Editor-in-Chief sTopPicksFrom2016: Part One filethe hearts of patients with a primary diagnosis of AD, affecting myocardial function. METHODS The authors examined myocardial function

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JACC Editor-in-Chief

Dr. Valentin Fuster.

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HIGHLIGHTS OF THE YEAR

Editor-in-Chief’s Top Picks From 2016:Part One
Valentin Fuster, MD, PHD
Each week, I record audio summaries for every article in JACC, as well as an issue summary. While this process has been

incredibly time-consuming, I have become quite familiar with every paper that we publish. Thus, I personally select papers

(both original investigations and review articles) from 15 distinct specialties each year for your review. In addition to my

personal choices, I have included manuscripts that have been the most accessed or downloaded on our websites, as

well as those selected by the JACCEditorial Boardmembers. In order to present the full breadth of this important research in

a consumable fashion, we will present these manuscripts in this issue of JACC.

Part One includes the sections: Basic & Translational Research, Cardiac Failure, Cardiomyopathies/Myocardial &

Pericardial Diseases, Congenital Heart Disease, Coronary Disease & Interventions, and CVD Prevention & Health

Promotion (1–74).

Part Two will include the sections: CV Medicine & Society, Hypertension, Imaging, Metabolic & Lipid Disorders,

Rhythm Disorders, Valvular Heart Disease, and Vascular Medicine.

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ASIC & TRANSLATIONAL RESEARCH
Ab Amyloid Pathology Affects the Hearts ofPatients With Alzheimer’s Disease:Mind the Heart

L. Troncone, et al.

BACKGROUND Individually, heart failure (HF) andAlzheimer’s disease (AD) are severe threats to popu-lation health, and their potential coexistence is analarming prospect. In addition to sharing analogousepidemiological and genetic profiles, biochemicalcharacteristics, and common triggers, the authorsrecently recognized common molecular and patho-logical features between the 2 conditions. Whereascognitive impairment has been linked to HF throughperfusion defects, angiopathy, and inflammation,whether patients with AD present with myocardialdysfunction, and if the 2 conditions bear a commonpathogenesis as neglected siblings are unknown.

OBJECTIVES Here, the authors investigated whetheramyloid beta (Ab) protein aggregates are present inthe hearts of patients with a primary diagnosis of AD,affecting myocardial function.

METHODS The authors examined myocardial functionin a retrospective cross-sectional study from a cohort

of AD patients and age-matched controls. Imagingand proteomics approaches were used to identifyand quantify Ab deposits in AD heart and brainspecimens compared with controls. Cell shorteningand calcium transients were measured on isolatedadult cardiomyocytes.

RESULTS Echocardiographic measurements ofmyocardial function suggest that patients with ADpresent with an anticipated diastolic dysfunction. Asin the brain, Ab40 and Ab42 are present in the heart,and their expression is increased in AD.

CONCLUSIONS Here, the authors provide the firstreport of the presence of compromised myocardialfunction and intramyocardial deposits of Ab in ADpatients. The findings depict a novel biologicalframework in which AD may be viewed eitheras a systemic disease or as a metastatic disorderleading to heart, and possibly multiorgan failure.AD and HF are both debilitating and life-threatening conditions, affecting enormous patientpopulations. Our findings underline a previouslydismissed problem of a magnitude that willrequire new diagnostic approaches and treat-ments for brain and heart disease, and theircombination (1).

https://s3.amazonaws.com/ADFJACC/JACC6908/JACC6908_fustersummary_07




http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2017.01.004&domain=pdf

http://dx.doi.org/10.1016/j.jacc.2017.01.004

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AL (Light-Chain) Cardiac Amyloidosis:A Review of Diagnosis and Therapy

R.H. Falk, et al.

The amyloidoses are a group of protein-foldingdisorders in which $1 organ is infiltrated byproteinaceous deposits known as amyloid. Thedeposits are derived from 1 of several amyloidogenicprecursor proteins, and the prognosis of the disease isdetermined both by the organ(s) involved and thetype of amyloid. Amyloid involvement of the heart(cardiac amyloidosis) carries the worst prognosis ofany involved organ, and light-chain (AL) amyloidosisis the most serious form of the disease. The lastdecade has seen considerable progress inunderstanding the amyloidoses. In this review,current and novel approaches to the diagnosis andtreatment of cardiac amyloidosis are discussed, withparticular reference to AL amyloidosis in the heart (2).

Genetic and Pharmacological Inhibition ofTREM-1 Limits the Development ofExperimental Atherosclerosis

J. Joffre, et al.

BACKGROUND Innate immune responses activatedthrough myeloid cells contribute to the initiation,progression, and complications of atherosclerosis inexperimental models. However, the critical upstreampathways that link innate immune activation to foamcell formation are still poorly identified.

OBJECTIVES This study sought to investigate thehypothesis that activation of the triggering receptorexpressed on myeloid cells (TREM-1) plays a deter-minant role in macrophage atherogenic responses.

METHODS After genetically invalidating Trem-1 inchimeric Ldlr�/� Trem-1�/� mice and double knockoutApoE�/� Trem-1�/� mice, we pharmacologicallyinhibited Trem-1 using LR12 peptide.

RESULTS Ldlr�/� mice reconstituted with bonemarrow deficient for Trem-1 (Trem-1�/�) showed astrong reduction of atherosclerotic plaque size in boththe aortic sinus and the thoracoabdominal aorta,and were less inflammatory compared to plaques ofTrem-1þ/þ chimeric mice. Genetic invalidation ofTrem-1 led to alteration of monocyte recruitment intoatherosclerotic lesions and inhibited toll-like receptor4 (TLR 4)-initiated proinflammatory macrophage res-ponses. We identified a critical role for Trem-1 in theupregulation of cluster of differentiation 36 (CD36),thereby promoting the formation of inflammatoryfoam cells. Genetic invalidation of Trem-1 in

ApoE�/�/Trem-1�/� mice or pharmacological blockadeof Trem-1 in ApoE�/� mice using LR-12 peptide alsosignificantly reduced the development ofatherosclerosis throughout the vascular tree, andlessened plaque inflammation. TREM-1 wasexpressed in human atherosclerotic lesions, mainlyin lipid-rich areas with significantly higher levels ofexpression in atheromatous than in fibrous plaques.

CONCLUSIONS We identified TREM-1 as a majorupstream proatherogenic receptor. We propose thatTREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cellformation through coordinated and combinedactivation of CD36 and TLR4. Blockade of TREM-1signaling may constitute an attractive novel anddouble-hit approach for the treatment ofatherosclerosis (3).

Genetics and Genomics of Single-GeneCardiovascular Diseases: Common HereditaryCardiomyopathies as Prototypes of Single-GeneDisorders

A.J. Marian, et al.

This is the first of 2 review papers on genetics andgenomics appearing as part of the series on “omics.”Genomics pertains to all components of an organism’sgenes, whereas genetics involves analysis of a specificgene or genes in the context of heredity. The paperprovides introductory comments, describes the basisof human genetic diversity, and addresses thephenotypic consequences of genetic variants. Rarevariants with large effect sizes are responsible forsingle-gene disorders, whereas complex polygenicdiseases are typically due to multiple geneticvariants, each exerting a modest effect size. Toillustrate the clinical implications of genetic variantswith large effect sizes, 3 common forms of hereditarycardiomyopathies are discussed as prototypicexamples of single-gene disorders, including theirgenetics, clinical manifestations, pathogenesis, andtreatment. The genetic basis of complex traits isdiscussed in a separate paper (4).

Genetics: Implications for Prevention andManagement of Coronary Artery Disease

T.L. Assimes, et al.

An exciting new era has dawned for the prevention andmanagement of coronary artery disease (CAD) utilizinggenetic risk variants. The recent identification of over60 susceptibility loci for CAD confirms not only theimportance of established risk factors, but also the

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existence of many novel causal pathways that areexpected to improve our understanding of the geneticbasis of CAD and facilitate the development ofnew therapeutic agents over time. Concurrently,Mendelian randomization studies have providedintriguing insights on the causal relationship betweenCAD-related traits, and highlight the potentialbenefits of long-term modifications of risk factors.Last, genetic risk scores of CAD may serve not only asprognostic, but also as predictive markers, and carrythe potential to considerably improve the delivery ofestablished prevention strategies. This review willsummarize the evolution and discovery of geneticrisk variants for CAD and their current and futureclinical applications (5).

Genotype and Phenotype of TransthyretinCardiac Amyloidosis: THAOS (TransthyretinAmyloid Outcome Survey)

M.S. Maurer, et al.

BACKGROUND Transthyretin amyloidosis (ATTR) is aheterogeneous disorder with multiorgan involvementand a genetic or nongenetic basis.

OBJECTIVES The goal of this study was to describeATTR in the United States by using data from the THAOS(Transthyretin Amyloidosis Outcomes Survey) registry.

