20 years, reoperation-free survival was 60.4% (95% confidence interval: 56.2% to 64.2%) and the cumulative incidence of cardiac and valve-related deaths was 12%, noncardiac deaths 21.3%, reoperation on the MV 4.6%, infective endocarditis 1.1%, thromboembolism 10.3%, and bleeding 6.4%. The probability of recurrent moderate or severe MR was 12.5%, persistent or new moderate or severe tricuspid regurgitation (TR) 20.8%, and new atrial fibrillation (AF) 32.4%. Multivariable analysis identified older age, complete heart block, MV repair without annuloplasty ring, and the degree of myxomatous degeneration of the MV to be associated with recurrent MR. The development of AF and TR was unrelated to recurrent MR.
Conclusions
MV reoperation was uncommon after MV repair, but there was an increasing incidence of recurrent MR, TR, and new AF over time.

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

J Am Coll Cardiol: 27 Aug 2019; 74:1044-1053
David TE, David CM, Tsang W, Lafreniere-Roula M, Manlhiot C
J Am Coll Cardiol: 27 Aug 2019; 74:1044-1053 | PMID: 31439213
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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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Abstract

How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Pieske B, Tschöpe C, de Boer RA, Fraser AG, ... Seferovic P, Filippatos G

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the \'HFA-PEFF diagnostic algorithm\'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e\'), left ventricular (LV) filling pressure estimated using E/e\', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

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: 30 Aug 2019; epub ahead of print
Pieske B, Tschöpe C, de Boer RA, Fraser AG, ... Seferovic P, Filippatos G
Eur Heart J: 30 Aug 2019; epub ahead of print | PMID: 31504452
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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

Short-term decrease of left atrial size predicts clinical outcome in patients with severe aortic stenosis undergoing TAVR.

De Rosa R, Murray MI, Schranz D, Mas-Peiro S, ... Fichtlscherer S, Vasa-Nicotera M
Objectives
We investigated whether transcatheter aortic valve replacement (TAVR) results in a short-term decrease in left atrium (LA) size and whether such decrease may predict patients\' clinical outcome.
Background
Increased LA size is a hallmark of severe aortic stenosis (AS) and is associated with adverse patients\' cardiovascular outcome. Whether TAVR may lead to a decrease in LA size is not known.
Methods and results
Hundred and four patients with severe symptomatic AS and dilated LA undergoing TAVR were enrolled. LA volume was assessed by echocardiography before and shortly after TAVR (median time: 7 days). Composite rate of death and hospitalization for acutely decompensated heart failure (HF) was recorded and clinical status was assessed through NYHA-class evaluation at 12 months median follow-up. After TAVR, 49 patients (47%) demonstrated a decrease in LA volume. Despite a similar baseline NYHA class, patients with decrease in LA size had significant better improvement in clinical status respect to patients with unvaried LA size (NYHA post: 1.2 ± 0.6 vs. 1.8 ± 1.1, p = .001; NYHA reduction: -1.6 ± 0.9 vs. -0.9 ± 1.0, p = .002, respectively). Moreover, these patients had a significantly reduced rate of death or HF-hospitalization (4 vs. 29%, p = .001) and a significantly longer event-free-survival from Kaplan-Meier curves (p = .003). COX regression analysis showed that, among echocardiographic parameters, decrease in LA size was an independent predictor of clinical outcome (HR: 0.149, CI: 0.034-0.654, p = .012).
Conclusions
The lack of decrease in LA size shortly after TAVR is associated with significantly higher rates of death and HF-hospitalization, as well as with impaired improvement in clinical status during long-term follow-up.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print
De Rosa R, Murray MI, Schranz D, Mas-Peiro S, ... Fichtlscherer S, Vasa-Nicotera M
Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print | PMID: 31631509
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Impact:
Abstract

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.

Waksman R, Di Mario C, Torguson R, Ali ZA, ... Garcia-Garcia HM,
Background
Near-infrared spectroscopy (NIRS) intravascular ultrasound imaging can detect lipid-rich plaques (LRPs). LRPs are associated with acute coronary syndromes or myocardial infarction, which can result in revascularisation or cardiac death. In this study, we aimed to establish the relationship between LRPs detected by NIRS-intravascular ultrasound imaging at unstented sites and subsequent coronary events from new culprit lesions.
Methods
In this prospective, cohort study (LRP), patients from 44 medical centres were enrolled in Italy, Latvia, Netherlands, Slovakia, UK, and the USA. Patients with suspected coronary artery disease who underwent cardiac catheterisation with possible ad hoc percutaneous coronary intervention were eligible to be enrolled. Enrolled patients underwent scanning of non-culprit segments using NIRS-intravascular ultrasound imaging. The study had two hierarchal primary hypotheses, patient and plaque, each testing the association between maximum 4 mm Lipid Core Burden Index (maxLCBI) and non-culprit major adverse cardiovascular events (NC-MACE). Enrolled patients with large LRPs (≥250 maxLCBI) and a randomly selected half of patients with small LRPs (<250 maxLCBI) were followed up for 24 months. This study is registered with ClinicalTrials.gov, NCT02033694.
Findings
Between Feb 21, 2014, and March 30, 2016, 1563 patients were enrolled. NIRS-intravascular ultrasound device-related events were seen in six (0·4%) patients. 1271 patients (mean age 64 years, SD 10, 883 [69%] men, 388 [31%]women) with analysable maxLCBI were allocated to follow-up. The 2-year cumulative incidence of NC-MACE was 9% (n=103). Both hierarchical primary hypotheses were met. On a patient level, the unadjusted hazard ratio (HR) for NC-MACE was 1·21 (95% CI 1·09-1·35; p=0·0004) for each 100-unit increase maxLCBI) and adjusted HR 1·18 (1·05-1·32; p=0·0043). In patients with a maxLCBI more than 400, the unadjusted HR for NC-MACE was 2·18 (1·48-3·22; p<0·0001) and adjusted HR was 1·89 (1·26-2·83; p=0·0021). At the plaque level, the unadjusted HR was 1·45 (1·30-1·60; p<0·0001) for each 100-unit increase in maxLCBI. For segments with a maxLCBI more than 400, the unadjusted HR for NC-MACE was 4·22 (2·39-7·45; p<0·0001) and adjusted HR was 3·39 (1·85-6·20; p<0·0001).
Interpretation
NIRS imaging of non-obstructive territories in patients undergoing cardiac catheterisation and possible percutaneous coronary intervention was safe and can aid in identifying patients and segments at higher risk for subsequent NC-MACE. NIRS-intravascular ultrasound imaging adds to the armamentarium as the first diagnostic tool able to detect vulnerable patients and plaques in clinical practice.
Funding
Infraredx.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 26 Sep 2019; epub ahead of print
Waksman R, Di Mario C, Torguson R, Ali ZA, ... Garcia-Garcia HM,
Lancet: 26 Sep 2019; epub ahead of print | PMID: 31570255
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Abstract

Meta-Analysis of Transthoracic Echocardiography Versus Cardiac Magnetic Resonance for the Assessment of Aortic Regurgitation After Transcatheter Aortic Valve Implantation.

Papanastasiou CA, Kokkinidis DG, Jonnalagadda AK, Oikonomou EK, ... Myerson SG, Karamitsos TD

Residual aortic regurgitation (AR) is a major complication after transcatheter aortic valve implantation (TAVI). Although the echocardiographic assessment of post-TAVI AR remains challenging, cardiac magnetic resonance (CMR) allows direct quantification of AR. The aim of this study was to review the level of agreement between 2-dimensional transthoracic echocardiography (2D TTE) and CMR on grading the severity of AR after TAVI, and determine the accuracy of TTE in detecting moderate or severe AR. Electronic databases were searched in order to identify studies comparing 2D TTE to CMR for post-TAVI AR assessment. Kappa coefficient was used to determine the level of agreement between the 2 imaging modalities. CMR was used as the reference standard in order to assess the diagnostic accuracy of 2D TTE. Seven studies were included in this systematic review. Six studies reported a low correlation between 2D TTE and CMR (kappa coefficient ranging from -0.02 to 0.41), whereas one study showed good agreement with a kappa coefficient of 0.72. Given the heterogeneity in the included studies the diagnostic accuracy of TTE was evaluated by estimating the hierarchical summary receiver operator characteristic curve. The area under the curve for detection of moderate or severe AR with TTE was 0.83 (95% confidence interval 0.79 to 0.86). In conclusion, despite the reported significant disconcordance between TTE and CMR grading of AR, TTE has sufficient ability to discriminate moderate or severe AR from mild or none AR after TAVI in the clinical setting. CMR should be considered when TTE results are equivocal.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Oct 2019; 124:1246-1251
Papanastasiou CA, Kokkinidis DG, Jonnalagadda AK, Oikonomou EK, ... Myerson SG, Karamitsos TD
Am J Cardiol: 14 Oct 2019; 124:1246-1251 | PMID: 31466694
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Abstract

MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress.

Lambert JP, Luongo TS, Tomar D, Jadiya P, ... Shah NS, Elrod JW

The mitochondrial calcium uniporter (mtCU) is a ~700 kD multi-subunit channel residing in the inner mitochondrial membrane (IMM) required for mitochondrial Ca (mCa) uptake. Here we detail the contribution of MCUB, a paralog of the pore-forming subunit - MCU, in mtCU regulation and function and for the first time investigate MCUB\'s relevance to cardiac physiology.We created a stableknockout cell line () utilizing CRISPR-Cas9n technology and generated a cardiac-specific, tamoxifen-inducible MCUB mutant mouse (CAG-CAT-MCUB x MCM; MCUB-Tg) for in vivo assessment of cardiac physiology and response to ischemia-reperfusion (IR) injury. Live cell imaging and high-resolution spectrofluorometery were employed to determine intracellular Ca exchange and size-exclusion chromatography, blue native page and immunoprecipitation studies were utilized to determine the molecular function and impact of MCUB on the high-molecular weight mtCU complex.Using genetic gain- and loss-of-function approaches we show that MCUB expression displaces MCU from the functional mtCU complex and thereby decreases the association of MICU1 and MICU2 to alter channel gating. These molecular changes decrease MICU1/2-dependent cooperative activation of the mtCU thereby decreasing Ca uptake. Further, we show that MCUB incorporation into the mtCU is a stress-responsive mechanism to limit mCa2+ overload during cardiac injury. Indeed, overexpression of MCUB is sufficient to decrease infarct size following IR injury. However, MCUB incorporation into the mtCU does come at a cost, as acute decreases in Ca uptake impairs mitochondrial energetics and contractile function.In summary, we detail a new regulatory mechanism to modulate mtCU function and Ca uptake. Our results suggest that MCUB-dependent changes in mtCU stoichiometry is a prominent regulatory mechanism to modulate Ca uptake and cellular physiology.



Circulation: 18 Sep 2019; epub ahead of print
Lambert JP, Luongo TS, Tomar D, Jadiya P, ... Shah NS, Elrod JW
Circulation: 18 Sep 2019; epub ahead of print | PMID: 31533452
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Abstract

Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death.

Basso C, Iliceto S, Thiene G, Perazzolo Marra M

Despite a 2% to 3% prevalence of echocardiographically defined mitral valve prolapse (MVP) in the general population, the actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. The clinical profile is characterized by a patient, usually female, with mostly bileaflet myxomatous disease, mid-systolic click, repolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. Among the various pathophysiologic mechanisms of electrical instability, left ventricular fibrosis in the papillary muscles and inferobasal wall, mitral annulus disjunction, and systolic curling have been recently described by pathological and cardiac magnetic resonance studies in sudden death victims and patients with arrhythmic MVP. In addition, premature ventricular beats arising from the Purkinje tissue as ventricular fibrillation triggers have been documented by electrophysiologic studies in MVP patients with aborted sudden death. The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting premature ventricular beats because of a primary morphofunctional abnormality of the mitral valve annulus. The main clinical challenge is how to identify patients with arrhythmic MVP (which imaging technique and in which patient) and how to treat them to prevent sudden death. Thus, there is a necessity for prospective multicenter studies focusing on the prognostic role of cardiac magnetic resonance and electrophysiologic studies and on the therapeutic efficacy of targeted catheter ablation and mitral valve surgery in reducing the risk of life-threatening arrhythmias, as well as the role of implantable cardioverter defibrillators for primary prevention.



Circulation: 09 Sep 2019; 140:952-964
Basso C, Iliceto S, Thiene G, Perazzolo Marra M
Circulation: 09 Sep 2019; 140:952-964 | PMID: 31498700
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Abstract

Disruption of Ca Homeostasis and Connexin 43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in Plakophilin-2-Deficient Mice.

Kim JC, Pérez-Hernández M, Alvarado FJ, Maurya SR, ... Cerrone M, Delmar M
Background
Plakophilin-2 (PKP2) is classically defined as a desmosomal protein. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy. A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events consequent to PKP2 deficiency. Here, we sought to capture early molecular/cellular events that can act as nascent arrhythmic/cardiomyopathic substrates.
Methods
We used multiple imaging, biochemical and high-resolution mass spectrometry methods to study functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice (PKP2cKO) 14 days post-tamoxifen injection, a time point preceding overt electrical or structural phenotypes. Myocytes from right or left ventricular free wall were studied separately.
Results
Most properties of PKP2cKO left ventricular myocytes were not different from control; in contrast, PKP2cKO right ventricular (RV) myocytes showed increased amplitude and duration of Ca transients, increased Ca in the cytoplasm and sarcoplasmic reticulum, increased frequency of spontaneous Ca release events (sparks) even at comparable sarcoplasmic reticulum load, and dynamic Ca accumulation in mitochondria. We also observed early- and delayed-after transients in RV myocytes and heightened susceptibility to arrhythmias in Langendorff-perfused hearts. In addition, ryanodine receptor 2 in PKP2cKO-RV cells presented enhanced Ca sensitivity and preferential phosphorylation in a domain known to modulate Ca gating. RNAseq at 14 days post-tamoxifen showed no relevant difference in transcript abundance between RV and left ventricle, neither in control nor in PKP2cKO cells. Instead, we found an RV-predominant increase in membrane permeability that can permit Ca entry into the cell. Connexin 43 ablation mitigated the membrane permeability increase, accumulation of cytoplasmic Ca, increased frequency of sparks and early stages of RV dysfunction. Connexin 43 hemichannel block with GAP19 normalized [Ca] homeostasis. Similarly, protein kinase C inhibition normalized spark frequency at comparable sarcoplasmic reticulum load levels.
Conclusions
Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Connexin 43-dependent membrane conduit and repressed by protein kinase C inhibitors. Given that asymmetric Ca dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.