METHODS Demographic, clinical, and genetic featuresof patients enrolled in the THAOS registry in theUnited States (n ¼ 390) were compared with data frompatients from other regions of the world (ROW)(n ¼ 2,140). The focus was on the phenotypic expres-sion and survival in the majority of U.S. subjects withvaline-to-isoleucine substitution at position 122(Val122Ile) (n ¼ 91) and wild-type ATTR (n ¼ 189).

RESULTS U.S. subjects are older (70 vs. 46 years), moreoftenmale (85.4% vs. 50.6%), andmore often of Africandescent (25.4% vs. 0.5%) than the ROW. A significantlyhigher percentage of U.S. patients with ATTR amyloidseen at cardiology sites had wild-type disease than theROW (50.5% vs. 26.2%). In the United States, 34different mutations (n ¼ 201) have been reported,with the most common being Val122Ile (n ¼ 91; 45.3%)and Thr60Ala (n ¼ 41; 20.4%). Overall, 91 (85%) of 107patients with Val122Ile were from the United States,where Val122Ile subjects were younger and moreoften female and black than patients with wild-typedisease, and had similar cardiac phenotype but agreater burden of neurologic symptoms (pain,numbness, tingling, and walking disability) and worsequality of life. Advancing age and lower mean arterialpressure, but not the presence of a transthyretin

mutation, were independently associated with highermortality from a multivariate analysis of survival.

CONCLUSIONS In the THAOS registry, ATTR in theUnited States is overwhelmingly a disorder of older adultmale subjects with a cardiac-predominant phenotype.Val122Ile is the most common transthyretin mutation,and neurologic phenotypic expression differs betweenwild-type disease and Val122Ile, but survival fromenrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS];NCT00628745) (6).

Intratracheal Gene Delivery of SERCA2aAmeliorates Chronic Post-Capillary PulmonaryHypertension: A Large Animal Model

J. Aguero, et al.

BACKGROUND Pulmonary hypertension (PH) is char-acterized by pulmonary arterial remodeling that re-sults in increased pulmonary vascular resistance, rightventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca2þ-ATPase 2a(SERCA2a) in the pulmonary vasculature leads toperturbations in calcium ion (Ca2þ) homeostasis andtransition of pulmonary artery smooth muscle cellsto a proliferative phenotype.

OBJECTIVES We assessed the feasibility of sustainedpulmonary vascular SERCA2a gene expression usingaerosolized delivery of adeno-associated virus type 1(AAV1) in a large animal model of chronic PH andevaluated the efficacy of gene transfer regardingprogression of pulmonary vascular and RV remodeling.

METHODS A model of chronic post-capillary PH wascreated in Yorkshire swine by partial pulmonary veinbanding. Development of chronic PH was confirmedhemodynamically, and animals were randomized tointratracheal administration of aerosolized AAV1carrying the human SERCA2a gene (n ¼ 10,AAV1.SERCA2a group) or saline (n ¼ 10). Therapeuticefficacy was evaluated 2 months after gene delivery.

RESULTS Transduction efficacy after intratrachealdelivery of AAV1 was confirmed by b-galactosidasedetection in the distal pulmonary vasculature. Treat-ment with aerosolized AAV1.SERCA2a prevented dis-ease progression as evaluated by mean pulmonaryartery pressure, vascular resistance, and limitedvascular remodeling quantified by histology. Thera-peutic efficacy was supported further by the preser-vation of RV ejection fraction (p ¼ 0.014) andimprovement of the RV end-diastolic pressure–volume relationship in PH pigs treated withaerosolized AAV1.SERCA2a.

https://clinicaltrials.gov/ct2/results?term=NCT00628745&Search=Search



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CONCLUSIONS Airway-based delivery of AAVvectors to the pulmonary arteries was feasible,efficient, and safe in a clinically relevant chronicPH model. Vascular SERCA2a overexpressionresulted in beneficial effects on pulmonary arterialremodeling, with attendant improvements in pul-monary hemodynamics and RV performance, andmight offer therapeutic benefit by modifyingfundamental pathophysiology in pulmonary vasculardiseases (7).

Leukocytes Link Local and Systemic Inflammationin Ischemic Cardiovascular Disease: An Expanded“Cardiovascular Continuum”

P. Libby, et al.

Physicians have traditionally viewed ischemic heartdisease in a cardiocentric manner: plaques grow inarteries until they block blood flow, causing acutecoronary and other ischemic syndromes. Recent researchprovides new insight into the integrative biology ofinflammation as it contributes to ischemic cardiovasculardisease. These results have revealed hithertounsuspected inflammatory signaling networks at work inthese disorders that link the brain, autonomic nervoussystem, bone marrow, and spleen to the atheroscleroticplaque and to the infarcting myocardium. A burgeoningclinical published data indicates that such inflammatorynetworks—far from a mere laboratory curiosity—operatein our patients and can influence aspects of ischemiccardiovascular disease that determine decisively clinicaloutcomes. These new findings enlarge the circle of thetraditional “cardiovascular continuum” beyond the heartand vessels to include the nervous system, the spleen,and the bone marrow (8).

Long Noncoding RNAs: From Clinical Genetics toTherapeutic Targets?

R.A. Boon, et al.

Recent studies suggest that the majority of the humangenome is transcribed, but only about 2% accountsfor protein-coding exons. Long noncoding RNAs(lncRNAs) constitute a heterogenic class of RNAs thatincludes, for example, intergenic lncRNAs, antisensetranscripts, and enhancer RNAs. Moreover, alternativesplicing can lead to the formation of circular RNAs.In support of putative functions, GWAS forcardiovascular diseases have shown predictive single-nucleotide polymorphisms in lncRNAs, such as the9p21 susceptibility locus that encodes the lncRNAantisense noncoding RNA in the INK4 locus (ANRIL).Many lncRNAs are regulated during disease. For

example, metastasis-associated lung adenocarcinomatranscript 1 (MALAT1) and myocardial infarction-associated transcript (MIAT) were shown to affectendothelial cell functions and diabetic retinopathy,whereas lincRNA-p21 controls neointima formation.In the heart, several lncRNAs were shown to actas microRNA sponges and to control ischemia-reperfusion injury or act as epigenetic regulators. Inthis review, the authors summarize the currentunderstanding of lncRNA functions and their role asbiomarkers in cardiovascular diseases (9).

MicroRNAs in Cardiovascular Disease

T. Barwari, et al.

Micro-ribonucleic acids (miRNAs) are in the spotlight aspost-transcriptional regulators of gene expression.Morethan 1,000 miRNAs are encoded in the human genome.In this review, we provide an introduction to miRNAbiology and research methodology, and highlightadvances in cardiovascular research to date. Thisincludes the potential of miRNAs as therapeutic targetsin cardiac and vascular disease, and their use as novelbiomarkers. Although some miRNA therapies arealready undergoing clinical evaluation, we stress theimportance of integrating current knowledge of miRNAbiology into a systemic context. Discovery studiesfocus on miRNA effects within one specific organ,whereas the expression of most miRNAs is notrestricted to a single tissue. Because most miRNA-based therapies act systemically, this may precludewidespread clinical use. The development of moretargeted interventions will bolster well-informedclinical applications, increasing the chances of successand minimizing the risk of setbacks for miRNA-basedtherapeutics (10).

Natural History of Wild-Type TransthyretinCardiac Amyloidosis and Risk Stratification Usinga Novel Staging System

M. Grogan, et al.

BACKGROUND Wild-type transthyretin cardiacamyloidosis (ATTRwt) is increasingly recognized as animportant cause of heart failure.

OBJECTIVES The purpose of this study was to deter-mine the natural history of ATTRwt and the predictorsof survival.

METHODS We retrospectively reviewed patientsdiagnosed with ATTRwt at the Mayo Clinic through2013 and recorded clinical data and survival data.Factors affecting overall survival (OS) were identified,and a prognostic staging system was developed.


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RESULTS The median age of the 360 patientsdiagnosed before death was 75 years (range: 47 to94 years), and 91% were male. Presenting signs andsymptoms included dyspnea or heart failure in 67%and atrial arrhythmias in 62%. Median OS from diag-nosis was 3.6 years and did not change over time.Multivariate predictors of mortality included age,ejection fraction, pericardial effusion, N-terminal pro–B-type natriuretic peptide, and troponin T. A stagingsystem was developed that used thresholds oftroponin T (0.05 ng/ml) and N-terminal pro–B-typenatriuretic peptide (3,000 pg/ml). The respective4-year OS estimates were 57%, 42%, and 18% forstage I (both values below cutoff), stage II (oneabove), and stage III (both above), respectively.Stage III patients were at an increased risk ofmortality after adjustment for age and sex comparedwith stage I patients (hazard ratio: 3.6; p < 0.001).

CONCLUSIONS The natural history of ATTRwt is poor.We report a novel cardiac biomarker staging systemthat enables risk stratification in an era of emergingtreatment strategies (11).