Circulation: 16 Sep 2019; 140:1015-1030
Kim JC, Pérez-Hernández M, Alvarado FJ, Maurya SR, ... Cerrone M, Delmar M
Circulation: 16 Sep 2019; 140:1015-1030 | PMID: 31315456
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Abstract

Transseptal access for left heart structural interventions in the setting of prior atrial septal defect closure.

Yap J, Chen S, Stripe BR, Smith TWR, Rogers JH, Singh GD

A transseptal puncture is critical for \"left-sided\" structural heart interventions. Procedures such as transcatheter edge-to-edge repair (MitraClip) and left atrial appendage (LAA) closure (Watchman) require precise puncture of the interatrial septum (IAS), and the presence of a prior atrial septal defect (ASD) closure device poses a challenge. We aim to present a successfully completed case of MitraClip and Watchman in the presence of ASD closure device in two different patients. A review of the literature will be reported, and pertinent clinical and technical considerations will be discussed in depth to achieve procedural success. In summary, transseptal puncture for left heart structural interventions is feasible in the presence of a prior ASD/patent foramen ovale closure device. A detailed understanding of the anatomical considerations as well as the use of multimodality imaging to evaluate the IAS will aid in improving procedural success rates.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 21 Oct 2019; epub ahead of print
Yap J, Chen S, Stripe BR, Smith TWR, Rogers JH, Singh GD
Catheter Cardiovasc Interv: 21 Oct 2019; epub ahead of print | PMID: 31638326
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Abstract

Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Attributable to a Human Myosin Regulatory Light Chain Mutation.

Zaleta-Rivera K, Dainis A, Ribeiro AJS, Cordero P, ... Wheeler MT, Ashley EA
Background
Restrictive cardiomyopathy is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy directed at the underlying cause. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of restrictive cardiomyopathy in a mouse model.
Methods
A short hairpin RNA (M7.8L) was selected from a pool for specificity and efficacy. Two groups of myosin regulatory light chain N47K transgenic mice were injected with M7.8L packaged in adeno-associated virus 9 at 3 days of age and 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine maximal oxygen uptake and left ventricular mass. At the end of treatment, heart, lung, liver, and kidney tissue was harvested to determine viral tropism and for transcriptomic and proteomic analysis. Cardiomyocytes were isolated for single-cell studies.
Results
A one-time injection of AAV9-M7.8L RNAi in 3-day-old humanized regulatory light chain mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed at 16 weeks postinjection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight, and attenuated a pathological increase in left ventricular mass. Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of contraction, relaxation, and calcium kinetics. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II and the transcription activator Brg1 were reduced, suggesting recovery toward a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts, and endogenous microRNAs were preserved, suggesting that the RNAi pathway was not saturated.
Conclusions
Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed towards human restrictive cardiomyopathy. This is a promising step toward targeted therapy for a prevalent human disease.



Circulation: 26 Aug 2019; 140:765-778
Zaleta-Rivera K, Dainis A, Ribeiro AJS, Cordero P, ... Wheeler MT, Ashley EA
Circulation: 26 Aug 2019; 140:765-778 | PMID: 31315475
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Abstract

Novel Genetic Locus Influencing Retinal Venular Tortuosity Is Also Associated With Risk of Coronary Artery Disease.

Veluchamy A, Ballerini L, Vitart V, Schraut KE, ... Palmer CNA, Doney ASF
Objective
The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 () for retinal venular tortuosity (), and one at 13q34 () for retinal arteriolar tortuosity (); these 2 loci were subsequently confirmed in 3 independent cohorts (N=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in / was rs1808382 (β=-0.109; SE=0.015; =2.39×10-) and inwas rs7991229 (β=0.103; SE=0.015; =4.66×10-). Notably, the / locus associated withis also associated with coronary artery disease, heart rate, and atrial fibrillation.
Conclusions
Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.



Arterioscler Thromb Vasc Biol: 09 Oct 2019:ATVBAHA119312552; epub ahead of print
Veluchamy A, Ballerini L, Vitart V, Schraut KE, ... Palmer CNA, Doney ASF
Arterioscler Thromb Vasc Biol: 09 Oct 2019:ATVBAHA119312552; epub ahead of print | PMID: 31597446
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Abstract

TLR (Toll-Like Receptor) 4 Antagonism Prevents Left Ventricular Hypertrophy and Dysfunction Caused by Neonatal Hyperoxia Exposure in Rats.

Mian MOR, He Y, Bertagnolli M, Mai-Vo TA, ... Luu TM, Nuyt AM

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium (LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1β expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.



Hypertension: 29 Sep 2019; 74:843-853
Mian MOR, He Y, Bertagnolli M, Mai-Vo TA, ... Luu TM, Nuyt AM
Hypertension: 29 Sep 2019; 74:843-853 | PMID: 31476902
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Abstract

Staging Cardiac Damage in Patients With Hypertension.

Seko Y, Kato T, Shiba M, Morita Y, ... Haruna T, Inoko M

Ventricular and extraventricular response to pressure overload may be a common process in aortic stenosis and hypertension. We aimed to evaluate the association of a newly defined staging classification characterizing the extent of cardiac damage, originally developed for aortic stenosis, with long-term outcomes in patients with hypertension. We retrospectively analyzed 1639 patients with hypertension who had undergone both scheduled transthoracic echocardiography and electrocardiography in 2013 in a Japanese hospital, after excluding severe and moderate aortic stenosis, aortic regurgitation, mitral stenosis, previous myocardial infarction, or cardiomyopathy. We classified patients according to the presence or absence of cardiac damage as detected on echocardiography as follows: stage 0, no cardiac damage (n=858; 52.3%); stage 1, left ventricular damage (n=358; 21.8%); stage 2, left atrial or mitral valve damage (n=360; 22.0%); or stage 3 and 4, pulmonary vasculature, tricuspid valve, or right ventricular damage (n=63; 3.8%). The primary outcome was a composite of all-cause death and major adverse cardiac events. Cumulative 3-year incidence of the primary outcome was 15.5% in stage 0, 20.7% in stage 1, 31.8% in stage 2, and 60.6% in stage 3. After adjusting for confounders, the stage was incrementally associated with higher risk of the primary outcome (per 1-stage increase: hazard ratio, 1.46 [95% CI, 1.31-1.61]; <0.001). The staging classification characterizing the extent of cardiac damage, originally developed for aortic stenosis, was associated with long-term outcomes in patients with hypertension in a stepwise manner.



Hypertension: 03 Nov 2019:HYPERTENSIONAHA11913797; epub ahead of print
Seko Y, Kato T, Shiba M, Morita Y, ... Haruna T, Inoko M
Hypertension: 03 Nov 2019:HYPERTENSIONAHA11913797; epub ahead of print | PMID: 31679419
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Abstract

Computed Tomography: Assessment of Coronary Inflammation and Other Plaque Features.

Oikonomou EK, West HW, Antoniades C

Unstable coronary plaques that are prone to erosion and rupture are the major cause of acute coronary syndromes. Our expanding understanding of the biological mechanisms of coronary atherosclerosis and rapid technological advances in the field of medical imaging has established cardiac computed tomography as a first-line diagnostic test in the assessment of suspected coronary artery disease, and as a powerful method of detecting the vulnerable plaque and patient. Cardiac computed tomography can provide a noninvasive, yet comprehensive, qualitative and quantitative assessment of coronary plaque burden, detect distinct high-risk morphological plaque features, assess the hemodynamic significance of coronary lesions and quantify the coronary inflammatory burden by tracking the effects of arterial inflammation on the composition of the adjacent perivascular fat. Furthermore, advances in machine learning, computational fluid dynamic modeling, and the development of targeted contrast agents continue to expand the capabilities of cardiac computed tomography imaging. In our Review, we discuss the current role of cardiac computed tomography in the assessment of coronary atherosclerosis, highlighting its dual function as a clinical and research tool that provides a wealth of structural and functional information, with far-reaching diagnostic and prognostic implications.



Arterioscler Thromb Vasc Biol: 11 Sep 2019:ATVBAHA119312899; epub ahead of print
Oikonomou EK, West HW, Antoniades C
Arterioscler Thromb Vasc Biol: 11 Sep 2019:ATVBAHA119312899; epub ahead of print | PMID: 31510795
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Abstract

Extensive Left Atrial Ablation was Associated with Exacerbation of Left Atrial Stiffness and Dyspnea.

Moon I, Lee SY, Lee E, Lee SR, ... Choi EK, Oh S
Introduction
The left atrium (LA), including the pulmonary vein antrum, is the main target of catheter ablation for atrial fibrillation (AF). However, there is a lack of data on the effect of extensive LA ablation on LA stiffness. This study sought to investigate the impact of extensive LA ablation on LA stiffness and dyspnea after the restoration of sinus rhythm.
Methods
In total, 97 AF patients (80 patients who only underwent pulmonary vein isolation [PVI] and 17 patients who underwent extensive LA ablation) were investigated. Extensive LA ablation was defined as PVI plus at least two sets of LA linear-line ablation. LA stiffness was estimated using the ratio of E/e\' to global longitudinal LA strain, as measured by echocardiography. The clinical outcomes we evaluated were AF recurrence and composite dyspnea, which we defined as newly prescribed diuretics or hospitalization for heart failure.
Results
Patients were 59.3±10.0 years old on average, and 68 (70.1%) were male. There were no significant differences in baseline characteristics or echocardiographic parameters before ablation between the two groups. After ablation, LA stiffness was higher in the extensive ablation group compared to that in the PVI group (0.9±0.6 vs. 0.5±0.3, respectively, P=0.017). Multivariable linear regression analysis showed that extensive ablation increased LA stiffness (ß=0.363, P<0.001). AF recurrence was similar in both groups; however, composite dyspnea outcomes were worse in the extensive ablation group (P=0.003).
Conclusion
Extensive LA ablation was associated with a worsening of LA stiffness. This might explain dyspnea despite the successful restoration of sinus rhythm. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 20 Oct 2019; epub ahead of print
Moon I, Lee SY, Lee E, Lee SR, ... Choi EK, Oh S
J Cardiovasc Electrophysiol: 20 Oct 2019; epub ahead of print | PMID: 31637795
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Abstract

Role of the lymphatic vasculature in cardiovascular medicine.

Telinius N, Hjortdal VE

The lymphatic vasculature has traditionally been considered important for removal of excessive fluid from the interstitial space, absorption of fat from the intestine and the immune system. Advances in molecular medicine and imaging have provided us with new tools to study the lymphatics. This has revealed that the vessels are actively involved in regulation of immune cell trafficking and inflammation. We now know much about how new lymphatic vessels are created (lymphangiogenesis) and that this is important in, for example, wound healing and tissue repair. The best characterised pathway for lymphangiogenesis is the vascular endothelial growth factor C (VEGF-C)/VEGFR3 pathway. Over recent years, there has been an increasing interest in the role of the lymphatics in cardiovascular medicine. Preclinical studies have shown that lymphangiogenesis and immune cell trafficking play a role in cardiovascular conditions such as atherosclerosis, recovery after myocardial infarction and rejection of cardiac allografts. Targeting the VEGF-C/VEGFR3 pathway can be beneficial in these conditions. The clinical spectrum of lymphatic abnormalities and lymphoedema is wide and overlaps with congenital heart disease. Important long-term complications to the Fontan circulation involves the lymphatics. New and improved imaging modalities has improved our understanding and management of these patients. Lymphatic leaks and flow abnormalities can be successfully treated, minimally invasively, with percutaneous embolisation. Future research will prove if the preclinical findings that point to a role of the lymphatics in several cardiovascular conditions will result in new treatment options.

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

Heart: 03 Oct 2019; epub ahead of print
Telinius N, Hjortdal VE
Heart: 03 Oct 2019; epub ahead of print | PMID: 31585946
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Impact:
Abstract

Nonfocal Transient Neurological Attacks Are Associated With Cerebral Small Vessel Disease.

Oudeman EA, Greving JP, Van den Berg-Vos RM, Biessels GJ, ... Kappelle LJ,

Background and Purpose- Nonfocal transient neurological attacks (TNAs), such as unsteadiness, bilateral weakness, or confusion, are associated with an increased risk of stroke and dementia. Cerebral ischemia plays a role in their pathogenesis, but the precise mechanisms are unknown. We hypothesized that cerebral small vessel disease is involved in the pathogenesis of TNAs and assessed the relation between TNAs and manifestations of cerebral small vessel disease on magnetic resonance imaging. Methods- We included participants from the HBC (Heart-Brain Connection) study. In this study, hemodynamic and cardiovascular contributions to cognitive impairment have been studied in patients with heart failure, carotid artery occlusion, or possible vascular cognitive impairment, as well as in a reference group. We excluded participants with a history of stroke or transient ischemic attacks. The occurrence of the following 8 TNAs was assessed with a standardized interview: unconsciousness, confusion, amnesia, unsteadiness, bilateral leg weakness, blurred vision, nonrotatory dizziness, and paresthesias. The occurrence of TNAs was related to the presence of lacunes or white matter hyperintensities (Fazekas score, ≥2; early confluent or confluent lesions) in logistic regression analysis, adjusted for age, sex, and hypertension. Results- Of 304 participants (60% men; mean age, 67±9 years), 63 participants (21%) experienced ≥1 TNAs. Lacunes and early confluent or confluent white matter hyperintensities were more common in participants with TNAs than in participants without TNAs (35% versus 20%; adjusted odds ratio, 2.32 [95% CI, 1.22-4.40] and 48% versus 27%; adjusted odds ratio, 2.65 [95% CI, 1.44-4.90], respectively). Conclusions- In our study, TNAs are associated with the presence of lacunes and early confluent or confluent white matter hyperintensities of presumed vascular origin, which indicates that cerebral small vessel disease might play a role in the pathogenesis of TNAs.



Stroke: 21 Oct 2019:STROKEAHA119025328; epub ahead of print
Oudeman EA, Greving JP, Van den Berg-Vos RM, Biessels GJ, ... Kappelle LJ,
Stroke: 21 Oct 2019:STROKEAHA119025328; epub ahead of print | PMID: 31637974
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Impact:
Abstract

Hypertension in aortic stenosis: relationship with revealed symptoms and functional measures on treadmill exercise.

Saeed S, Mancia G, Rajani R, Parkin D, Chambers JB
Background
The impact of hypertension on symptoms and functional capacity during exercise treadmill test (ETT) in apparently asymptomatic patients with aortic stenosis is poorly understood.
Methods
A total of 314 patients (age 65 ± 12 years, 68% men) with moderate or severe asymptomatic aortic stenosis underwent baseline echocardiography and ETT. Hypertension was defined as a history of elevated blood pressure (BP), past or current treatment with antihypertensive agents or a BP at the baseline clinic visit more than 140/90 mmHg.
Results
There were 229 (73%) patients with hypertension who were older, more likely to have diabetes, hypercholesterolemia and coronary artery disease, larger left atrial diameters, higher left ventricular (LV) mass and a higher proportion of LV hypertrophy than normotensive patients. In a univariate logistic regression analysis hypertension and clinic SBP were not associated with revealed symptoms. In a multivariate logistic regression analysis, lower peak SBP [odds ratio (OR) 1.02;95% confidence interval (CI) 1.00-1.04, P = 0.017] and rapid early rise in heart rate (OR 15.03; 95% CI 6.23-36.24, P < 0.001) were associated with a higher risk of revealed symptoms while the use of antihypertensive treatment was associated with a lower risk of revealed symptoms (OR 0.40; 95% CI 0.18-0.89, P = 0.025), independent of age, obesity, LV ejection fraction and aortic valve area. In a linear regression analysis, after adjustment for age, sex and BMI, hypertension did not retain an association with lower metabolic equivalents (β = -0.06, P = 0.311).
Conclusion
Hypertension in aortic stenosis patients was associated with a high cardiovascular disease burden, but did not interact with symptoms or functional capacity during ETT. Hypertension does not interfere with the clinical interpretation of exercise testing.



J Hypertens: 30 Oct 2019; 37:2209-2215
Saeed S, Mancia G, Rajani R, Parkin D, Chambers JB
J Hypertens: 30 Oct 2019; 37:2209-2215 | PMID: 31157741
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Impact:
Abstract

Associations Between Left Ventricular Structure, Function, and Cerebral Amyloid: The ARIC-PET Study.

Johansen MC, Mosley TH, Knopman DS, Wong DF, ... Solomon SD, Gottesman RF

Background and Purpose- Cardiovascular disease is a known risk factor for cognitive decline, although the mechanisms remain unclear. We hypothesize that Aβ (β-amyloid), a core pathology of Alzheimer\'s disease, will be associated with subclinical cardiac structure and function echocardiogram indices. Methods- Three hundred six nondemented participants from the ARIC study (Atherosclerosis Risk in Communities Study) underwent florbetapir positron emission tomography and 2D echocardiography (echo). Cross-sectional associations between echo markers of left ventricular structure and function and global cortical Aβ (≥1.2 standardized uptake value ratio were evaluated using multivariable logistic regression with interaction terms when appropriate. Results- Participants ranged in age from 67 to 88 years, were 57% female and 42% black. Per 1 cm increase in end-diastolic left ventricular diameter, the odds of elevated florbetapir standardized uptake value ratio doubled (odds ratio, 2.04 [95% CI, 1.10-3.77]), with similar findings when excluding mild cognitive impairment (odds ratio, 2.61 [95% CI, 1.22-5.59]). Conclusions- We have demonstrated a significant association between a marker of left ventricular structure and elevated florbetapir standardized uptake value ratio, identified using positron emission tomography. Ongoing prospective work will help determine if changes in cardiac structure and function either precede, or occur simultaneously with deposition of amyloid.



Stroke: 09 Oct 2019:STROKEAHA119027220; epub ahead of print
Johansen MC, Mosley TH, Knopman DS, Wong DF, ... Solomon SD, Gottesman RF
Stroke: 09 Oct 2019:STROKEAHA119027220; epub ahead of print | PMID: 31597548
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Abstract

Contemporary epidemiology and outcomes in recurrent infective endocarditis.

Freitas-Ferraz AB, Tirado-Conte G, Vilacosta I, Olmos C, ... Carnero M, San Román JA
Objective
Recurrent infective endocarditis (IE) is a major complication of patients surviving a first episode of IE. This study sought to analyse the current state of recurrent IE in a large contemporary cohort.
Methods
1335 consecutive episodes of IE were recruited prospectively in three tertiary care centres in Spain between 1996 and 2015. Episodes were categorised into group I (n=1227), first-IE episode and group II (n=108), recurrent IE (8.1%). After excluding six patients, due to lack of relevant data, group II was subdivided into IIa (n=87), reinfection (different microorganism), and IIb (n=15), relapse (same microorganism within 6 months of the initial episode).
Results
The cumulative burden and incidence of recurrence was slightly lower in the second decade of the study (2006-2015) (7.17 vs 4.10 events/100 survivors and 7.51% vs 3.82, respectively). Patients with reinfections, compared with group I, were significantly younger, had a higher frequency of HIV infection, were more commonly intravenous drug users (IVDU) and prosthetic valve carriers, had less embolic complications and cardiac surgery, with similar in-hospital mortality. IVDU was found to be an independent predictor of reinfection (HR 3.92, 95% CI 1.86 to 8.28).In the relapse IE group, prosthetic valve endocarditis (PVE) and periannular complications were more common. Among patients treated medically, those with PVE had a higher relapse incidence (4.82% vs 0.43% in native valve IE, p=0.018).and PVE were independent predictors of relapse (HR 3.14, 95% CI 1.11 to 8.86 and 3.19, 95% CI 1.13 to 9.00, respectively) and in-hospital-mortality was similar to group I. Three-year all-cause mortality was similar in recurrent episodes compared with single episodes.
Conclusion
Recurrent IE remains a frequent late complication. IVDU was associated with a fourfold increase in the risk of reinfection. PVE treated medically and infections caused byincreased the risk of relapse. In-hospital and long-term mortality was comparable among groups.

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

Heart: 02 Oct 2019; epub ahead of print
Freitas-Ferraz AB, Tirado-Conte G, Vilacosta I, Olmos C, ... Carnero M, San Román JA
Heart: 02 Oct 2019; epub ahead of print | PMID: 31582567
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Abstract

Implications of serial coronary computed tomography angiography in the evaluation of coronary plaque progression.

Dahal S, Budoff MJ
Purpose of review
The purpose is to review the use of coronary computed tomography (CT) angiography to assess coronary plaque burden/progression and to discuss about recent clinical trials that have utilized this imaging modality to study the effect of new pharmacotherapies on plaque burden/progression.
Recent findings
There are numerous clinical trials that have utilized coronary CT angiography to demonstrate the potential benefits of statins, apixaban, rivaroxaban, aged garlic extract, biologic agents, and omega-3 fatty acids to reduce coronary plaque progression. Coronary CT angiography can identify high-risk plaques and can also quantify total plaque burden, both of which are independent risk factors to predict major adverse cardiac events.
Summary
Coronary heart disease remains one of the leading cause of mortality in the world. Utilizing coronary CT angiography, it is possible to identify rupture-prone plaques and also to quantify the total plaque burden. New pharmacotherapies that have the potential to reduce plaque progression have been used in clinical trials and these trials have utilized coronary CT angiography to track coronary atheroma progression. In future, we will see frequent utilization of coronary CT angiography to track coronary atheroma.



Curr Opin Lipidol: 04 Oct 2019; epub ahead of print
Dahal S, Budoff MJ
Curr Opin Lipidol: 04 Oct 2019; epub ahead of print | PMID: 31592788
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Abstract

Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management.

Van De Bruaene A, Toh N, Hickey EJ, Benson L, ... Williams WG, Roche SL
Objective
This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).
Methods
We analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.
Results
A total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.
Conclusion
PH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.

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

Heart: 29 Sep 2019; 105:1471-1478
Van De Bruaene A, Toh N, Hickey EJ, Benson L, ... Williams WG, Roche SL
Heart: 29 Sep 2019; 105:1471-1478 | PMID: 31053610
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Abstract

HIV and pericardial fat are associated with abnormal cardiac structure and function among Ugandans.

Buggey J, Yun L, Hung CL, Kityo C, ... McComsey GA, Longenecker CT
Objectives
To examine the relationship between pericardial fat (PCF) and cardiac structure and function among HIV-infected patients in the sub-Saharan African country of Uganda. People living with HIV (PLHIV) have altered fat distribution and an elevated risk for heart failure. Whether altered quantity and radiodensity of fat surrounding the heart relates to cardiac dysfunction in this population is unknown.
Methods
One hundred HIV-positive Ugandans on antiretroviral therapy were compared with 100 age and sex-matched HIV-negative Ugandans; all were >45 years old with >1 cardiovascular disease risk factor. Subjects underwent ECG-gated non-contrast cardiac CT and transthoracic echocardiography with speckle tracking strain imaging. Multivariable linear and logistic regression models were used to explore the association of PCF with echocardiographic outcomes.
Results
Median age was 55% and 62% were female. Compared with uninfected controls, PLHIV had lower body mass index (27 vs 30, p=0.02) and less diabetes (26% vs 45%, p=0.005). Median left ventricular (LV) ejection fraction was 67%. In models adjusted for traditional risk factors, HIV was associated with 10.3 g/m higher LV mass index (LVMI) (95% CI 3.22 to 17.4; p=0.005), 0.87% worse LV global longitudinal strain (GLS) (95% CI -1.66 to -0.07; p=0.03) and higher odds of diastolic dysfunction (OR 1.96; 95% CI 0.95 to 4.06; p=0.07). In adjusted models, PCF volume was significantly associated with increased LVMI and worse LV GLS, while PCF radiodensity was associated with worse LV GLS (all p<0.05).
Conclusions
In Uganda, HIV infection, PCF volume and density are associated with abnormal cardiac structure and function.

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

Heart: 18 Sep 2019; epub ahead of print
Buggey J, Yun L, Hung CL, Kityo C, ... McComsey GA, Longenecker CT
Heart: 18 Sep 2019; epub ahead of print | PMID: 31537637
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Abstract

Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction.

Mougenot N, Mika D, Czibik G, Marcos E, ... Derumeaux G, Lipskaia L
Aims
Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of β-adrenergic/cAMP signalling. Our objective was to evaluate cardiac cAMP signalling as age increases between 2 months and 12 months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age.
Methods and results
Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2- and 12 months old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased phosphodiesterase and PKA activity, and increased phosphorylation of several PKA targets including sarco(endo)plasmic-reticulum-calcium-ATPase (SERCA2a) cofactor phospholamban (PLN) and GSK3α/β a main regulator of hypertrophic growth and ageing. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2-month-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-month-old NTG and AC8TG, PLN and GSK3α/β phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Haemodynamics demonstrated an increased contractile function in 2- and 12-month-old AC8TG, but not in NTG. In contrast, echocardiography and tissue Doppler imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-month-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to heart failure (HF) and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG when compared with NTG.
Conclusion
Our data demonstrated an early and accelerated cardiac remodelling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signalling can accelerate cardiac ageing, partly through GSK3α/β phosphorylation.

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

Cardiovasc Res: 30 Sep 2019; 115:1778-1790
Mougenot N, Mika D, Czibik G, Marcos E, ... Derumeaux G, Lipskaia L
Cardiovasc Res: 30 Sep 2019; 115:1778-1790 | PMID: 30605506
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Abstract

Computed tomographic coronary angiography in risk stratification prior to non-cardiac surgery: a systematic review and meta-analysis.

Koshy AN, Ha FJ, Gow PJ, Han HC, ... Teh AW, Farouque O
Objectives
Utility of CT coronary angiography (CTA) and coronary artery calcium (CAC) scoring in risk stratification prior to non-cardiac surgery is unclear. Although current guidelines recommend stress testing in intermediate-high risk individuals, over one-third of perioperative major adverse cardiovascular events (MACE) occur in patients with a negative study. This systematic review and meta-analysis evaluates the value of CTA and CAC score in preoperative risk prognostication prior to non-cardiac surgery.
Methods
MEDLINE, PubMed and EMBASE databases were searched for articles published up to June 2018. Summary ORs for degree of coronary artery disease (CAD) and perioperative MACE were pooled using a random-effects model.
Results
Eleven studies were included. Two hundred and fifty-two (7.2%) MACE occurred in 3480 patients. Risk of perioperative MACE rose with the severity and extent of CAD on CTA (no CAD 2.0%; non-obstructive 4.1%; obstructive single-vessel 7.1%; obstructive multivessel 23.1%, p<0.001). Multivessel disease (MVD) demonstrated the greatest risk (OR 8.9, 95% CI 5.1 to 15.3, p<0.001). Increasing CAC score was associated with higher perioperative MACE (CAC score: ≥100 OR 5.1, ≥1000 OR 10.4, both p<0.01). In a cohort deemed high risk by established clinical indices, absence of MVD on CTA demonstrated a negative predictive value of 96% (95% CI 92.8 to 98.4) for predicting freedom from MACE.
Conclusions
Severity and extent of CAD on CTA conferred incremental risk for perioperative MACE in patients undergoing non-cardiac surgery. The \'rule-out\' capability of CTA is comparable to other non-invasive imaging modalities and offers a viable alternative for risk stratification of patients undergoing non-cardiac surgery.
Trial registration number
CRD42018100883.

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

Heart: 30 Aug 2019; 105:1335-1342
Koshy AN, Ha FJ, Gow PJ, Han HC, ... Teh AW, Farouque O
Heart: 30 Aug 2019; 105:1335-1342 | PMID: 31018953
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Abstract

3D image integration guidance for Cryo Balloon Pulmonary Vein Isolation procedures.