Patient-Specific and Genome-Edited InducedPluripotent Stem Cell–Derived CardiomyocytesElucidate Single-Cell Phenotype ofBrugada Syndrome

P. Liang, et al.

BACKGROUND Brugada syndrome (BrS), a disorderassociated with characteristic electrocardiogram pre-cordial ST-segment elevation, predisposes afflictedpatients to ventricular fibrillation and sudden cardiacdeath. Despite marked achievements in outlining theorgan level pathophysiology of the disorder, theunderstanding of human cellular phenotype haslagged due to a lack of adequate human cellularmodels of the disorder.

OBJECTIVES The objective of this study was toexamine single cell mechanism of Brugada syndromeusing induced pluripotent stem cell–derived car-diomyocytes (iPSC-CMs).

METHODS This study recruited 2 patients with type 1 BrScarrying 2 different sodium voltage-gated channel alphasubunit 5 variants as well as 2 healthy control subjects.We generated iPSCs from their skin fibroblasts by usingintegration-free Sendai virus. We used directeddifferentiation to create purified populations of iPSC-CMs.

RESULTS BrS iPSC-CMs showed reductions in inwardsodium current density and reduced maximalupstroke velocity of action potential compared withhealthy control iPSC-CMs. Furthermore, BrS iPSC-CMsdemonstrated increased burden of triggered activity,

abnormal calcium (Ca2þ) transients, and beatinginterval variation. Correction of the causative variantby genome editing was performed, and resultantiPSC-CMs showed resolution of triggered activity andabnormal Ca2þ transients. Gene expression profiling ofiPSC-CMs showed clustering of BrS compared withcontrol subjects. Furthermore, BrS iPSC-CM geneexpression correlated with gene expression from BrShuman cardiac tissue gene expression.

CONCLUSIONS Patient-specific iPSC-CMs were able torecapitulate single-cell phenotype features of BrS,including blunted inward sodium current, increasedtriggered activity, and abnormal Ca2þ handling. Thisnovel human cellular model creates futureopportunities to further elucidate the cellular diseasemechanism and identify novel therapeutic targets (12).

Proteomics Research in Cardiovascular Medicineand Biomarker Discovery

M.P.Y. Lam, et al.

Proteomics is a systems physiology discipline to addressthe large-scale characterization of protein species withina biological system, be it a cell, a tissue, a body biofluid,an organism, or a cohort population. Building onadvances from chemical analytical platforms (e.g., massspectrometry and other technologies), proteomicsapproaches have contributed powerful applications incardiovascular biomedicine, most notably in: 1) thediscovery of circulating protein biomarkers of heartdiseases from plasma samples; and 2) the identificationof disease mechanisms and potential therapeutic targetsin cardiovascular tissues, in both preclinical models andtranslational studies. Contemporary proteomicsinvestigations offer powerful means to simultaneouslyexamine tens of thousands of proteins in varioussamples, and understand their molecular phenotypes inhealth and disease. This concise review introduces studydesign considerations, example applications and usecases, as well as interpretation and analysis ofproteomics data in cardiovascular biomedicine (13).

TheEmergingRoleofMetabolomics in theDiagnosisand Prognosis of Cardiovascular Disease

J.R. Ussher, et al.

Perturbations in cardiac energy metabolism aremajor contributors to a number of cardiovascularpathologies. In addition, comorbidities associated withcardiovascular disease (CVD) can alter systemic andmyocardial metabolism, often contributing tothe worsening of cardiac function and healthoutcomes. State-of-the-art metabolomic technologies



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give us the ability to measure thousands of metabolitesin biological fluids or biopsies, providing us with ametabolic fingerprint of individual patients. Thesemetabolic profiles may serve as diagnostic and/orprognostic tools that have the potential to significantlyalter the management of CVD. Herein, the authorsreview how metabolomics can assist in theinterpretation of perturbed metabolic processes, andhow this has improved our ability to understand thepathology of ischemic heart disease, atherosclerosis,and heart failure. Taken together, the integration ofmetabolomics with other “omics” platforms willallow us to gain insight into pathophysiological interac-tions of metabolites, proteins, genes, and disease states,while advancing personalized medicine (14).

Translation of Human-Induced PluripotentStem Cells: From Clinical Trial in a Dish toPrecision Medicine

N. Sayed, et al.

The prospect of changing the plasticity of terminallydifferentiated cells toward pluripotency hascompletely altered the outlook for biomedicalresearch. Human-induced pluripotent stem cells(iPSCs) provide a new source of therapeutic cells freefrom the ethical issues or immune barriers of humanembryonic stem cells. iPSCs also confer considerableadvantages over conventional methods of studyinghuman diseases. Since its advent, iPSC technologyhas expanded with 3 major applications: diseasemodeling, regenerative therapy, and drug discovery.Here we discuss, in a comprehensive manner, therecent advances in iPSC technology in relation tobasic, clinical, and population health (15).

C
ARDIAC FAILURE
A Test in Context: Critical Evaluation ofNatriuretic Peptide Testing in Heart Failure

G.S. Francis, et al.

Circulating natriuretic peptide measurements havebeen used extensively over the past 15 years todiagnose and monitor patients with heart failure. Weare still learning how complex the dynamics ofnatriuretic peptides can be in the interpretation oftest results in individual patients. Althoughnatriuretic peptide measurements are widely used inpractice, there are questions regarding why thesepeptides may not necessarily track with blood volumeor invasive hemodynamic measurements inindividual patients. Interpretation of natriuretic

peptide measurements will depend on many factors,including special patient populations, obesity, renalfunction, the state of congestion or decongestion, andwhether patients are receiving specific therapies.Natriuretic peptide measurements have clearlyrevolutionized clinical care for patients with heartfailure, but further research should provide insightsto help use these measurements to individualizepatient care beyond the current guidelines (16).

Bariatric Surgery and Emergency DepartmentVisits and Hospitalizations for Heart FailureExacerbation: Population-Based,Self-Controlled Series

Y.J. Shimada, et al.

BACKGROUND The United States is battling obesity andheart failure (HF) epidemics. Although studies have sug-gested relationships between obesity and HF morbidity,little is known regarding the effects of substantial weightreduction in obese patients with HF.

OBJECTIVES This study investigated whether bariat-ric surgery is associated with a decreased rate of HFexacerbation.

METHODS We performed a self-controlled case seriesstudy of obese patients with HF who underwentbariatric surgery, using the population-basedemergency department (ED) and inpatient sample inCalifornia, Florida, and Nebraska. Primary outcomewas ED visit or hospitalization for HF exacerbationfrom 2005 to 2011. We used conditional logisticregression to compare the outcome event rate duringsequential 12-month periods, using pre-surgerymonths 13 to 24 as the reference period.

RESULTS We identified 524 patients with HFwho underwent bariatric surgery. During the referenceperiod, 16.2% of patients had an ED visit or hospitali-zation for HF exacerbation. The rate remained un-changed in the subsequent 12-month pre-surgeryperiod (15.3%; p ¼ 0.67). In the first 12-month periodafter bariatric surgery, we observed a nonsignificantlyreduced rate (12.0%; p ¼ 0.052). However, the ratewas significantly lower in the subsequent 13 to 24months after bariatric surgery (9.9%; adjusted oddsratio: 0.57; p ¼ 0.003). By contrast, there was nosignificant reduction in the rate of HF exacerbationamong obese patients who underwent nonbariatricsurgery (i.e., cholecystectomy, hysterectomy).

CONCLUSIONS Our findings indicate that bariatricsurgery is associated with a decline in the rate of HFexacerbation requiring ED evaluation or hospitaliza-tion among obese patients with HF (17).


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Cardiac Recovery During Long-TermLeft Ventricular Assist Device Support

O. Wever-Pinzon, et al.

BACKGROUND The number of centers with left ven-tricular assist device (LVAD) research programsfocused on cardiac recovery is very small. Therefore,this phenomenon has been reported in real-worldmulti-center registries as a rare event.

OBJECTIVES This study evaluated the incidence ofcardiac recovery with an a priori LVAD implantationstrategy of bridge-to-recovery (BTR) and constructed arecovery predictive model.

METHODS The study included LVAD recipients regis-tered in the Interagency Registry for Mechanically Assis-ted Circulatory Support (INTERMACS). Cardiac recoverywas evaluated in BTR and non-BTR patients. A weightedscore was derived and externally validated in patients ofthe Utah Cardiac Recovery (UCAR) program.

RESULTS Of 15,138 INTERMACS patients, cardiacrecovery occurred in 192 (1.3%). The incidence of recoverywas 11.2% (n¼ 14) in BTR compared with 1.2% (n¼ 178) innon-BTR patients (p< 0.0001). Independent predictors ofrecovery included: age <50 years, non-ischemiccardiomyopathy, time from cardiac diagnosis <2 years,absence of ICD, creatinine #1.2 mg/dl, and LVEDD <6.5cm (c-index: 0.85; p < 0.0001). A weighted score termedI-CARS, effectively stratified patients based on theirprobability of recovery. I-CARS was validated in theUCAR cohort (n ¼ 190) with good performance (AUC:0.94; 95% CI: 0.91 to 0.98). One-year survival after LVADexplantation, available in INTERMACS for 21 (11%)patients, was 86%.