Bourier F, Vlachos K, Lam A, Martin CA, ... Jaïs P, Sacher F
Background
We present a new, easily applicable approach for the guidance of cryo balloon (CB) pulmonary vein isolation (PVI) procedures that uses the combination of a 3D mapping system image integration module and CT-derived anatomy. The aim of this retrospective, non-randomized study was to investigate (1) an alternative use for an established radiofrequency image integration module for cryo procedures; (2) a guidance technology for cryo PVI based on integrated CT anatomy; and (3) its clinical impact.
Methods and results
CT LA-angiography was performed in n=50 consecutive patients prior to a CB PVI procedure, and a 3D-reconstruction of the cardiac anatomy was segmented. N=25 patients were treated using conventional fluoroscopy; n=25 patients were treated using the 3D image integration technique. In the image integration group, the CARTO3 UNIVU (Biosense Webster, USA) module was used for image integration of 3D anatomy and fluoroscopic imaging. Transseptal puncture and cryo PVI were guided by 3D-overlay imaging. Procedures were feasible without complications in all patients and cryo PVI procedures were successfully guided using the image integration technique. The intraprocedural time needed to perform image integration was 37±10sec. Fluoroscopy time was 31.7±11.7min in the conventional group and 20.1±7.9min in the image integration group (p<0.001), procedure time was 116.3±29.0min in the conventional group vs. 101.2±20.9min in the 3D group (p=0.04).
Conclusions
3D-overlay guidance of CB PVI is feasible, safe, and applicable in real time with minimal effort. It may significantly reduce radiation exposure by introducing 3D information, known from electroanatomic mapping systems, into cryo PVI procedures. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 22 Oct 2019; epub ahead of print
Bourier F, Vlachos K, Lam A, Martin CA, ... Jaïs P, Sacher F
J Cardiovasc Electrophysiol: 22 Oct 2019; epub ahead of print | PMID: 31646698
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Abstract

In vivo ratiometric optical mapping enables high-resolution cardiac electrophysiology in pig models.

Lee P, Quintanilla JG, Alfonso-Almazán JM, Galán-Arriola C, ... Loew LM, Filgueiras-Rama D
Aims
Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models.
Methods and results
First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63-138) cm/s vs. 51 (41-64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217-254) ms vs. 192 (182-233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min-1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA.
Conclusions
In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.

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

Cardiovasc Res: 31 Aug 2019; 115:1659-1671
Lee P, Quintanilla JG, Alfonso-Almazán JM, Galán-Arriola C, ... Loew LM, Filgueiras-Rama D
Cardiovasc Res: 31 Aug 2019; 115:1659-1671 | PMID: 30753358
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Abstract

Frequent Cognitive Impairment in Patients With Disorders Along the Heart-Brain Axis.

Hooghiemstra AM, Leeuwis AE, Bertens AS, Biessels GJ, ... , van der Flier WM

Background and Purpose- Patients with cardiovascular disease are at increased risk for cognitive decline. We studied the occurrence and profile of cognitive impairment in 3 patient groups as exemplar conditions of hemodynamic disturbances at different levels of the heart-brain axis, including patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (possible vascular cognitive impairment [VCI]). Methods- In 555 participants (160 HF, 107 COD, 160 possible VCI, 128 reference participants; 68±9 years; 36% F; Mini-Mental State Examination 28±2), we assessed cognitive functioning with a comprehensive test battery. Test scores were transformed into -scores. Compound -scores were constructed for: memory, language, attention/psychomotor speed, executive functioning, and global cognitive functioning. We rated cognitive domains as impaired when -score≤-1.5. Based on the number of impaired domains, patients were classified as cognitively normal, minor, or major cognitive impairment. We used general linear models and χ tests to compare cognitive functioning between patient groups and the reference group. Results- Age, sex, and education adjusted global cognitive functioning z-score was lower in patients with COD (β [SE]=-0.46 [0.10], <0.001) and possible VCI (β [SE]=-0.80 [0.09], 0.001) compared with reference participants. On all domains, -scores were lower in patients with COD and possible VCI compared with reference participants. Patients with HF had lower z-scores on attention/speed and language compared with reference participants. Cognitive impairment was observed in 18% of HF, 36% of COD, and 45% possible VCI. There was no difference in profile of impaired cognitive domains between patient groups. Memory and attention-psychomotor speed were most commonly affected, followed by executive functioning and language. Conclusions- A substantial part of patients with HF and COD had cognitive impairment, which warrants vigilance for the occurrence of cognitive impairment. These results underline the importance of an integrative approach in medicine in patients presenting with disorders in the heart-brain axis.



Stroke: 04 Nov 2019:STROKEAHA119026031; epub ahead of print
Hooghiemstra AM, Leeuwis AE, Bertens AS, Biessels GJ, ... , van der Flier WM
Stroke: 04 Nov 2019:STROKEAHA119026031; epub ahead of print | PMID: 31684846
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Abstract

Quality of life and functional limitations after pulmonary embolism and its prognostic relevance.

Keller K, Tesche C, Gerhold-Ay A, Nickels S, ... Konstantinides SV, Lankeit M
Background
While the importance of patients\' quality of life (QoL) in chronic cardiac or pulmonary disease is uncontroversial, the burden of an acute pulmonary embolism (PE) on QoL has received little attention thus far.
Objectives
We aimed to validate the German PEmb-QoL questionnaire, identify associations between QoL and clinical/functional parameters, and investigate the prognostic relevance of QoL for long-term survival in survivors of an acute PE episode.
Patients/methods
Patients were invited for a clinical follow-up visit including assessment of QoL using the German PEmb-QoL questionnaire 6 months after an objectively confirmed PE at a single center. Internal consistency reliability, construct-related validity, and regressions between PEmb-QoL and clinical patient-characteristics were assessed using standard scale construction techniques.
Results
Overall, 101 patients [median age, 69 ([interquartile range] IQR 57-75) years; women, 48.5%] were examined 208 (IQR 185-242) days after PE. Internal consistency reliability and construct-related validity of the PEmb-QoL questionnaire were acceptable. As many as 47.0% of patients reported dyspnea, 27.5% had right ventricular (RV) dysfunction on transthoracic echocardiography (TTE), and 25.3% were diagnosed with post-PE impairment (PPEI) at 6-month follow-up. Furthermore, 15.9% of patients were diagnosed with depression 6 months after an acute PE. The QoL was affected by dyspnea, preexisting pulmonary disease, and PPEI, and a reduced QoL was associated with an increased risk for long-term mortality after an observation period of 3.6 years.
Conclusions
The German PEmb-QoL questionnaire is a reliable instrument for assessing QoL 6 months after PE. The QoL was affected by dyspnea, preexisting pulmonary disease, and PPEI and was associated with long-term mortality.

© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 30 Oct 2019; 17:1923-1934
Keller K, Tesche C, Gerhold-Ay A, Nickels S, ... Konstantinides SV, Lankeit M
J Thromb Haemost: 30 Oct 2019; 17:1923-1934 | PMID: 31344319
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Abstract

Heart Failure in Ischemic Stroke: Relevance for Acute Care and Outcome.

Siedler G, Sommer K, Macha K, Marsch A, ... Schwab S, Kallmünzer B

Background and Purpose- Heart failure (HF) in patients with acute ischemic stroke constitutes the source of various detrimental pathophysiologic mechanisms including prothrombotic and proinflammatory states, worsening of cerebral tissue oxygenation, and hemodynamic impairment. In addition, HF might affect the safety and efficacy of the acute recanalization stroke therapies. Methods- Patients treated with intravenous recombinant tissue-type plasminogen activator or mechanical recanalization at a universitary stroke center were included into a prospective registry. Patients received cardiological evaluation, including echocardiography, during acute care. Functional outcome was assessed after 90 days by structured telephone interviews. Safety and efficacy of intravenous thrombolysis and mechanical thrombectomy were investigated among patients with HF and compared with patients with normal cardiac function after propensity score matching. Results- One thousand two hundred nine patients were included. HF was present in 378 patients (31%) and an independent predictor of unfavorable functional outcome. Recanalization rates were equal among patients with HF after intravenous thrombolysis and after mechanical recanalization or combined treatment. The rate of secondary intracranial hemorrhage was not different (7% versus 8%; =0.909 after thrombolysis and 15% versus 20%, =0.364 after mechanical recanalization or combined therapy). Early mortality within 48 hours after admission was equal (<1.5% in both groups). Conclusions- In this real-world cohort of patients with stroke, HF was an independent predictor of unfavorable functional long-term outcome, while the safety and efficacy of intravenous thrombolysis and mechanical recanalization appeared unaffected.



Stroke: 26 Sep 2019:STROKEAHA119026139; epub ahead of print
Siedler G, Sommer K, Macha K, Marsch A, ... Schwab S, Kallmünzer B
Stroke: 26 Sep 2019:STROKEAHA119026139; epub ahead of print | PMID: 31558143
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Abstract

Sustained Monomorphic Ventricular Tachycardia in Nonischemic Heart Disease: Arrhythmia-Substrate Correlations That Inform the Approach to Ablation.

Kanagasundram A, John RM, Stevenson WG

As the population of patients with implanted defibrillators has grown, an increasing number of patients nonischemic cardiomyopathies are requiring therapy to reduce ventricular arrhythmias. Most of these arrhythmias are related to areas of ventricular scar. Although the pathophysiology of scar development is not well understood in these diseases, advances in cardiac imaging and mapping are better characterizing the scar locations that give rise to the arrhythmias. Here, we review the pathophysiologic and electrocardiographic correlations that inform ablation strategies for ventricular tachycardia in these diseases.



Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007312
Kanagasundram A, John RM, Stevenson WG
Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007312 | PMID: 31661970
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Abstract

Effect of Heart Rate Variability on the Association Between the Apnea-Hypopnea Index and Cerebral Small Vessel Disease.

Del Brutto OH, Mera RM, Costa AF, Castillo PR

Background and Purpose- The apnea-hypopnea index (AHI) is associated with cerebral small vessel disease (cSVD), but pathogenesis of this association is elusive. We aimed to assess the effect of nighttime heart rate variability (HRV)-as a proxy of sympathetic upregulation-on the aforementioned association. Methods- Atahualpa residents aged ≥60 years undergoing brain magnetic resonance imaging, polysomnography, and 24-hour Holter monitoring (N=176) were included. The presence of moderate-to-severe white matter hyperintensities, deep cerebral microbleeds, lacunar infarcts, and >10 enlarged basal ganglia perivascular spaces were added for estimating the cSVD score. Interaction models were fitted to assess the effect modification of nighttime HRV in the association between the AHI and the cSVD score, and mediation analysis was utilized to assess the proportion of total effect by nighttime HRV on this association. Results- Generalized linear models showed a significant association between the AHI and the cSVD score (P=0.025), as well as a significant inverse association between nighttime HRV and the cSVD score (P=0.002), but no association between daytime HRV and the cSVD score (P=0.097). Interaction models showed a significant interaction of nighttime HRV on the association between AHI and the cSVD score (P=0.001), and mediation analysis found that the percent of total effect between AHI and cSVD score mediated by HRV was 30.8%. Predictive marginal means of the cSVD score were highly significant when the 10th percentile of nighttime HRV was compared across categories of 10th and 90th percentiles of the AHI (cSVD score margins, 0.61 [95% CI, 0.37-0.86] versus 1.67 [95% CI, 1.26-2.09]). Contour plots showed the effect of nighttime (but not daytime) HRV on the association between AHI and the cSVD score. Conclusions- This study shows an important effect of nighttime HRV on the association between the AHI and the cSVD score and provides further support for the role of sympathetic overactivity on this association.



Stroke: 30 Aug 2019; 50:2486-2491
Del Brutto OH, Mera RM, Costa AF, Castillo PR
Stroke: 30 Aug 2019; 50:2486-2491 | PMID: 31345136
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Abstract

Dietary Saturated Fat Promotes Arrhythmia by Activating NOX2 (NADPH Oxidase 2).

Joseph LC, Avula UMR, Wan EY, Reyes MV, ... Colecraft HM, Morrow JP
Background
Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism.
Methods
We investigated this hypothesis by feeding mice high-fat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks.
Results
We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high statured fat diet and resulted in less inducible ventricular tachycardia. High saturated fat diet activates CaMK (Ca/calmodulin-dependent protein kinase) in the heart, which contributes to abnormal calcium handling, promoting arrhythmia.
Conclusions
We conclude that NOX2 deletion or pharmacological inhibition prevents the arrhythmogenic effects of a high saturated fat diet, in part mediated by activation of CaMK. This work reveals a molecular mechanism linking cardiac metabolism to arrhythmia and suggests that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.



Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007573
Joseph LC, Avula UMR, Wan EY, Reyes MV, ... Colecraft HM, Morrow JP
Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007573 | PMID: 31665913
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Impact:
Abstract

Risk reduction and right heart reverse remodeling by upfront triple combination therapy in pulmonary arterial hypertension.

D\'Alto M, Badagliacca R, Argiento P, Romeo E, ... Golino P, Naeije R
Background
Combinations of therapies are currently recommended for the most severely ill patients with pulmonary arterial hypertension (PAH), and excellent results have been reported with triple upfront combination of these drugs. We evaluated the effects of this approach on right ventricular (RV) function and outcome in patients with severe PAH.
Methods
Twenty-one patients aged 44±15 years with newly diagnosed high-risk idiopathic PAH that was non-reversible by the inhalation of nitric oxide were treated upfront with a combination of ambrisentan, tadalafil and subcutaneous treprostinil between 2014 and 2018. Clinical evaluation, World Health Organization functional class, 6-min walk distance, biomarkers, echocardiography and right heart catheterization data were recorded at baseline and during follow-up.
Results
At a median follow-up of 2 years, all patients were still alive. The REVEAL score decreased from 10±1 to 5±1, right atrial pressure from 13±3 to 5±2 mmHg, mean pulmonary artery pressure from 60±9 to 42±5 mmHg, pulmonary vascular resistance (PVR) from 16.4±4.4 to 5.5±1.3 Wood units, NT-proBNP from 3379±1921 to 498±223 pg/mL and World Health Organization functional class from 3.4±0.5 to 2.0±0.4 (all p<0.001). Cardiac index increased from 1.8±0.3 to 3.5±0.8 L/min/m and 6-min walk distance from 158±130 to 431±66 m (both p<0.001). Echocardiography showed decreased right atrial and RV areas, improved left ventricular eccentricity index and increased fractional area change (all p<0.001) in proportion to treatment-induced decrease in PVR.
Conclusions
Triple upfront combination therapy with ambrisentan, tadalafil and subcutaneous treprostinil in severe non-reversible PAH is associated with considerable clinical and hemodynamic improvement and right heart reverse remodeling.