CONCLUSIONS The incidence of cardiac recovery ishigher in patients implanted with an a priori BTRstrategy. We developed a simple tool to help identifypatients in whom recovery is feasible. In BTR patientswith favorable characteristics, I-CARS suggests a 24%probability of successful LVAD explantation. Large-scale studies to better address post-explantationoutcomes are warranted (18).

Effect of Aldosterone Antagonism on ExerciseTolerance in Heart Failure With PreservedEjection Fraction

W. Kosmala, et al.

BACKGROUND Impaired functional capacity is a hall-mark of patients with heart failure with preservedejection fraction (HFpEF). Despite the association ofHFpEF with reduced myocardial compliance attrib-uted to fibrosis, spironolactone has not been shown to

alter outcomes—perhaps reflecting the heterogeneityof underlying pathological mechanisms.

OBJECTIVES The authors sought to identify im-provement in exercise capacity with spironolactone inthe subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflowvelocity and mitral annular early diastolic velocity(E/e0) reflecting elevation of left ventricular (LV)filling pressure.

METHODS In this randomized, blinded, parallel-group,placebo-controlled trial, 150 subjects (age 67 � 9 years)with exertional dyspnea (New York Heart Associationfunctional class II to III, left ventricular ejectionfraction >50%, diastolic dysfunction, and exertionalE/e0 >13), excluding those with ischemic heartdisease, were recruited in a tertiary cardiology center.Patients were randomized to 6 months of oral spirono-lactone 25 mg/day or matching placebo. Primaryoutcomes were improvements in peak oxygen uptake(VO2) and exertional E/e0 ratio, and secondaryoutcomes were improvements in exercise bloodpressure response and global LV longitudinal strain.

RESULTS At follow-up, 131 patients completedtherapy—64 taking spironolactone and 67 placebo. Atbaseline, subjects had substantial exercise limitation(peak VO2 64 � 17% predicted). The spironolactonegroup showed improvement in exercise capacity(increment in peak VO2 [2.9 ml/min/kg (95%confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs.0.3 ml/min/kg (95% CI: �0.5 to 1.1 ml/min/kg);p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI:0.9 to 3.2 ml/min/kg) vs. �0.9 ml/min/kg (95% CI: �3.4to 1.6 ml/min/kg); p ¼ 0.03], and O2 uptake efficiency[0.19 (95% CI: 0.06 to 0.31) vs. �0.07 (95% CI: �0.17to 0.04); p ¼ 0.002]), with reduction in exercise-induced increase in E/e0 (�3.0 [95% CI: �3.9 to �2.0]vs. 0.5 [95% CI: �0.6 to 1.6]; p < 0.001). There was asignificant interaction of spironolactone and changein E/e0 on VO2 (p ¼ 0.039).

CONCLUSIONS In patients with HFpEF and abnormaldiastolic response to exertion, improvement in exer-cise E/e0 mediates the beneficial effect of spi-ronolactone on exercise capacity. Identification ofexercise-induced increase in LV filling pressure inpatients with HFpEF may define a subgroup withwarranting trial of spironolactone (19).

High-Output Heart Failure: A 15-Year Experience

Y.N.V. Reddy, et al.

BACKGROUND High-output heart failure (HF) is anunusual cause of cardiac failure that has not beenwell-characterized.



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OBJECTIVES This study sought to characterize theetiologies, pathophysiology, clinical and hemody-namic characteristics, and outcomes of high-outputHF in the modern era.

METHODS We performed a retrospective analysis ofall consecutive patients referred to the Mayo Cliniccatheterization laboratory for hemodynamic assess-ment between 2000 and 2014. Subjects with definiteHF, as defined by the Framingham criteria, werecompared to controls of similar age and sex.

RESULTS The most common etiologies of high-outputHF (n ¼ 120) were obesity (31%), liver disease (23%),arteriovenous shunts (23%), lung disease (16%), andmyeloproliferative disorders (8%). Compared withcontrols (n ¼ 24), subjects with high-output HFdisplayed eccentric left ventricular remodeling,greater natriuretic peptide activation, higher fillingpressures, pulmonary hypertension, and increasedcardiac output, despite similar ejection fraction.Elevated cardiac output in high-output HF patientswas related to both lower arterial afterload(decreased systemic vascular resistance) and highermetabolic rate. Mortality was increased in high-output HF as compared with controls (hazard ratio:3.4; 95% confidence interval: 1.6 to 7.6).Hemodynamics and outcomes were poorest amongstpatients with the lowest systemic vascular resistance.

CONCLUSIONS High-output HF is an important causeof clinical HF in the modern era that is related toexcessive vasodilation, and most frequently caused byobesity, arteriovenous shunts, and liver disease.Given the high mortality and increasing prevalence ofthese comorbidities in Western countries, high-outputHF must be considered in the differential diagnosis ofpatients presenting with dyspnea, congestion, and anormal ejection fraction (20).

Influence of Sacubitril/Valsartan (LCZ696) on30-Day Readmission After Heart FailureHospitalization

A.S. Desai, et al.

BACKGROUND Patients with heart failure (HF) are athigh risk for hospital readmission in the first 30 daysfollowing HF hospitalization.

OBJECTIVES This study sought to determine if treat-ment with sacubitril/valsartan (LCZ696) reduces ratesof hospital readmission at 30-days following HFhospitalization compared with enalapril.

METHODS We assessed the risk of 30-day readmission forany cause following investigator-reported hospitalizationsfor HF in the PARADIGM-HF trial, which randomized

8,399 participants with HF and reduced ejection fractionto treatment with LCZ696 or enalapril.

RESULTS Accounting for multiple hospitalizations perpatient, there were 2,383 investigator-reported HFhospitalizations, of which 1,076 (45.2%) occurred insubjects assigned to LCZ696 and 1,307 (54.8%)occurred in subjects assigned to enalapril. Rates ofreadmission for any cause at 30 days were 17.8% inLCZ696-assigned subjects and 21.0% in enalapril-assigned subjects (odds ratio: 0.74; 95% confidenceinterval: 0.56 to 0.97; p ¼ 0.031). Rates of readmissionfor HF at 30-days were also lower in subjects assignedto LCZ696 (9.7% vs. 13.4%; odds ratio: 0.62; 95%confidence interval: 0.45 to 0.87; p ¼ 0.006). Thereduction in both all-cause and HF readmissionswith LCZ696 was maintained when the time windowfrom discharge was extended to 60 days and insensitivity analyses restricted to adjudicated HFhospitalizations.

CONCLUSIONS Compared with enalapril, treatmentwith LCZ696 reduces 30-day readmissions for anycause following discharge from HF hospitalization (21).

Pre-Capillary, Combined, and Post-CapillaryPulmonary Hypertension: A PathophysiologicalContinuum

C.F. Opitz, et al.

BACKGROUND Pulmonary hypertension (PH) ishemodynamically classified as pre-capillary (as seenin idiopathic pulmonary arterial hypertension[IPAH]) or post-capillary (as seen in heart failurewith preserved ejection fraction [HFpEF]). Overlapsbetween these conditions exist. Some patientspresent with risk factors for left heart disease butpre-capillary PH, whereas patients with HFpEF mayhave combined pre- and post-capillary PH.

OBJECTIVES This study sought to further charac-terize similarities and differences among patientpopulations with either PH-HFpEF or IPAH.

METHODS We used registry data to analyze clinicalcharacteristics, hemodynamics, and treatment re-sponses in patients with typical IPAH (<3 risk factorsfor left heart disease; n ¼ 421), atypical IPAH ($3 riskfactors for left heart disease; n ¼ 139), and PH-HFpEF(n ¼ 226) receiving PH-targeted therapy.

RESULTS Compared with typical IPAH, patients withatypical IPAH and PH-HFpEF were older, had a higherbody mass index, had more comorbidities, and had alower 6-min walking distance, whereas meanpulmonary artery pressure (46.9 � 13.3 mm Hg vs.43.9 � 10.7 mm Hg vs. 45.7 � 9.4 mm Hg,


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respectively) and cardiac index (2.3 � 0.8 l/min/m2 vs.2.2 � 0.8 l/min/m2 vs. 2.2 � 0.7 l/min/m2, respectively)were comparable among groups. After initiation oftargeted PH therapies, all groups showedimprovement in exercise capacity, functional class,and natriuretic peptides from baseline to 12 months,but treatment effects were less pronounced inpatients with PH-HFpEF than typical IPAH; withatypical IPAH in between. Survival rates at 1, 3, and5 years were almost identical for the 3 groups.

CONCLUSIONS Patients with atypical IPAH sharefeatures of both typical IPAH and PH-HFpEF,suggesting that there may be a continuum betweenthese conditions (22).

Predicting Persistent Left VentricularDysfunction Following Myocardial Infarction:The PREDICTS Study

G.C. Brooks, et al.

BACKGROUND Persistent severe left ventricular (LV)systolic dysfunction after myocardial infarction (MI) isassociated with increased mortality and is a class Iindication for implantation of a cardioverter-defibrillator.

OBJECTIVES This study developed models andassessed independent predictors of LV recovery to>35% and $50% after 90-day follow-up in patientspresenting with acute MI and severe LV dysfunction.

METHODS Our multicenter prospective observationalstudy enrolled participants with ejection fraction (EF)of #35% at the time of MI (n ¼ 231). Predictors for EFrecovery to >35% and $50% were identified aftermultivariate modeling and validated in a separatecohort (n ¼ 236).

RESULTS In the PREDICTS (PREDiction of ICdTreatment Study) study, 43% of patients hadpersistent EF #35%, 31% had an EF of 36% to 49%,and 26% had an EF $50%. The model that bestpredicted recovery of EF to >35% included EF atpresentation, length of stay, prior MI, lateral wallmotion abnormality at presentation, and peaktroponin. The model that best predicted recovery ofEF to $50% included EF at presentation, peaktroponin, prior MI, and presentation with ventricularfibrillation or cardiac arrest. After predictors weretransformed into point scores, the lowest pointscores predicted a 9% and 4% probability of EF re-covery to >35% and $50%, respectively, whereasprofiles with the highest point scores predicted an87% and 49% probability of EF recovery to >35%and $50%, respectively.

CONCLUSIONS In patients with severe systolicdysfunction following acute MI with an EF #35%, 57%had EF recovery to >35%. A model using clinical var-iables present at the time of MI can help predict EFrecovery (23).

C
ARDIOMYOPATHIES/MYOCARDIAL &PERICARDIAL DISEASES
A Case-Control Study of Risk Markers andMortality in Takotsubo Stress Cardiomyopathy

P. Tornvall, et al.

BACKGROUND Takotsubo stress cardiomyopathy(TSC) is a syndrome characterized by transientmyocardial dysfunction with unknown etiology.Although recent studies have suggested that the syn-drome is associated with comorbidity and has a dismalprognosis, there is a lack of comprehensive datadescribing the epidemiology and prognosis of TSC.

OBJECTIVES This study compared risk markers andmortality in patients with TSC with that of individualswith or without coronary artery disease (CAD).

METHODS Patients with TSC and control subjectswere identified from the Swedish Coronary Angiog-raphy and Angioplasty Register between 2009 and2013 and linked with the Swedish national patientregistry, cause of death registry, prescription drugregistry, and education and income registries.

RESULTS Patients with TSC were characterized by alow cardiovascular risk factor profile but withincreased chronic obstructive pulmonary disease,migraine, and affective disorders. The use of beta-blockers was less common but use of b2-adrenergicagonist agents was more common in patients withTSC compared with either of the control groups.Being a patient with TSC was associated with ahazard ratio of 2.1 for death compared with thecontrol subjects without CAD (95% confidenceinterval: 1.4 to 3.2). This was similar to the excessmortality risk seen among the CAD control subjectscompared with control subjects without CAD(hazard ratio: 2.5; 95% confidence interval: 1.8 to 3.3).These associations remained significant afteradjusting for CAD risk factors and risk markers for TSC.

CONCLUSIONS The findings of increased risk associ-ated with b2-adrenergic agonist agents together withstress related to affective disorders emphasize thepathogenic role of sympathetic stimulation. Theprognosis regarding mortality is worse than in controlsubjects without CAD and similar to patients with CADemphasizing the urgent need for studies on optimaltreatment of TSC (24).



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Arrhythmogenic Right Ventricular Cardiomyopathy:Clinical Course and Predictors of Arrhythmic Risk

A. Mazzanti, et al.

BACKGROUND Arrhythmogenic right ventricular car-diomyopathy (ARVC) is a leading cause of suddencardiac death, but its progression over time and pre-dictors of arrhythmias are still being defined.

OBJECTIVES This study sought to describe the clin-ical course of ARVC and occurrence of life-threateningarrhythmic events (LAE) and cardiovascular mortality;identify risk factors associated with increased LAErisk; and define the response to therapy.

METHODS We determined the clinical course of 301consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayedentry. Predictors of LAE over 5.8 years of follow-upwere determined with Cox multivariable analysis.Treatment efficacy was assessed comparing LAErates during matched time intervals.

RESULTS A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100person-years between ages 21 and 40 years, and in2.4 per 100 person-years between ages 41 and 60years. Cumulative probability of a first LAE atfollow-up was 14% at 5 years, 23% at 10 years, and30% at 15 years. Higher risk of LAE was predictedby atrial fibrillation (hazard ratio [HR]: 4.38;p ¼ 0.002), syncope (HR: 3.36; p < 0.001),participation in strenuous exercise after the diag-nosis (HR: 2.98; p ¼ 0.028), hemodynamicallytolerated sustained monomorphic ventricular tachy-cardia (HR: 2.19; p ¼ 0.023), and male sex (HR: 2.49;p ¼ 0.012). No difference was observed in theoccurrence of LAE before and after treatment withamiodarone, beta-blockers, sotalol, or ablation. Atotal of 81 patients received an implantablecardioverter-defibrillator, 34 were successfullydefibrillated.

CONCLUSIONS The high risk of life-threateningarrhythmias in patients with ARVC spans fromadolescence to advanced age, reaching its peakbetween ages 21 and 40 years. Atrial fibrillation,syncope, participation in strenuous exerciseafter the diagnosis of ARVC, hemodynamicallytolerated sustained monomorphic ventriculartachycardia, and male sex predicted lethalarrhythmias at follow-up. The lack of efficacy ofantiarrhythmic therapy and the life-saving role ofthe implantable cardioverter-defibrillator highlightthe importance of risk stratification for patientmanagement (25).

Complicated Pericarditis: Understanding RiskFactors and Pathophysiology to Inform Imagingand Treatment

P.C. Cremer, et al.

Most patients with acute pericarditis have a benigncourse and a good prognosis. However, a minority ofpatients develop complicated pericarditis, and the careof these patients is the focus of this review.Specifically, we address risk factors, multimodalityimaging, pathophysiology, and novel treatments. Theauthors conclude that: 1) early high-dosecorticosteroids, a lack of colchicine, and an elevatedhigh-sensitivity C-reactive protein are associated withthe development of complicated pericarditis; 2) inselect cases, cardiovascular magnetic resonanceimaging may aid in the assessment of pericardialinflammation and constriction; 3) given phenotypicsimilarities between recurrent idiopathic pericarditisand periodic fever syndromes, disorders of theinflammasome may contribute to relapsing attacks;and 4) therapies that target the inflammasome maylead to more durable remission and resolution. Finally,regarding future investigations, the authors discussthe potential of cardiovascular magnetic resonance toinform treatment duration and the need to comparesteroid-sparing treatments to pericardiectomy (26).

Constrictive Pericarditis Versus RestrictiveCardiomyopathy?

M.J. Garcia, et al.

About one-half of the patients with congestive heartfailure have preserved left ventricular ejection fraction(HFpEF). Although the etiology of HFpEF is mostcommonly related to long-standing hypertension andatherosclerosis, a significant number of suspectedHFpEF patients have a restrictive cardiomyopathy orchronic pericardial disease. Recognizing these syn-dromes is important because early diagnosis may leadto instituting specific therapy that may prolong survival,improve quality of life, and/or recognize and treat anunderlying systemic disorder. Advances in diagnosticimaging, biomarkers, and genetic testing today allowidentification of the specific etiology in most cases. Novelpharmacological, immunologic, and surgical therapiesare leading to improved quality of life and survival (27).

Differentiation of Constriction and Restriction:Complex Cardiovascular Hemodynamics

J.B. Geske, et al.

Differentiation of constrictive pericarditis (CP) fromrestrictive cardiomyopathy (RCM) is a complex and


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often challenging process. Because CP is a potentiallycurable cause of heart failure and therapeutic optionsfor RCM are limited, distinction of these 2 conditionsis critical. Although different in regard to etiology,prognosis, and treatment, CP and RCM share acommon clinical presentation of predominantlyright-sided heart failure, in the absence of significantleft ventricular systolic dysfunction or valve disease,due to impaired ventricular diastolic filling.Fundamental to the diagnosis of either condition is aclear understanding of the underlying hemodynamicprinciples and pathophysiology. We present acontemporary review of the pathophysiology,hemodynamics, diagnostic assessment, andtherapeutic approach to patients presenting with CPand RCM (28).