Copyright © 2019. Published by Elsevier Inc.

Chest: 25 Sep 2019; epub ahead of print
D'Alto M, Badagliacca R, Argiento P, Romeo E, ... Golino P, Naeije R
Chest: 25 Sep 2019; epub ahead of print | PMID: 31563498
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Impact:
Abstract

Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.

Karlsson T, Rask-Andersen M, Pan G, Höglund J, ... Ek WE, Johansson Å

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease, as well as all-cause, cardiovascular-specific and cancer-specific mortality. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.



Nat Med: 30 Aug 2019; 25:1390-1395
Karlsson T, Rask-Andersen M, Pan G, Höglund J, ... Ek WE, Johansson Å
Nat Med: 30 Aug 2019; 25:1390-1395 | PMID: 31501611
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Impact:
Abstract

Estimated Ventricular Size, Asthma Severity, and Exacerbations: The Severe Asthma Research Program III Cohort.

Ash SY, Sanchez-Ferrero GV, Schiebler ML, Rahaghi FN, ... San Jose Estepar R,
Background
Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size.
Methods
We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.
Results
Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations.
Conclusions
In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.
Trial registry
ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov.

Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chest: 11 Sep 2019; epub ahead of print
Ash SY, Sanchez-Ferrero GV, Schiebler ML, Rahaghi FN, ... San Jose Estepar R,
Chest: 11 Sep 2019; epub ahead of print | PMID: 31521672
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Impact:
Abstract

Assessment of the 2017 AHA/ACC/HRS Guideline Recommendations for Implantable Cardioverter-Defibrillator Implantation in Cardiac Sarcoidosis.

Kazmirczak F, Chen KA, Adabag S, von Wald L, ... Akçakaya M, Shenoy C
Background
Implantable cardioverter-defibrillators are used to prevent sudden cardiac death in patients with cardiac sarcoidosis. The most recent recommendations for implantable cardioverter-defibrillator implantation in these patients are in the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. These recommendations, based on observational studies or expert opinion, have not been assessed. We aimed to assess them.
Methods
We performed a large retrospective cohort study of patients with biopsy-proven sarcoidosis and known or suspected cardiac sarcoidosis that underwent cardiovascular magnetic resonance imaging. Patients were followed for a composite end point of significant ventricular arrhythmia or sudden cardiac death. The discriminatory performance of the Guideline recommendations was tested using time-dependent receiver operating characteristic analyses. The optimal cutoff for the extent of late gadolinium enhancement predictive of the composite end point was determined using the Youden index.
Results
In 290 patients, the class I and IIa recommendations identified all patients who experienced the composite end point during a median follow-up of 3.0 years. Patients meeting class I recommendations had a significantly higher incidence of the composite end point than those meeting class IIa recommendations. Left ventricular ejection fraction (LVEF) >35% with >5.7% late gadolinium enhancement on cardiovascular magnetic resonance imaging was as sensitive as and significantly more specific than LVEF >35% with any late gadolinium enhancement. Patients meeting 2 class IIa recommendations, LVEF >35% with the need for a permanent pacemaker and LVEF >35% with late gadolinium enhancement >5.7%, had high annualized event rates. Excluding 2 class IIa recommendations, LVEF >35% with syncope and LVEF >35% with inducible ventricular arrhythmia, resulted in improved discrimination for the composite end point.
Conclusions
We assessed the Guideline recommendations for implantable cardioverter-defibrillator implantation in patients with known or suspected cardiac sarcoidosis and identified topics for future research.



Circ Arrhythm Electrophysiol: 30 Aug 2019; 12:e007488
Kazmirczak F, Chen KA, Adabag S, von Wald L, ... Akçakaya M, Shenoy C
Circ Arrhythm Electrophysiol: 30 Aug 2019; 12:e007488 | PMID: 31431050
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Impact:
Abstract

Right ventricular-pulmonary arterial uncoupling in mild-to-moderate systemic hypertension.

Vriz O, Pirisi M, Bossone E, Fadl ElMula FEM, Palatini P, Naeije R
Background
Mild-to-moderate hypertension with preserved left ventricular (LV) function may be associated with right ventricular (RV) dysfunction and increased pulmonary vascular resistance (PVR).
Methods
The present study explored the adequacy of RV-pulmonary arterial (PA) coupling in 211 never-treated hypertensive patients (mean blood pressure, BP 112 ± 12 mmHg) and 246 controls (BP 93 ± 12 mmHg). They underwent a comprehensive transthoracic Doppler echocardiography, and RV-PA coupling was estimated by the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio (TAPSE/PASP).
Results
Compared with the controls, hypertensive patients had increased LV wall thickness and decreased trans-mitral E/A with only slight but significant increase in transmitral Doppler E wave to tissue Doppler mitral annulus e\' wave ratio (6.3 ± 1.9 vs. 5.8 ± 1. 5, P < 0.05). RV dimensions and indices of either systolic or diastolic function were not different. PASP was increased in the hypertensive patients (25 ± 7 vs. 21 ± 7 mmHg, P < 0.001), as was PVR estimated from the tricuspid regurgitation velocity to right ventricular outflow tract velocity ratio (1.7 ± 0.4 vs. 1.5 ± 0.5 Wood units, P < 0.001). The TAPSE/PASP ratio was decreased (1.08 ± 0.35 vs. 1.43 ± 0.67 mm/mmHg, P < 0.001). This difference was mainly driven by male hypertensive patients. At multivariable analysis, the only independent predictors of decreased TAPSE/PASP were age and blood pressure.
Conclusion
The TAPSE/PASP is markedly decreased in hypertension without heart failure, chiefly in men, with only slight increases in estimates of LV filling pressure or PVR, suggesting RV-PA uncoupling.



J Hypertens: 18 Sep 2019; epub ahead of print
Vriz O, Pirisi M, Bossone E, Fadl ElMula FEM, Palatini P, Naeije R
J Hypertens: 18 Sep 2019; epub ahead of print | PMID: 31568058
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Impact:
Abstract

The prognostic value of myocardial perfusion imaging in patients with type 2 myocardial infarction.

Colon CM, Marshell RL, Roth CP, Farag AA, Iskandrian AE, Hage FG
Objectives
The aim of this retrospective study is to evaluate the prognostic role of myocardial perfusion imaging (MPI) in patients with type 2 myocardial infarction (T2MI).
Background
T2MI is an increasingly common diagnosis in clinical practice. The management of this condition is controversial and the prognostic value of MPI has not been established in this setting.
Methods
We retrospectively studied T2MI patients who underwent vasodilator gated MPI within 90 days of T2MI at a single tertiary care institution in 2013. Abnormal myocardial perfusion was defined as the perfusion defect involving ≥ 5% of left ventricular (LV) myocardium. Abnormal LV ejection fraction (EF) was defined as < 50% by gated images. The primary outcome was a composite of death, myocardial infarction (other than index event) or coronary revascularization (CR).
Results
There were 234 patients (62 ± 14 years, 57% men) with T2MI (peak troponin 0.2 ng/ml, interquartile 0.1-1.4), of whom 136 (58%) had an abnormal MPI. During a median follow-up of 20 months, 155 patients (66%) had the primary outcome (39% death, 42% MI, 5% CR). An abnormal MPI was associated with an increased risk of the primary outcome with a hazard ratio of 1.56, 95%CI (1.12-2.18, P = .008) that remained statistically significant after multivariate adjustment (1.45, 95%CI (1.02-2.06, P = .04))).
Conclusions
Patients with T2MI are at high risk for death or cardiac events in the intermediate term. More than one-half of patients with T2MI have an abnormal MPI and this is associated with the increased risk of cardiac events during follow-up. Risk stratification with MPI after T2MI may identify patients who would benefit from aggressive risk reduction.



J Nucl Cardiol: 22 Oct 2019; epub ahead of print
Colon CM, Marshell RL, Roth CP, Farag AA, Iskandrian AE, Hage FG
J Nucl Cardiol: 22 Oct 2019; epub ahead of print | PMID: 31646467
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Impact:
Abstract

Associations of awake and asleep blood pressure and blood pressure dipping with abnormalities of cardiac structure: the Coronary Artery Risk Development in Young Adults study.

Bello NA, Jaeger BC, Booth JN, Abdalla M, ... Muntner P, Shimbo D
Objectives
To evaluate the associations of high awake blood pressure (BP), high asleep BP, and nondipping BP, determined by ambulatory BP monitoring (ABPM), with left ventricular hypertrophy (LVH) and geometry.
Methods
Black and white participants (n = 687) in the Coronary Artery Risk Development in Young Adults study underwent 24-h ABPM and echocardiography at the Year 30 Exam in 2015-2016. The prevalence and prevalence ratios of LVH were calculated for high awake SBP (≥130 mmHg), high asleep SBP (≥110 mmHg), the cross-classification of high awake and asleep SBP, and nondipping SBP (percentage decline in awake-to-asleep SBP < 10%). Odds ratios for abnormal left ventricular geometry associated with these phenotypes were calculated.
Results
Overall, 46.0 and 49.1% of study participants had high awake and asleep SBP, respectively, and 31.1% had nondipping SBP. After adjustment for demographics and clinical characteristics, high awake SBP was associated with a prevalence ratio for LVH of 2.79 [95% confidence interval (95% CI) 1.63-4.79]. High asleep SBP was also associated with a prevalence ratio for LVH of 2.19 (95% CI 1.25-3.83). There was no evidence of an association between nondipping SBP and LVH (prevalence ratio 0.70, 95% CI 0.44-1.12). High awake SBP with or without high asleep SBP was associated with a higher odds ratio of concentric remodeling and hypertrophy.
Conclusion
Awake and asleep SBP, but not the decline in awake-to-asleep SBP, were associated with increased prevalence of cardiac end-organ damage.



J Hypertens: 27 Aug 2019; epub ahead of print
Bello NA, Jaeger BC, Booth JN, Abdalla M, ... Muntner P, Shimbo D
J Hypertens: 27 Aug 2019; epub ahead of print | PMID: 31464800
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Impact:
Abstract

Association between reduced myocardial contraction fraction and cardiovascular disease outcomes: The Multi-Ethnic Study of Atherosclerosis.

Abdalla M, Akwo EA, Bluemke DA, Lima JAC, ... Maurer MS, Bertoni AG
Background
The myocardial contraction fraction (MCF: stroke volume to myocardial volume) is a volumetric measure of left ventricular myocardial shortening. We examined the relationship of MCF, measured by cardiac magnetic resonance imaging (cMRI), to incident cardiovascular (CV) events within the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
Participants (n = 5000, aged 45-84 years) underwent cMRI.
Primary outcome
CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease: CHD death, and stroke death).
Secondary outcomes
CHD and heart failure (HF) events. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for outcomes.
Results
There were 299 incident CVD, 188 CHD, and 151 HF events over 10.2 years. The lowest MCF quartile was associated with an increased risk for incident CVD [HR 2.42, CI: 1.58-3.72], CHD [HR 2.32, CI: 1.36-3.96] and HF events [HR 1.99, CI: 1.15-3.44]. In a model adjusted for demographics, CV risk factors, antihypertensive and lipid-lowering medication use, each standard deviation decrease in MCF was associated with incident CVD [HR 1.42, CI: 1.23-1.64], CHD [HR 1.40, CI: 1.17-1.67] and HF [HR 1.58, CI: 1.30-1.94]. In a subgroup analysis of participants with preserved ejection fraction and without left ventricular hypertrophy, the lowest MCF quartile and each standard deviation decrease in MCF was also associated with an increased risk for incident CVD in fully-adjusted analyses.
Conclusions
MCF is a novel measure that can be measured using cMRI. In this multi-ethnic cohort, MCF is a measure that can be used to predict incident CVD events.

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

Int J Cardiol: 14 Oct 2019; 293:10-16
Abdalla M, Akwo EA, Bluemke DA, Lima JAC, ... Maurer MS, Bertoni AG
Int J Cardiol: 14 Oct 2019; 293:10-16 | PMID: 31327521
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Impact:
Abstract

Women with coronary microvascular dysfunction and no obstructive coronary artery disease have reduced exercise capacity.

Bechsgaard DF, Hove JD, Suhrs HE, Bové KB, ... Gustafsson I, Prescott E
Background
Both coronary microvascular dysfunction (CMD) and reduced exercise capacity are associated with adverse cardiovascular prognosis. The association between CMD and cardiopulmonary exercise testing (CPET) derived exercise capacity in symptomatic individuals without obstructive coronary artery disease (CAD) is not clear. We investigated whether exercise capacity was reduced in women with angina, CMD and no obstructive CAD compared with sex-matched controls. Furthermore, we assessed the association between CMD and other CPET-derived variables.
Methods
All participants underwent transthoracic Doppler echocardiography of the left anterior descending artery with dipyridamole-induced vasodilation and CPET using ergometer cycle with an incremental test protocol.
Results
We included 99 women with angina and no obstructive CAD (patients) and 27 asymptomatic women (controls), age (mean ± standard deviation) 61 ± 10 and 58 ± 10 years, respectively. Patients had a higher burden of risk factors compared with controls, while the weekly physical activity level was comparable between the groups (p = 0.72). CMD was present in 27 (27%) patients and 5 (19%) controls. Peak VO was significantly reduced in patients with CMD compared with controls with normal coronary microvascular function ((median (IQR) 17.3 (15.5-21.3) vs. 27.3 (21.6-30.8) ml/kg/min; age-adjusted p = 0.001), independent of cardiovascular risk factors (p = 0.041). Presence of CMD in symptomatic women was also associated with diminished heart rate reserve (p < 0.001) and blunted heart rate recovery.
Conclusions
Women with angina, CMD and no obstructive CAD have markedly reduced exercise capacity compared with sex-matched controls. Moreover, combination of angina and CMD is associated with impaired heart rate response and heart rate recovery.

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

Int J Cardiol: 14 Oct 2019; 293:1-9
Bechsgaard DF, Hove JD, Suhrs HE, Bové KB, ... Gustafsson I, Prescott E
Int J Cardiol: 14 Oct 2019; 293:1-9 | PMID: 31345648
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Impact:
Abstract

Spatial Accuracy of a Clinically Established Noninvasive Electrocardiographic Imaging System for the Detection of Focal Activation in an Intact Porcine Model.