First Experience With Percutaneous Mitral ValvePlication as Primary Therapy for SymptomaticObstructive Hypertrophic Cardiomyopathy

P. Sorajja, et al.

BACKGROUND Few therapeutic options exist for pa-tients with severe heart failure due to obstructivehypertrophic cardiomyopathy (HCM) who are atunacceptable surgical risk. We hypothesized thatpercutaneous plication of the mitral valve couldreduce left ventricular outflow tract (LVOT) obstruc-tion and associated mitral regurgitation, therebyleading to amelioration of heart failure symptoms.

OBJECTIVES This study sought to evaluate the po-tential effectiveness of percutaneous mitral valveplication as a therapy for patients with symptomatic,obstructive HCM.

METHODS Six patients (age 83 � 8 years; 5 women),judged as not optimal candidates for septal myec-tomy, were referred for management of severe, drug-refractory heart failure symptoms due to obstructiveHCM (New York Heart Association functional classIII). Each underwent percutaneous mitral valveleaflet plication to reduce systolic anterior motion(SAM) and mitral regurgitation using thetranscatheter mitral clip system.

RESULTS The procedure was completed in 5 patientswith placement of a single clip at the A2-P2 segmentsof the mitral valve. One other patient experiencedcardiac tamponade, leading to termination of theprocedure. Among the 5 treated patients, percuta-neous plication with the eliminated SAM and conse-quently decreased the intraoperative LVOT gradient(91 � 44 mm Hg to 12 � 6 mm Hg; p ¼ 0.007), left atrialpressure (29 � 11 mm Hg to 20 � 8 mm Hg; p ¼ 0.06),and mitral regurgitation grade (3.0 � 0 vs. 0.8 � 0.4;

p ¼ 0.0002) associated with improved cardiac output(in n ¼ 4; 3.0 � 0.6 l/min to 4.3 � 1.2 l/min; p ¼ 0.03).Over follow-up of 15 � 4 months, symptomimprovement to New York Heart Associationfunctional class I or II occurred in all patients.Follow-up echocardiography after 15 � 4 monthsdemonstrated continued absence of SAM andsignificant reduction in mitral regurgitation,although high systolic LVOT velocities (i.e., >4 m/s)were evident in 3 of the 5 treated patients.

CONCLUSIONS This is a report of percutaneous mitralvalve plication as a primary therapy in the manage-ment of severely symptomatic, obstructive HCM pa-tients. This initial experience suggests thatpercutaneous mitral valve plication may be effectivefor symptom relief in such patients via reduction ofSAM and mitral regurgitation. The significance ofpersistent elevations of LVOT velocities in some pa-tients requires further study (29).

Left Ventricular Noncompaction:A Distinct Genetic Cardiomyopathy?

E. Arbustini, et al.

Left ventricular noncompaction (LVNC) describes aventricular wall anatomy characterized by prominentleft ventricular (LV) trabeculae, a thin compactedlayer, and deep intertrabecular recesses. Individualvariability is extreme, and trabeculae represent a sortof individual “cardioprinting.” By itself, the diagnosisof LVNC does not coincide with that of a“cardiomyopathy” because it can be observed inhealthy subjects with normal LV size and function,and it can be acquired and is reversible. Rarely,LVNC is intrinsically part of a cardiomyopathy; theparadigmatic examples are infantile tafazzinopathies.When associated with LV dilation and dysfunction,hypertrophy, or congenital heart disease, the geneticcause may overlap. The prevalence of LVNC in healthyathletes, its possible reversibility, and increasingdiagnosis in healthy subjects suggests cautious use ofthe term LVNC cardiomyopathy, which describes themorphology but not the functional profile of thecardiomyopathy (30).

Left Ventricular Noncompaction: AnatomicalPhenotype or Distinct Cardiomyopathy?

J.R. Weir-McCall, et al.

BACKGROUND There is considerable overlap betweenleft ventricular noncompaction (LVNC) and othercardiomyopathies. LVNC has been reported in up to40% of the general population, raising questions



992

about whether it is a distinct pathological entity, aremodeling epiphenomenon, or merely an anatomicalphenotype.

OBJECTIVES The authors determined the prevalenceand predictors of LVNC in a healthy population using4 cardiac magnetic resonance imaging diagnosticcriteria.

METHODS Volunteers >40 years of age (N ¼ 1,651) withno history of cardiovascular disease (CVD), a 10-yearrisk of CVD < 20%, and a B-type natriuretic peptidelevel greater than their gender-specific medianunderwent magnetic resonance imaging scan as partof the TASCFORCE (Tayside Screening for CardiacEvents) study. LVNC ratios were measured on thehorizontal and vertical long axis cine sequences. Allindividuals with a noncompaction ratio of $2underwent short axis systolic and diastolic LVNC ratiomeasurements, and quantification of noncompactedand compacted myocardial mass ratios. Those whomet all 4 criteria were considered to have LVNC.

RESULTS Of 1,480 participants analyzed, 219 (14.8%)met $1 diagnostic criterion for LVNC, 117 (7.9%)met 2 criteria, 63 (4.3%) met 3 criteria, and 19 (1.3%)met all 4 diagnostic criteria. There was no difference indemographic or allometric measures between thosewith and without LVNC. Long axis noncompaction ra-tios were the least specific, with current diagnosticcriteria positive in 219 (14.8%), whereas the non-compacted to compacted myocardial mass ratio was themost specific, only being met in 61 (4.4%).

CONCLUSIONS A significant proportion of an asymp-tomatic population free from CVD satisfy all currentlyused cardiac magnetic resonance imaging diagnosticcriteria for LVNC, suggesting that those criteria havepoor specificity for LVNC, or that LVNC is ananatomical phenotype rather than a distinct cardio-myopathy (31).

Long-Term Prognostic Value of Cardiac MagneticResonance in Left Ventricle Noncompaction:A Prospective Multicenter Study

D. Andreini, et al.

BACKGROUND Cardiac magnetic resonance (CMR) isuseful for the diagnosis of left ventricular non-compaction (LVNC). However, there are limited dataregarding its prognostic value.

OBJECTIVES The goal of this study was to evaluatethe prognostic relevance of CMR findings in patientswith LVNC.

METHODS A total of 113 patients with an echocardio-graphic diagnosis of LVNC underwent CMR at 5 referral

centers. CMRdiagnostic criterion of LVNC (noncompacted/compacted ratio >2.3 in end-diastole) was confirmed in allpatients. We performed left ventricular (LV) and rightventricular quantitative analysis and late gadoliniumenhancement (LGE) assessments and analyzed thefollowing LVNC diagnostic criteria: left ventricularnoncompacted myocardial mass (LV-ncMM) >20% and>25%, total LV-ncMM index >15 g/m2, noncompacted/compacted ratio $3:1 $1 of segments 1 to 3 and 7 to 16or $2:1 in at least 1 of segments 4 to 6 of the AmericanHeart Association model. Outcome was a composite ofthromboembolic events, heart failure hospitalizations,ventricular arrhythmias, and cardiac death.

RESULTS At a mean follow-up of 48 � 24 months,cardiac events (CEs) occurred in 36 patients (16 heartfailure hospitalizations, 10 ventricular arrhythmias, 5cardiac deaths, and 5 thromboembolic events). LVdilation, impaired LV ejection fraction, and LV-ncMM>20% was significantly more frequent in patientswith CEs. LV fibrosis was detected by using LGE in 11cases. CMR predictors of CEs were LV dilation andLGE. LGE was associated with improved prediction ofCEs, compared with clinical data and CMR functionalparameters in all 3 models. No CEs occurred inpatients without dilated cardiomyopathy and/or LGE.

CONCLUSIONS In patients with LVNC evaluated byusing CMR, the degree of LV trabeculation seems tohave no prognostic impact over and above LV dilation,LV systolic dysfunction, and presence of LGE (32).

Pheochromocytoma Is Characterized byCatecholamine-Mediated Myocarditis, Focaland Diffuse Myocardial Fibrosis, andMyocardial Dysfunction

V.M. Ferreira, et al.

BACKGROUND Pheochromocytoma is associated withcatecholamine-induced cardiac toxicity, but theextent and nature of cardiac involvement in clinicalcohorts is not well-characterized.

OBJECTIVES This study characterized the cardiacphenotype in patients with pheochromocytoma usingcardiac magnetic resonance (CMR).

METHODS A total of 125 subjects were studied,including patients with newly diagnosed pheochro-mocytoma (n ¼ 29), patients with previously surgicallycured pheochromocytoma (n ¼ 31), healthy controlsubjects (n ¼ 51), and hypertensive control subjects(HTN) (n ¼ 14), using CMR (1.5-T) cine, strain imagingby myocardial tagging, late gadolinium enhancement,and native T1 mapping (Shortened Modified Look-Locker Inversion recovery [ShMOLLI]).