Hohmann S, Rettmann ME, Konishi H, Borenstein A, ... Newman LK, Packer DL
Background
Noninvasive electrocardiographic imaging (ECGi) is used clinically to map arrhythmias before ablation. Despite its clinical use, validation data regarding the accuracy of the system for the identification of arrhythmia foci is limited.
Methods
Nine pigs underwent closed-chest placement of endocardial fiducial markers, computed tomography, and pacing in all cardiac chambers with ECGi acquisition. Pacing location was reconstructed from biplane fluoroscopy and registered to the computed tomography using the fiducials. A blinded investigator predicted the pacing location from the ECGi data, and the distance to the true pacing catheter tip location was calculated.
Results
A total of 109 endocardial and 9 epicardial locations were paced in 9 pigs. ECGi predicted the correct chamber of origin in 85% of atrial and 92% of ventricular sites. Lateral locations were predicted in the correct chamber more often than septal locations (97% versus 79%, =0.01). Absolute distances in space between the true and predicted pacing locations were 20.7 (13.8-25.6) mm (median and [first-third] quartile). Distances were not significantly different across cardiac chambers.
Conclusions
The ECGi system is able to correctly identify the chamber of origin for focal activation in the vast majority of cases. Determination of the true site of origin is possible with sufficient accuracy with consideration of these error estimates.



Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007570
Hohmann S, Rettmann ME, Konishi H, Borenstein A, ... Newman LK, Packer DL
Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007570 | PMID: 31707808
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Impact:
Abstract

Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans.

Cacheux M, Strauss B, Raad N, Ilkan Z, ... Hulot JS, Akar FG
Background
STIM1 (stromal interaction molecule 1) is a calcium (Ca) sensor that regulates cardiac hypertrophy by triggering store-operated Ca entry. Because STIM1 binding to phospholamban increases sarcoplasmic reticulum Ca load independent of store-operated Ca entry, we hypothesized that it controls electrophysiological function and arrhythmias in the adult heart.
Methods
Inducible myocyte-restricted STIM1-KD (STIM1 knockdown) was achieved in adult mice using an αMHC (α-myosin heavy chain)-MerCreMer system. Mechanical and electrophysiological properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen-induced STIM1-Cre (STIM1-KD) and littermate controls for STIM1 (referred to as STIM1-Ctl) and for Cre without STIM deletion (referred to as Cre-Ctl).
Results
STIM1-KD mice (N=23) exhibited poor survival compared with STIM1-Ctl (N=22) and Cre-Ctl (N=11) with >50% mortality after only 8-days of cardiomyocyte-restricted STIM1-KD. STIM1-KD but not STIM1-Ctl or Cre-Ctl hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing-induced ventricular tachycardia/ventricular fibrillation (VT/VF). Examination of the electrophysiological substrate revealed decreased conduction velocity and increased AP duration (APD) heterogeneity in STIM1-KD. These features, however, were comparable in VT/VF(+) and VT/VF(-) hearts. We also uncovered a marked increase in the magnitude of APD alternans during rapid pacing, and the emergence of a spatially discordant alternans profile in STIM1-KD hearts. Unlike conduction velocity slowing and APD heterogeneity, the magnitude of APD alternans was greater (by 80%, <0.05) in VT/VF(+) versus VT/VF(-) STIM1-KD hearts. Detailed phase mapping during the initial beats of VT/VF identified one or more rotors that were localized along the nodal line separating out-of-phase alternans regions.
Conclusions
In an adult murine model with inducible and myocyte-specific STIM1 depletion, we demonstrate for the first time the regulation of spatially discordant alternans by STIM1. Early mortality in STIM1-KD mice is likely related to enhanced susceptibility to VT/VF secondary to discordant APD alternans.



Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007382
Cacheux M, Strauss B, Raad N, Ilkan Z, ... Hulot JS, Akar FG
Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007382 | PMID: 31726860
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Impact:
Abstract

Percutaneous occlusion of transseptal puncture-related free wall perforation at the coronary sinus with a ventricular septal occluder during left atrial appendage closure: A case report.

Bai Y, Zhang S, Qin YW, Zhao XX

Coronary sinus perforation is a life-threatening complication of transseptal puncture and needs to be repaired immediately. In this study, we report a case of a 74-year-old female patient with nonvalvular atrial fibrillation, who is a poor long-term anticoagulation candidate. During the manipulation of transseptal puncture, a perforation of the free right atrial wall at the coronary sinus ostium occurred, which was caused by the Brockenbrough needle and followed by the immediate advancement of an 8.5-French transseptal sheath. In consideration of the danger of cardiac tamponade after sheath removal, we decided to leave the 8.5-French sheath in the pericardial cavity. Then, we advanced a 6 mm ventricular septal occluder through the sheath. Finally, we achieved successful deployment of the device and closure of the perforation under the guidance of fluoroscopy and transthoracic echocardiography. Subsequently, the left atrial appendage orifice was occluded with a 21 mm Watchman device. This case illustrates that percutaneous device closure is feasible for inadvertent perforation of the free right atrial wall at the coronary sinus during transseptal puncture and should be considered as an alternative to surgery.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print
Bai Y, Zhang S, Qin YW, Zhao XX
Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print | PMID: 31696654
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Impact:
Abstract

Improvement in left ventricular function following higher-risk percutaneous coronary intervention in patients with ischemic cardiomyopathy.

Russo JJ, Prasad M, Doshi D, Karmpaliotis D, ... Moses JW, Kirtane AJ
Background
Surgical revascularization is associated with improved ventricular function and clinical outcomes among patients with ischemic cardiomyopathy. There are less extensive data on changes in ventricular function among patients with ischemic cardiomyopathy undergoing percutaneous coronary intervention (PCI). Accordingly, we sought to assess the extent and predictors of change in left ventricular ejection fraction (ΔLVEF) among patients undergoing hemodynamically-supported PCI.
Methods
We assessed ΔLVEF following hemodynamically-supported PCI (with Impella or intra-aortic balloon counterpulsation) among patients enrolled in the PROTECT II trial and cVAD registry. The ΔLVEF was compared among patients with paired echocardiography at baseline and at least 30 days of follow-up. Independent correlates of ΔLVEF (modeled continuously and with an absolute ΔLVEF≥5%) were assessed using multivariable models.
Results
Among the 689 patients with paired echocardiographic data included in the analysis, the mean LVEF improved from 24.8 ± 9.9% to 31.4 ± 13.3% after PCI, for a net increase of 6.5 ± 10.8% (p < .001). A total of 395 (57%) patients had ΔLVEF ≥ 5% following hemodynamically-supported PCI. The number of vessels treated was associated with ΔLVEF (ΔLVEF 5.5% with 1 vessel, 6.6% with 2 vessels, and 8.3% with 3 vessels, p for trend = .046). A lower baseline LVEF, absence of a history of congestive heart failure or aldosterone receptor antagonist use, and a greater number of vessels treated were independent correlates of LVEF improvement.
Conclusions
Among patients with severe left ventricular systolic dysfunction and paired echocardiographic assessments, an improvement in LVEF was observed following hemodynamically-supported PCI.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print
Russo JJ, Prasad M, Doshi D, Karmpaliotis D, ... Moses JW, Kirtane AJ
Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print | PMID: 31693292
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Impact:
Abstract

\"Between a rock and the mitral valve space\": Transcatheter mitral valve-in-valve implantation for paravalvular leak and refractory hemolysis complicated by circumflex coronary occlusion.

Adams HSL, Rajani R, Hildick-Smith D, Redwood S

Transcatheter mitral valve implantation (TMVI) is an emerging field in structural cardiology. A particularly difficult group to treat is high-risk patients requiring valve in mitral annular calcification (ViMAC) intervention, with overall poor procedural success and outcomes in recent registries. This case highlights an unusual complication of paravalvular regurgitation (PVL) through the uncovered stent frame of a balloon expandable transcatheter heart valve (THV) on the left ventricular side of the prosthesis, leading to mechanical hemolysis and subsequent anuric renal failure post a ViMAC procedure. Attempts to treat the PVL with an occlusion plug device were unsuccessful and led to left circumflex coronary occlusion secondary to mechanical compression of the vessel in the posterior mitral valve annulus, a previously unreported phenomenon. A repeat valve-in-valve procedure was performed to treat the PVL, and immediate angioplasty resolved the left circumflex occlusion. High-risk patients requiring TMVI pose multiple challenges to Heart Teams in the treatment of valve pathology. Optimal procedural planning, multimodality imaging, improved THVs, and the awareness of potential complications are fundamental in overcoming the learning curve of TMVI and improved outcome for patients requiring ViMAC.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print
Adams HSL, Rajani R, Hildick-Smith D, Redwood S
Catheter Cardiovasc Interv: 05 Nov 2019; epub ahead of print | PMID: 31696657
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Impact:
Abstract

Clinical Experience of Stereotactic Body Radiation For Refractory Ventricular Tachycardia in Advanced Heart Failure Patients.

Lloyd MS, Wight J, Schneider F, Hoskins M, ... Lerakis S, Higgins KA
Background
Stereotactic body radiation therapy (SBRT) has been shown to be effective in treating patients with refractory ventricular tachycardia.
Objective
We sought to describe outcomes for SBRT in advanced heart failure patients admitted for repeated ICD therapies who were refractory to standard treatments.
Methods
SBRT simulation, planning and treatments were performed using standard techniques with collaboration from a radiation oncologist, electrophysiologist and cardiac imaging specialist. Patients were treated with a single fraction 25 Gy while awake. Efficacy was assessed by total durations in seconds of ventricular tachycardia, frequency of anti-tachycardia pacing (ATP), and the quantity of shocks before and after treatment as recorded by implantable cardioverter-defibrillators (ICDs).
Results
A total of 10 patients (mean age 61, 3 female) were included. Etiologies of heart failure were ischemic in 40% (4/10) and nonischemic in 60% (6/10). Among 8 patients with available ICD data, the total reduction in seconds of detected VT was 69% (pre-treatment 1065 seconds/month vs. post-treatment 332 seconds/month). The total reduction in ATP sequences was 48% (17.3 pre-treatment and 8.9 post-treatment). Reduction in total ICD shocks after SBRT was 68% (2.9 shocks/month pre-treatment and 0.9 shocks/month post treatment). When excluding a single non-responder, there was a significant reduction in VT seconds (94%, p = 0.04) and a trend towards ICD shock reduction (90%, p = 0.07) post SBRT.
Conclusions
Noninvasive treatment with SBRT was feasible and modestly effective at reducing VT burden in the critically ill. This suggests that SBRT treatment may be a useful palliation for electrical storm.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 30 Sep 2019; epub ahead of print
Lloyd MS, Wight J, Schneider F, Hoskins M, ... Lerakis S, Higgins KA
Heart Rhythm: 30 Sep 2019; epub ahead of print | PMID: 31585181
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Abstract

Imaging of Sub-Endocardial Adipose Tissue and Fiber Orientation Distributions in the Human Left Atrium using Optical Coherence Tomography.

Lye TH, Marboe CC, Hendon CP
Background
Optical coherence tomography (OCT) has the potential to provide real-time imaging guidance for atrial fibrillation ablation, with promising results for lesion monitoring. OCT can also offer high-resolution imaging of tissue composition, but there is insufficient cardiac OCT data to inform the use of OCT to reveal important tissue architecture of the human left atrium. Thus, the objective of this study was to define OCT imaging data throughout the human left atrium, focusing on the distribution of adipose tissue and fiber orientation as seen from the endocardium.
Methods and results
Human hearts (n=7) were acquired for imaging the left atrium with OCT. A spectral-domain OCT system with 1325 nm center wavelength, 6.5 μm axial resolution, 15 μm lateral resolution, and a maximum imaging depth of 2.51 mm in air was used. Large-scale OCT image maps of human left atrial tissue were developed, with adipose thickness and fiber orientation extracted from the imaging data. OCT imaging showed scattered distributions of adipose tissue around the septal and pulmonary vein regions, up to a depth of about 0.43 mm from the endocardial surface. The total volume of adipose tissue detected by OCT over one left atrium ranged from 1.42 mm to 28.74 mm . Limited fiber orientation information primarily around the pulmonary veins and the septum could be identified.
Conclusion
OCT imaging could provide adjunctive information on the distribution of sub-endocardial adipose tissue, particularly around thin areas around the pulmonary veins and septal regions. Variations in OCT-detected tissue composition could potentially assist ablation guidance. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 28 Oct 2019; epub ahead of print
Lye TH, Marboe CC, Hendon CP
J Cardiovasc Electrophysiol: 28 Oct 2019; epub ahead of print | PMID: 31661178
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Abstract

Regadenoson Stress Perfusion Cardiac Magnetic Resonance Imaging in Children With Kawasaki Disease and Coronary Artery Disease.

Doan TT, Wilkinson JC, Loar RW, Pednekar AS, Masand PM, Noel CV

Coronary artery (CA) stenosis and occlusion in convalescent Kawasaki disease (KD) is progressive and may result in myocardial infarction. The use of regadenoson, a strong selective CA vasodilator with low side effect profile, for stress cardiac magnetic resonance (CMR) imaging has not been studied in children with KD. The safety, feasibility, and diagnostic utility of regadenoson stress CMR was assessed in children with KD and CA abnormalities. A retrospective review of regadenoson stress CMR in children with convalescent KD was performed. Hemodynamics changes after regadenoson administration and adverse effects were recorded. First-pass perfusion was evaluated at rest and during pharmacologic stress. The results were compared with anatomic CA imaging. Forty-one stress CMR (18 sedated examinations, 44%) were performed successfully in 32 patients. Median age was 11.2 years (range 2.2 to 18.6) and weight 41 kg (range 13 to 93.4). Heart rate increased 66 ± 25% (p <0.005) after regadenoson. Minor adverse events occurred in 6 sedated and 1 unsedated patients. Hypoperfusion during stress occurred in 16 of 41 (39%), including 5 inducible, 9 inducible and fixed, and 2 fixed lesions. Late gadolinium enhancement was present in 10 of 16 with hypoperfusion and in 1 without hypoperfusion. Stress CMR had 100% positive agreement and >90% negative and overall agreement with moderate-to-severe CA stenoses. Four patients with hypoperfusion underwent revascularization for severe CA stenoses. In conclusion, regadenoson stress CMR is hemodynamically safe and feasible in children with KD and CA disease. It has excellent agreement with CA angiography and aided decision-making to proceed with revascularization.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Sep 2019; 124:1125-1132
Doan TT, Wilkinson JC, Loar RW, Pednekar AS, Masand PM, Noel CV
Am J Cardiol: 30 Sep 2019; 124:1125-1132 | PMID: 31371063
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Abstract

Automated Intraprocedural Localization of Origin of Ventricular Activation Using Patient-Specific Computerized Tomography Imaging.

Zhou S, Sapp JL, Horáček BM, Warren JW, ... MacIntyre CJ, AbdelWahab A
Background
To facilitate catheter ablation of VT, we have previously developed an automated method to identify sources of LV activation in real time using 12-lead ECG, the accuracy of which depends on acquisition of a complete electroanatomic (EA) map.
Objective
To assess feasibility of using a registered cardiac CT rather than EA map to permit real-time localization and avoid errors introduced by incomplete maps.
Methods
Prior to LV VT ablation, 10 patients had CT imaging and 3D reconstruction of the cardiac surface to create a triangle mesh surface, which was registered to the EA map during the procedure and imported into the custom localization software. The software uses QRS integrals from leads III, V2, V6, derives personalized regression coefficients from pacing at ≥5 sites with known locations, and estimates location of unknown activation sites on the 3D patient-specific LV endocardial surface. Localization accuracy was quantified for VT-exit sites in millimeters by comparing the calculated against the known locations.
Results
The VT-exit site was identified for 20 VTs using activation and entrainment mapping, supplemented by pace-mapping at the scar margin. The automated localization software achieved incremental accuracy with additional pacing sites and had a mean localization error of 6.9 ± 5.7 mm for the 20 VTs.
Conclusions
Patient-specific CT geometry is feasible for use in real-time automated localization of ventricular activation and may avoid reliance on a complete electroanatomic map.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 24 Oct 2019; epub ahead of print
Zhou S, Sapp JL, Horáček BM, Warren JW, ... MacIntyre CJ, AbdelWahab A
Heart Rhythm: 24 Oct 2019; epub ahead of print | PMID: 31669770
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Abstract

Contemporary epidemiology of infective endocarditis in patients with congenital heart disease: A UK prospective study.

Cahill TJ, Jewell PD, Denne L, Franklin RC, ... Orchard E, Prendergast BD
Objectives
Infective endocarditis is a life-threatening complication of congenital heart disease (CHD), but there are few studies concerning the contemporary risk profile, preceding invasive procedures and outcomes in this patient population. The aim of this study was to investigate the epidemiology of infective endocarditis (IE) in patients with CHD.
Methods
Cases of IE in children and adults with CHD were prospectively recorded as part of the UK National Institute for Cardiovascular Outcomes Research (NICOR) National Congenital Heart Disease Audit. Patients were entered into the database between April 2008 and March 2016.
Results
Eight hundred episodes of IE were recorded in 736 patients with CHD. Sixty-five patients (9%) were infants (aged <1 year), 235 (32%) were children (aged 1-15 years), and 436 (59%) were adults (aged >15 years). The most common diagnoses were Tetralogy of Fallot (n = 150, 22.8%), ventricular septal defect (n = 129, 19.6%) and bicuspid aortic valve (n = 70, 10.7%). Dental procedures preceded 67 of 635 episodes (11%) of IE, and non-dental invasive procedures preceded 177 of 644 episodes (27.4%). The most common causative organisms were streptococci, accounting for 40% of cases. Overall in-hospital mortality was 6.7%. On multivariable analysis, adverse factors associated with in-hospital mortality were staphylococcal infection and presence of an underlying atrioventricular septal defect.
Conclusions
Infective endocarditis in patients with CHD is an ongoing clinical challenge. In contemporary practice in tertiary congenital centers, 1 of 15 patients do not survive to hospital discharge. Streptococci remain the most common causative organism, and antecedent dental or medical procedures were undertaken in a significant minority in the 3 months before diagnosis. The presence of an atrioventricular septal defect or staphylococcal infection is associated with significantly increased risk of early mortality.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am Heart J: 30 Aug 2019; 215:70-77
Cahill TJ, Jewell PD, Denne L, Franklin RC, ... Orchard E, Prendergast BD
Am Heart J: 30 Aug 2019; 215:70-77 | PMID: 31299559
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Abstract

Risk Stratification in Patients with Frequent Premature Ventricular Complexes in the Absence of Known Heart Disease.

Ghannam M, Siontis KC, Kim MH, Cochet H, ... Morady F, Bogun F
Background
Frequent premature ventricular complexes (PVCs) can be an indicator of structural heart disease.
Objective
The objective of this study was to determine the prevalence of scarring detected by cardiac magnetic resonance imaging (DE-CMR) in patients with frequent PVCs without apparent structural heart disease and to determine the value of programmed ventricular stimulation for risk stratification in patients with frequent PVCs and myocardial scarring.
Methods
DE-CMR imaging was performed in patients without apparent heart disease who had frequent PVCs and who were referred for ablation. In the presence of scarring, scar volume was measured and correlated with outcome variables. All patients underwent programmed ventricular stimulation (PVS) and were monitored for the occurrence of ventricular arrhythmias (VAs). Logistic regression was used to compare imaging and procedural findings with long term outcomes with adjustment for post-ablation ejection fraction (EF) Results: The study consisted of 272 patients (135 males, mean age: 52±15 years, EF: 52±12%). DE-CMR scar was found in 67 (25%) patients and 7(3%) were found to have inducible ventricular tachycardia (VT). The presence and amount of DE-CMR was related to the risk of long term VT independent of EF (HR 18.8(2.0-176.6], P=0.01 and HR 1.4[1.1-1.7]/cm scar, p<0.001, respectively). The positive predictive value and negative predictive value of PVS for VT during long-term follow-up were 71% and 100% respectively.
Conclusion
Preprocedural cardiac DE-CMR and programmed ventricular stimulation can be used to identify patients with frequent PVCs without apparent heart disease who are at risk of VT.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 29 Sep 2019; epub ahead of print
Ghannam M, Siontis KC, Kim MH, Cochet H, ... Morady F, Bogun F
Heart Rhythm: 29 Sep 2019; epub ahead of print | PMID: 31580899
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Abstract

Determining the impact of Benzathine penicillin G prophylaxis in children with latent rheumatic heart disease (GOAL trial): Study protocol for a randomized controlled trial.

Beaton A, Okello E, Engelman D, Grobler A, ... Sable C, Steer A

Rheumatic heart disease (RHD) remains a high prevalence condition in low- and middle-income countries. Most individuals with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Echocardiographic screening can detect latent RHD, but the impact of secondary prophylaxis in screen-detected individuals is not known.
Methods/design
This trial aims to determine if secondary prophylaxis with every-4-week injectable Benzathine penicillin G (BPG) improves outcomes for children diagnosed with latent RHD. This is a randomized controlled trial in consenting children, aged 5 to 17 years in Northern Uganda, confirmed to have borderline RHD or mild definite RHD on echocardiography, according to the 2012 World Heart Federation criteria. Qualifying children will be randomized to every-4-week injectable intramuscular BPG or no medical intervention and followed for a period of 2 years. Ongoing intervention adherence and retention in the trial will be supported through the establishment of peer support groups for participants in the intervention and control arms. A blinded echocardiography adjudication panel consisting of four independent experts will determine the echocardiographic classification at enrollment and trajectory through consensus review. The primary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic progression of latent RHD compared to those in the control arm. The secondary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic regression of latent RHD compared to those in the control arm. A sample size of 916 participants will provide 90% power to detect a 50% relative risk reduction assuming a 15% progression in the control group. The planned study duration is from 2018-2021.
Discussion
Policy decisions on the role of echocardiographic screening for RHD have stalled because of the lack of evidence of the benefit of secondary prophylaxis. The results of our study will immediately inform the standard of care for children diagnosed with latent RHD and will shape, over 2-3 years, practical and scalable programs that could substantially decrease the burden of RHD in our lifetime.
Trial registration
ClinicalTrials.gov: NCT03346525. Date Registered: November 17, 2017.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am Heart J: 30 Aug 2019; 215:95-105
Beaton A, Okello E, Engelman D, Grobler A, ... Sable C, Steer A
Am Heart J: 30 Aug 2019; 215:95-105 | PMID: 31301533
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Abstract

Cardiac resynchronization therapy by left bundle branch area pacing in heart failure patients with left bundle branch block.

Zhang W, Huang J, Qi Y, Wang F, ... Zhou X, Li R
Background
Cardiac resynchronization therapy (CRT) via biventricular pacing has demonstrated clinical benefits in heart failure (HF) patients with ventricular dyssynchrony. Other approaches of CRT is little known.
Objective
The purpose of this study was to assess the feasibility, safety, and efficacy of left bundle branch area pacing (LBBAP) in HF patients with left bundle branch block (LBBB).
Methods
Eleven consecutive HF patients with reduced left ventricular ejection fraction and LBBB and indicated for CRT were recruited. LBBAP was achieved via transventricular septal approach and characterized by narrower QRS duration, shortened peak left ventricular activation time, and right bundle branch conduction delay on the electrocardiogram. Electrocardiogram, echocardiogram, and cardiac function were evaluated at baseline and follow-up. Interventricular mechanical delay and 3-dimensional tissue synchronization imaging during LBBAP and intrinsic LBBB status were measured by echocardiography at follow-up.
Results
LBBAP significantly shortened QRS duration (from native 180.00 ± 15.86 ms to 129.09 ± 15.94 ms; P < .01) and left ventricular activation time (from native 108.18 ± 15.54 ms to 80.91 ± 9.95 ms; P < .01). Interventricular mechanical delay and the standard deviation of tissue synchronization imaging of 12 left ventricular (LV) segments were significantly shorter during LBBAP than in intrinsic LBBB status (both with P < .01). At a mean follow-up period of 6.7 months, New York Heart Association functional class, plasma level of B-type natriuretic peptide, LV end-systolic diameter, and left ventricular ejection fraction were significantly improved (all with P < .05 vs baseline).
Conclusion
The study demonstrates that LBBAP is clinically feasible in patients with systolic HF and LBBB. LBBAP can be a new CRT technique to correct LBBB, provide ventricular synchrony, and improve clinical symptoms with LV reverse remodeling.

Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 08 Sep 2019; epub ahead of print
Zhang W, Huang J, Qi Y, Wang F, ... Zhou X, Li R
Heart Rhythm: 08 Sep 2019; epub ahead of print | PMID: 31513945
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Abstract

Danish study of Non-Invasive testing in Coronary Artery Disease 2 (Dan-NICAD 2): Study design for a controlled study of diagnostic accuracy.

Rasmussen LD, Winther S, Westra J, Isaksen C, ... Bøtker HE, Böttcher M
Background
Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICAs) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has 3 equivalent main aims: (1) To examine the diagnostic precision of a sound-based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. (2) To compare the diagnostic accuracy of 3T cardiac magnetic resonance imaging (3T CMRI), rubidium positron emission tomography (Rb-PET), and CT-derived fractional flow reserve (FFR) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. (3) To compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using Rb-PET as reference standard.
Methods
Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to coronary CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule out obstructive CAD, patients will be examined by 3T CMRI Rb-PET, FFR, ICA, and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90% diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion.
Discussion
The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in 3 different steps: risk stratification prior to coronary CTA, diagnostic strategy after coronary CTA, and invasive wireless QFR analysis as an alternative to ICA-FFR.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am Heart J: 30 Aug 2019; 215:114-128
Rasmussen LD, Winther S, Westra J, Isaksen C, ... Bøtker HE, Böttcher M
Am Heart J: 30 Aug 2019; 215:114-128 | PMID: 31323454
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Abstract

Accumulation of coronary risk factors is associated with progression of mitral annular calcification in patients undergoing dialysis therapy: A long-term follow-up study.

Usuku H, Yamamoto E, Arima Y, Takashio S, ... Matsui H, Tsujita K
Background
In patients undergoing dialysis therapy, mitral annular calcification (MAC) is a powerful predictor of cardiovascular events and all-cause mortality. However, there is little data on predictors for MAC progression in patients undergoing dialysis therapy.
Methods and results
We retrospectively analyzed 98 hemodialysis-dependent patients in Japanese Red Cross Kumamoto Hospital who underwent routine transthoracic echocardiography (TTE) in 2017. Three patients with history of surgical valve replacement or severe valvular heart diseases were excluded. In the 95 enrolled patients, MAC was detected by TTE in 28 patients (29%). A multivariate logistic regression analysis revealed that duration of hemodialysis therapy was independently associated with presence of MAC (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.02-1.16; p < 0.01). Among the 95 patients, 72 patients also underwent routine TTE 5 years previously in 2012. In these patients, progression of MAC from 2012 to 2017 was observed in 11 patients (15%). A multivariate logistic regression analysis revealed that number of coronary risk factors (OR: 2.67; 95% CI: 1.24-5.76; p = 0.01), baseline MAC diameter (OR: 1.23; 95% CI: 1.05-1.45; p = 0.01), and left atrial diameter (OR: 0.81; 95% CI: 0.68-0.95; p = 0.01) were significantly associated with progression of MAC.
Conclusions
Accumulation of coronary risk factors was associated with progression of MAC in patients undergoing dialysis. Management of coronary risk factors may be important for inhibition of MAC progression.

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

Int J Cardiol: 14 Oct 2019; 293:248-253
Usuku H, Yamamoto E, Arima Y, Takashio S, ... Matsui H, Tsujita K
Int J Cardiol: 14 Oct 2019; 293:248-253 | PMID: 31160076
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Abstract

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

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

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



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

Impact of Tricuspid Regurgitation in Patients With Heart Failure and Mitral Valve Disease from a Nationwide Cohort Study.