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RESULTS Patients who were newly diagnosed withpheochromocytoma, compared with healthy and HTNcontrol subjects, had impaired left ventricular (LV) ejec-tion fraction (<56% in 38% of patients), peak systoliccircumferential strain (p < 0.05), and diastolic strain rate(p< 0.05). They had highermyocardial T1 (974� 25ms, ascompared with 954� 16 ms in healthy and 958 � 23 ms inHTN subjects; p< 0.05), areas ofmyocarditis (median 22%LV with T1 >990 ms, as compared with 1% in healthy and2% in HTN subjects; p < 0.05), and focal fibrosis (59% hadnonischemic late gadolinium enhancement, as comparedwith 14% in HTN subjects). Post-operatively, impaired LVejection fraction typically normalized, but systolic anddiastolic strain impairment persisted. Focal fibrosis(median 5% LV) and T1 abnormalities (median 12% LV)remained, the latter of which may suggest some diffusefibrosis. Previously cured patients demonstratedabnormal diastolic strain rate (p < 0.001), myocardial T1

(median 12% LV), and small areas of focal fibrosis(median 1% LV). LV mass index was increased in HTNcompared with healthy control subjects (p < 0.05), butnot in the 2 pheochromocytoma groups.

CONCLUSIONS This first systematic CMR study char-acterizing the cardiac phenotype in pheochromocy-toma showed that cardiac involvement was frequentand, for some variables, persisted after curative sur-gery. These effects surpass those of hypertensiveheart disease alone, supporting a direct role of cate-cholamine toxicity that may produce subtle but long-lasting myocardial alterations (33).

The Diagnosis and Evaluation of DilatedCardiomyopathy

A.G. Japp, et al.

Dilated cardiomyopathy (DCM) is best understood as thefinal common response of myocardium to diverse geneticand environmental insults. A rigorous work-up canexclude alternative causes of left ventricular (LV) dilationand dysfunction, identify etiologies that may respond tospecific treatments, and guide family screening. Asignificant proportion of DCM cases have an underlyinggenetic or inflammatory basis. Measurement of LV sizeand ejection fraction remain central to diagnosis, riskstratification, and treatment, but other aspects of cardiacremodeling inform prognosis and carry therapeuticimplications. Assessment of myocardial fibrosis predictsboth risk of sudden cardiac death and likelihood of LVfunctional recovery, and has significant potential toguide patient selection for cardioverter-defibrillatorimplantation. Detailed mitral valve assessment is likelyto assume increasing importance with the emergence of

percutaneous interventions for functional mitralregurgitation. Detection of pre-clinical DCM couldsubstantially reduce morbidity and mortality by allowingearly instigation of cardioprotective therapy (34).

The Quest for New Approaches in Myocarditisand Inflammatory Cardiomyopathy

S. Heymans, et al.

Myocarditis is a diverse group of heart-specific immuneprocesses classified by clinical and histopathologicalmanifestations. Up to 40% of dilated cardiomyopathy isassociated with inflammation or viral infection. Recentexperimental studies revealed complex regulatory rolesfor several microribonucleic acids and T-cell andmacrophage subtypes. Although the prevalence ofmyocarditis remained stable between 1990 and 2013 atabout 22 per 100,000 people, overall mortality fromcardiomyopathy and myocarditis has decreased since2005. The diagnostic and prognostic value of cardiacmagnetic resonance has increased with new, higher-sensitivity sequences. Positron emission tomography hasemerged as a useful tool for diagnosis of cardiacsarcoidosis. The sensitivity of endomyocardial biopsymay be increased, especially in suspected sarcoidosis, bythe use of electrogram guidance to target regions ofabnormal signal. Investigational treatments on the basisof mechanistic advances are entering clinical trials.Revised management recommendations regardingathletic participation after acute myocarditis haveheightened the importance of early diagnosis (35).

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ONGENITAL HEART DISEASE
Aortic Valve Replacement and the RossOperation in Children and Young Adults

M.T.A. Sharabiani, et al.

BACKGROUND There are several options available foraortic valve replacement (AVR), with few comparativereports in the literature. The optimal choice for AVR ineach age group is not clear.

OBJECTIVES The study sought to report and compareoutcomes after AVR in the young using data from anational database.

METHODS AVR procedures were compared afteradvanced matching, both in pairs and in a 3-waymanner, using a Bayesian dynamic survival model.

RESULTS A total of 1,501 patients who underwent AVR inthe United Kingdom between 2000 and 2012 wereincluded. Of these, 47.8% had a Ross procedure, 37.8% amechanical AVR, 10.9% a bioprosthesis AVR, and 3.5% a



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homograft AVR, with Ross patients being significantlyyounger when compared to the other groups. Overall sur-vivalat 12yearswas94.6%. Inchildren, theRossprocedurehad a 12.7% higher event-free probability (death or anyreintervention) at 10 years when compared to mechanicalAVR (p ¼ 0.05). We also compared all procedures exceptthe homograft in a matched population of young adults,where the bioprosthesis had the lowest event-freeprobability of 78.8%, followed by comparable results inmechanical AVR and Ross, with 86.3% and 89.6%,respectively. Younger age was associated with mortalityand pulmonary reintervention in the Ross group andwith aortic reintervention in the mechanical AVR. Of all 3options, only the patients undergoing the Ross procedureapproached the survival of the general population.

CONCLUSIONS AVR in the young achieves good re-sults, with the Ross being overall better suited for thisage group, especially in children. Although freedomfrom aortic valve reintervention is superior after theRoss procedure, the need for homograft reinterven-tions is an issue to take into account. All methods haveadvantages and limitations, with reinterventions be-ing an issue in the long term for all, more crucially insmaller children (36).

Etiology of Sudden Death in Sports: InsightsFrom a United Kingdom Regional Registry

G. Finocchiaro, et al.

BACKGROUND Accurate knowledge of causes of sud-den cardiac death (SCD) in athletes and its precipi-tating factors is necessary to establish preventativestrategies.

OBJECTIVES This study investigated causes of SCDand their association with intensive physical activityin a large cohort of athletes.

METHODS Between 1994 and 2014, 357 consecutivecases of athletes who died suddenly (mean 29 � 11years of age, 92% males, 76% Caucasian, 69%competitive) were referred to our cardiac pathologycenter. All subjects underwent detailed post-mortemevaluation, including histological analysis by anexpert cardiac pathologist. Clinical information wasobtained from referring coroners.

RESULTS Sudden arrhythmic death syndrome (SADS)was the most prevalent cause of death (n ¼ 149 [42%]).Myocardial disease was detected in 40% of cases,including idiopathic left ventricular hypertrophy(LVH) and/or fibrosis (n ¼ 59, 16%); arrhythmogenicright ventricular cardiomyopathy (ARVC) (13%); andhypertrophic cardiomyopathy (HCM) (6%). Coronaryartery anomalies occurred in 5% of cases. SADS and

coronary artery anomalies affected predominantlyyoung athletes (# 35 years of age), whereas myocar-dial disease was more common in older individuals.SCD during intense exertion occurred in 61% of cases;ARVC and left ventricular fibrosis most strongly pre-dicted SCD during exertion.

CONCLUSIONS Conditions predisposing to SCD insports demonstrate a significant age predilection. Thestrong association of ARVC and left ventricular fibrosiswith exercise-induced SCD reinforces the need forearly detection and abstinence from intense exercise.However, almost 40% of athletes die at rest,highlighting the need for complementary preventivestrategies (37).

High-Risk Cardiac Disease in Pregnancy:Part I

U. Elkayam, et al.

The incidence of pregnancy in women withcardiovascular disease is rising, primarily due to theincreased number of women with congenital heartdisease reaching childbearing age and the changingdemographics associated with advancing maternalage. Although most cardiac conditions are welltolerated during pregnancy and women can deliversafely with favorable outcomes, there are somecardiac conditions that have significant maternal andfetal morbidity and mortality. The purpose of thispaper is to review the available published reports andprovide recommendations on the management ofwomen with high-risk cardiovascular conditionsduring pregnancy (38).

Thrombotic and Embolic ComplicationsAssociated With Atrial Arrhythmia After FontanOperation: Role of Prophylactic Therapy

A.C. Egbe, et al.

BACKGROUND There are limited data about the risk ofthrombotic and embolic complication (TEC) in adultswith atrial arrhythmia after Fontan operation.

OBJECTIVES This study sought to determine the riskof TEC in this population and the role of anti-coagulation therapy in TEC prevention.

METHODS This was a retrospective review of adultswith atrial arrhythmia after Fontan operation who wereevaluated at the Mayo Clinic between 1994 to 2014. TECwas classified into 2 groups: systemic TEC, defined asintracardiac thrombus, ischemic stroke, or systemicarterial embolus; and nonsystemic TEC, defined asFontan conduit/right atrial thrombus or pulmonary


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embolus. Patients were divided into 3 groups: anti-coagulation, antiplatelet, and no therapy cohorts.