Kadri AN, Gajulapalli RD, Sammour YM, Chahine J, ... Harb SC, Kapadia S

Concomitant heart failure (HF) and mitral valve disease (MVD) portend significant morbidity and mortality. Although associated Tricuspid regurgitation (TR) is a common occurrence in this scenario, it is not well known whether there are additional prognostic implications. We sought to assess whether coexistent TR is associated with higher readmission rates or increased mortality in patients with HF and MVD. We identified 1,520,871 encounters with a primary diagnosis of HF in the 2013 to 2014 Nationwide Readmission Database. We excluded patients without MVD, patients <18 years old, those with rheumatic heart disease and infective endocarditis. We also excluded patients who were discharged in December, hospital transfers, and cases where follow-up or outcomes were missing. Logistic regression was used to evaluate the association between baseline characteristics (including the presence of tricuspid valve disease), mortality as well as 30-day readmission rates. A total of 221,127 admissions with HF and MVD were identified. Median age was 79 years (IQR, 67 to 87), 55% were female, 2.7% died during hospitalization, and the 30-day readmission rate was 20.3%. Nearly 1/3 had concomitant TR (n = 78,356, 35%). The presence of TR was neither associated with elevated risk of mortality (hazard ratio 0.98, 95% confidence interval 0.93 to 1.04) nor 30-day readmission rate (odds ratio 1.01, 95% confidence interval 0.98 to 1.03). HF accounted for 33% of 30-day readmissions, while combined cardiac causes accounted for 54%. In conclusion concomitant TR in patients with HF and MVD was not associated with worse short-term outcomes in terms of inpatient hospital mortality and 30-day readmission rates.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Sep 2019; 124:926-931
Kadri AN, Gajulapalli RD, Sammour YM, Chahine J, ... Harb SC, Kapadia S
Am J Cardiol: 14 Sep 2019; 124:926-931 | PMID: 31331634
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Abstract

Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium.

Jiang L, Li L, Ruan Y, Zuo S, ... Liu N, Ma CS
Background
Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear.
Objective
The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms.
Methods
In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca handling and action potentials in atrial myocytes were evaluated.
Results
Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca handling disorders in atrial myocytes, such as reduced Ca transient amplitude, enhanced spontaneous Ca release, and reduced sarcoplasmic Ca capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17.
Conclusion
The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca handling disorders in the atrium.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 30 Aug 2019; 16:1374-1382
Jiang L, Li L, Ruan Y, Zuo S, ... Liu N, Ma CS
Heart Rhythm: 30 Aug 2019; 16:1374-1382 | PMID: 30959203
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Abstract

Usefulness of Blunted Heart Rate Reserve as an Imaging-Independent Prognostic Predictor During Dipyridamole Stress Echocardiography.

Cortigiani L, Carpeggiani C, Landi P, Raciti M, Bovenzi F, Picano E

A blunted heart rate (HR) response during dipyridamole myocardial perfusion imaging has been associated with a poor outcome. To assess the value of HR response in patients who underwent high-dose dipyridamole stress echocardiography (SE), we retrospectively selected a sample of 3,059 patients (none with pacemakers or atrial fibrillation; mean age 66 ± 11 years). All underwent high-dose (0.84 mg/kg) dipyridamole SE for evaluation of known or suspected coronary artery disease and/or heart failure in 2 laboratories of Pisa-IFC and Lucca. HR (with 12-lead ECG) was obtained each minute and recorded at rest and peak stress. HR reserve (HRR) was calculated as the peak/rest HR ratio. All patients were followed up. Patients were randomly divided into the modeling and validation group of equal size. During a median follow-up time of 1,004 days, 321 hard events occurred: 231 deaths and 90 nonfatal myocardial infarctions. HRR ≤ 1.22 identified by receiver operating characteristic analysis in the modeling group was an independent predictor of infarction-free survival in the modeling (hazard ratio 1.83, 95% confidence interval [CI] 1.30 to 2.60, p = 0.001), in the validation (hazard ratio 1.47, 95% CI 1.08 to 2.01, p = 0.02), and in the overall group (hazard ratio 1.60, 95% CI 1.27 to 2.02, p <0.0001), either off- or on-β blockers. Five-year event rate increased from 8% to 24 % from the highest (≥1.41) to the lowest (≤1.14) HRR quartile. In conclusion, blunted HRR is a useful nonimaging predictor of adverse events during high-dose dipyridamole SE, independent of inducible ischemia, and beta-blocker therapy.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Sep 2019; 124:972-977
Cortigiani L, Carpeggiani C, Landi P, Raciti M, Bovenzi F, Picano E
Am J Cardiol: 14 Sep 2019; 124:972-977 | PMID: 31324358
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Abstract

A Practical Guide to Assess the Reproducibility of Echocardiographic Measurements.

Bunting KV, Steeds RP, Slater LT, Rogers JK, Gkoutos GV, Kotecha D

Echocardiography plays an essential role in the diagnosis and assessment of cardiovascular disease. Measurements derived from echocardiography are also used to determine the severity of disease, its progression over time, and to aid in the choice of optimal therapy. It is therefore clinically important that echocardiographic measurements be reproducible, repeatable, and reliable. There are a variety of statistical tests available to assess these parameters, and in this article the authors summarize those available for use by echocardiographers to improve their clinical practice. Correlation coefficients, linear regression, Bland-Altman plots, and the coefficient of variation are explored, along with their limitations. The authors also provide an online tool for the easy calculation of these statistics in the clinical environment (www.birmingham.ac.uk/echo). Quantifying and enhancing the reproducibility of echocardiography has important potential to improve the value of echocardiography as the basis for good clinical decision-making.

Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 21 Oct 2019; epub ahead of print
Bunting KV, Steeds RP, Slater LT, Rogers JK, Gkoutos GV, Kotecha D
J Am Soc Echocardiogr: 21 Oct 2019; epub ahead of print | PMID: 31653530
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Abstract

Usefulness of 3-Tesla Cardiac Magnetic Resonance to Detect Mitral Annular Disjunction in Patients With Mitral Valve Prolapse.

Essayagh B, Iacuzio L, Civaia F, Avierinos JF, Tribouilloy C, Levy F

Mitral annulus disjunction (MAD) is characterized by a separation between the atrial wall mitral junction and the left ventricular (LV) free wall. Little is known regarding cardiac magnetic resonance (CMR) performance to detect MAD and its prevalence in mitral valve prolapse (MVP). Based on 89 MVP patients (63 women; mean age 64 ± 13) referred for CMR assessment of MR, either from myxomatous mitral valve disease (MMVP) (n = 40; 45%) or fibroelastic disease (n = 49; 55%), we sought to assess the frequency of MAD and its consequences on LV morphology. Patients were classified in 2 groups according to MAD presence (MAD+) or absence (MAD-). MAD (measuring 8 ± 4 mm) was diagnosed in 35% (31 of 89) of MVP patients, more frequently in MMVP than fibroelastic disease (60% vs 14%). MAD+ was associated with MMVP; bileaflet MVP and nonsustain ventricular tachycardia but not with the severity of MR. Diagnostic accuracy of transthoracic echocardiography for the detection of MAD was fair (65% sensitivity, 96% specificity) with CMR as reference. MAD+ showed significantly enlarged basal and mid LV diameters and enlarged mitral-annulus diameter. In patients with late gadolinium enhancement, presence of LV fibrosis at level of papillary muscle was more frequent in MAD+. After adjustment on age and MR severity, MMVP, and enlarged end-systolic mitral annulus diameter were independently associated with MAD+. In conclusion, MAD was present in about 1/3 of MVP patients, mostly in MMVP and independent of MR severity. Enlarged mitral-annulus and basal LV diameters, nonsustain ventricular tachycardia and papillary muscle fibrosis were associated with MAD presence.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 09 Sep 2019; epub ahead of print
Essayagh B, Iacuzio L, Civaia F, Avierinos JF, Tribouilloy C, Levy F
Am J Cardiol: 09 Sep 2019; epub ahead of print | PMID: 31606191
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Abstract

Risk factors and localization of silent cerebral infarction in patients with atrial fibrillation.

Miki K, Nakano M, Aizawa K, Hasebe Y, ... Fukuda K, Shimokawa H
Background
It is important to identify the risk factors and localization of silent cerebral infarction (SCI), especially in younger patients with atrial fibrillation (AF).
Objective
The purpose of this study was to examine the characteristics and risk factors for SCI in AF patients, with particular attention to localization of SCI.
Methods
The study enrolled 286 consecutive neurologically asymptomatic patients who underwent AF ablation from January 2014 to July 2017 (age 61.7 ± 10.2 [SD] years; 208 male and 78 female). All patients underwent magnetic resonance imaging (MRI) before ablation.
Results
SCIs were classified independently by 2 radiologists as follows: cardiogenic SCI in 19 (10.6%), lacunar SCI in 13 (8.9%), undetermined causes in 6 (1.6%), and no SCI in 248 (controls, 78.7%). Importantly, no patients with CHADS-VASc score 0 had SCI on MRI. In univariable analysis, significant risk factors for lacunar SCI included age (P = .007), hypertension (P = .037), congestive heart failure (P = .040), left atrial (LA) diameter (P = .013), and cardio-ankle vascular index (P = .004). In multivariable analysis, significant risk factors for cardiogenic SCI were AF duration (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.00-1.02; P = .038), ankle-brachial pressure index (OR 0.002; 95% CI 0-0.68; P = .030), and LA abnormality (OR 8.99; 95% CI 2.78-31.00; P <.001), defined by the presence of spontaneous echo contrast and/or decreased LA appendage emptying velocity.
Conclusion
The study results indicate that among AF patients, SCIs localized in the cerebral cortex and cerebellum are frequently noted, for which cardiogenic mechanisms may be mainly involved; CHADS-VASc score could be useful for screening SCI; and LA abnormality is the specific marker for cardiogenic SCI, providing useful information for risk stratification of SCI.

Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 30 Aug 2019; 16:1305-1313
Miki K, Nakano M, Aizawa K, Hasebe Y, ... Fukuda K, Shimokawa H
Heart Rhythm: 30 Aug 2019; 16:1305-1313 | PMID: 30898584
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Abstract

Assessment and Implications of Right Ventricular Afterload in Tetralogy of Fallot.

Egbe AC, Taggart NW, Reddy YNV, Sufian M, ... Obokata M, Borlaug BA

Patients with tetralogy of Fallot (TOF) have abnormal right ventricular (RV) afterload because of residual or recurrent outflow tract obstruction, often with abnormal pulmonary artery (PA) vascular function. The purpose of this study was to determine if RV afterload was independently associated with death and/or heart transplant in patients with TOF. This is a retrospective study of TOF patients that underwent cardiac catheterization for clinical indications at Mayo clinic between 1990 and 2015. Invasively measured RV systolic pressure (RVSP) was used to define RV afterload. To explore clinical utility for echocardiographic estimates of invasive data, correlations between invasive and Doppler-derived indices of RV afterload were examined. Among 266 patients with TOF (age 35 ± 14 years, TOF-pulmonary atresia 117 [44%]), RVSP was 72 ± 28 mm Hg, PA systolic pressure 45 ± 19 mm Hg, mean PA pressure 27 ± 10 mm Hg, pulmonary vascular resistance 4.2 ± 3.1 WU, and PA wedge pressure 14 ± 5 mm Hg. Over a mean follow up of 12.9 years, there were 35 deaths and 4 heart transplants. Invasively measured RVSP (hazard ratio 1.25, 95% confidence interval 1.12 to 1.37; p <0.001) and TOF-pulmonary atresia (hazard ratio 1.18, 95% confidence interval 1.08 to 1.41; p = 0.023) were independent risk factors for death and/or transplant. Doppler-derived RVSP was well-correlated with invasive RVSP (r = 0.92, p <0.001), and was also independently associated with the combined end point. RVSP, a composite measure of RV afterload, is independently prognostic in patients with TOF, and can be reliably assessed using Doppler echocardiography. Further study is required to test whether interventions to reduce RVSP can improve outcomes in patients with TOF.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 08 Sep 2019; epub ahead of print
Egbe AC, Taggart NW, Reddy YNV, Sufian M, ... Obokata M, Borlaug BA
Am J Cardiol: 08 Sep 2019; epub ahead of print | PMID: 31586531
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Abstract

Role of extensive diagnostic workup in young athletes and nonathletes with complex ventricular arrhythmias.

Narducci ML, Pelargonio G, La Rosa G, Inzani F, ... Zeppilli P, Crea F
Background
Ventricular arrhythmias (VAs) are the most common cause of death in athletes. The differences in the electroanatomic substrate in athletes and nonathletes with complex VA are unknown.
Objective
The purpose of this study was to compare the electroanatomic substrate of complex VA in athletes vs nonathletes.
Methods
The study prospectively enrolled young athletes and nonathletes with VA. Patients underwent 2-dimensional echocardiography, cardiac magnetic resonance (CMR) imaging, coronary angiography, 3-dimensional electroanatomic mapping (3D-EAM), and 3D-EAM-guided endomyocardial biopsy (EMB). Follow-up included 24-hour electrocardiographic Holter or implantable cardioverter-defibrillator/loop recorder interrogation for VA recurrence.
Results
Thirty-three patients were enrolled: 18 competitive athletes (56%) and 15 nonathletes (44%). Left ventricular and right ventricular (RV) findings by echocardiography and CMR did not show structural disease. Nine athletes (50%) were asymptomatic compared to 1 nonathlete (7%; P <.05). Unifocal origin of VA was reported in 14 athletes (93%) and 17 nonathletes (94%). Athletes showed a larger RV unipolar than bipolar scar (18 ± 17 cm vs 3 ± 3.8 cm; P = .04). Diagnostic yield of EMB was 50% in athletes and 40% in nonathletes. Among athletes, the final diagnosis was myocarditis in 2, arrhythmogenic ventricular right cardiomyopathy in 1, and focal replacement fibrosis in 1. Among nonathletes, EMB revealed focal replacement fibrosis in 4 cases. At median follow-up of 18.7 months, Kaplan-Meier curves showed lower VA recurrence in detrained athletes than nonathletes (53% vs 6%; P = .02).
Conclusion
This study showed the need for extensive diagnostic workup in apparently healthy young patients with complex VA in order to characterize concealed cardiomyopathies.

Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 27 Aug 2019; epub ahead of print
Narducci ML, Pelargonio G, La Rosa G, Inzani F, ... Zeppilli P, Crea F
Heart Rhythm: 27 Aug 2019; epub ahead of print | PMID: 31470130
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