RESULTS We followed 278 patients, mean age 31 � 9years, for 88 � 14 months (1,464 patient-years).Patient groups included antiplatelet (n ¼ 181),anticoagulation (n ¼ 91), and no therapy (n ¼ 6).There were 97 TEC in 81 patients (29%); 32 weresystemic, yielding an event rate of 2.1 systemic TECper 100 patient-years, and 65 were nonsystemic TEC,yielding an event rate of 4.4 nonsystemic TEC per100 patient-years. Prevalence of TEC was 18% and55% at 5 and 10 years, respectively. Atriopulmonaryconnection was a risk factor for TEC (hazard ratio:2.31; 95% confidence interval: 1.61 to 4.64), and TECwere associated with higher risk of death andhospitalization (p < 0.0001). Anticoagulation wasprotective against TEC and resulted in a reduction ofTEC risk by 2.5 TEC per 100 patient-years.Anticoagulation was also associated with lower riskof death and hospitalization (p ¼ 0.02). Bleedingcomplications occurred in 21 (7%) patients and weresimilar in all groups.

CONCLUSIONS Anticoagulation was associated withlower TEC rate and lower risk of death and hospitali-zation, without a significant increase in bleeding risk.Perhaps anticoagulation should be the preferred pre-ventive strategy (39).

C
ORONARY DISEASE & INTERVENTIONS
A Polylactide Bioresorbable Scaffold ElutingEverolimus for Treatment of Coronary Stenosis:5-Year Follow-Up

P.W. Serruys, et al.

BACKGROUND Long-term benefits of coronary stenosistreatment with an everolimus-eluting bioresorbablescaffold are unknown.

OBJECTIVES This study sought to evaluate clinicaland imaging outcomes 5 years after bioresorbablescaffold implantation.

METHODS In the ABSORB multicenter, single-armtrial, 45 (B1) and 56 patients (B2) underwentcoronary angiography, intravascular ultrasound(IVUS), and optical coherence tomography (OCT) atdifferent times. At 5 years, 53 patients without targetlesion revascularization underwent final imaging.

RESULTS Between 6 months/1 year and 5 years,angiographic luminal late loss remained unchanged(B1: 0.14 � 19 mm vs. 0.13 � 0.33 mm; p ¼ 0.7953; B2:0.23 � 0.28 mm vs. 0.18 � 0.32 mm; p ¼ 0.5685). When

patients with a target lesion revascularization wereincluded, luminal late loss was 0.15 � 0.20 mm versus0.15 � 0.24 mm (p ¼ 0.8275) for B1 and 0.30 � 0.37 mmversus 0.32 � 0.48 mm (p ¼ 0.8204) for B2. At 5 years,in-scaffold and -segment binary restenosis was 7.8%(5 of 64) and 12.5% (8 of 64). On IVUS, the minimumlumen area of B1 decreased from 5.23 � 0.97 mm2 at6 months to 4.89 � 1.81 mm2 at 5 years (p ¼ 0.04),but remained unchanged in B2 (4.95 � 0.91 mm2 at1 year to 4.84 � 1.28 mm2 at 5 years; p ¼ 0.5). At5 years, struts were no longer discernable by OCTand IVUS. On OCT, the minimum lumen area in B1decreased from 4.51 � 1.28 mm2 at 6 months to3.65 � 1.39 mm2 at 5 years (p ¼ 0.01), but remainedunchanged in B2, 4.35 � 1.09 mm2 at 1 year and4.12 � 1.38 mm2 at 5 years (p ¼ 0.24). Overall, the5-year major adverse cardiac event rate was 11.0%,without any scaffold thrombosis.

CONCLUSIONS At 5 years, bioresorbable scaffold im-plantation in a simple stenotic lesion resulted in stablelumen dimensions and low restenosis and majoradverse cardiac event rates. (ABSORB Clinical Inves-tigation, Cohort B [ABSORB B]; NCT00856856) (40).

A Test in Context: High-SensitivityC-Reactive Protein

P.M. Ridker

The inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) adds prognostic informationon cardiovascular risk comparable to blood pressureor cholesterol. Values <1, 1 to 3, and >3 mg/l indicatelower, average, or higher relative cardiovascular risk,respectively. Global risk algorithms that includehsCRP outperform those solely using Framinghamcovariates. Although diet, exercise, and smokingcessation are first steps for patients with aproinflammatory response, JUPITER (Justification forthe Use of Statins in Prevention: an Intervention TrialEvaluating Rosuvastatin) trial data demonstrate thatstatins reduce by 47% the rate of first myocardialinfarction, stroke, or confirmed cardiovascular deathwhen given to patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/l(hazard ratio: 0.53; 95% confidence interval: 0.40to 0.69; p < 0.00001). In current U.S. guidelines,hsCRP carries a class IIb assessment and is mostappropriate in primary prevention when clinicaldecisions to initiate statin therapy are uncertain.Ongoing multinational trials are pursuing whetherreducing inflammation will decrease vascular eventrates (41).

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Beyond Coronary Calcification, Family History,and C-Reactive Protein: Cholesterol EffluxCapacity and Cardiovascular Risk Prediction

P. Mody, et al.

BACKGROUND Cholesterol efflux capacity (CEC),which is a key step in the reverse cholesterol transportpathway, is independently associated with athero-sclerotic cardiovascular disease (ASCVD). However,whether it predicts ASCVD beyond validated novelrisk markers is unknown.

OBJECTIVES This study assessed if CEC improvedACSVD risk prediction beyond using coronary arterycalcium (CAC), family history (FH), and high-sensitivity C-reactive protein (hs-CRP).

METHODS CEC, CAC, self-reported FH, and hs-CRPwere assessed among participants without baselineASCVD who were enrolled in the Dallas HeartStudy (DHS). ASCVD was defined as a first nonfatalmyocardial infarction (MI) or stroke, coronaryrevascularization, or cardiovascular death, assessedover a median 9.4 years. Risk prediction wasassessed using various modeling techniques andimprovements in the c-statistic, the integrateddiscrimination index (IDI), and the net reclassificationindex (NRI).

RESULTS The mean age of the population (N ¼ 1,972)was 45 years, 52% had CAC (>0), 31% had FH, and 58%had elevated hs-CRP ($2 mg/l). CEC greater than themedian was associated with a 50% reducedincidence of ASCVD in those with CAC (5.4% vs.10.5%; p ¼ 0.003), FH (5.8% vs. 10%; p ¼ 0.05), andelevated hs-CRP (3.8% vs. 7.9%; p ¼ 0.004). CECimproved all metrics of discrimination andreclassification when added to CAC (c-statistic,p ¼ 0.004; IDI, p ¼ 0.02; NRI: 0.38; 95% confidenceinterval [CI]: 0.13 to 0.53), FH (c-statistic, p ¼ 0.006;IDI, p ¼ 0.008; NRI: 0.38; 95% CI: 0.13 to 0.55), orelevated hs-CRP (c-statistic p ¼ 0.008; IDI p ¼ 0.02;NRI: 0.36; 95% CI: 0.12 to 0.52).

CONCLUSIONS CEC improves ASCVD risk predictionbeyond using CAC, FH, and hs-CRP and warrantsconsideration as a novel ASCVD risk marker (42).

Cardiac Sarcoidosis

D.H. Birnie, et al.

Clinically manifest cardiac involvement occurs inperhaps 5% of patients with sarcoidosis. The3 principal manifestations of cardiac sarcoidosis(CS) are conduction abnormalities, ventriculararrhythmias, and heart failure. An estimated 20% to

25% of patients with pulmonary/systemic sarcoidosishave asymptomatic cardiac involvement (clinicallysilent disease). In 2014, the first internationalguideline for the diagnosis and management of CSwas published. In 7 patients with clinically manifestCS, the extent of left ventricular dysfunction seems tobe the most important predictor of prognosis. Thereis controversy in published reports as to the outcomeof patients with clinically silent CS. Despite a paucityof data, immunosuppression therapy (primarily withcorticosteroids) has been advocated for the treatmentof clinically manifest CS. Device therapy, primarilywith implantable cardioverter-defibrillators, is oftenrecommended for patients with clinically manifestdisease (43).

Causes of Death Following PCI Versus CABG inComplex CAD: 5-Year Follow-Up of SYNTAX

M. Milojevic, et al.

BACKGROUND There are no data available on specificcauses of death from randomized trials that havecompared coronary artery bypass grafting (CABG) withpercutaneous coronary intervention (PCI).

OBJECTIVES The purpose of this study was to inves-tigate specific causes of death, and its predictors, afterrevascularization for complex coronary disease inpatients.

METHODS An independent Clinical Events Committeeconsisting of expert physicians who were blinded tothe study treatment subclassified causes of deathas cardiovascular (cardiac and vascular), noncar-diovascular, or undetermined according to the trialprotocol. Cardiac deaths were classified as suddencardiac, related to myocardial infarction (MI), andother cardiac deaths.

RESULTS In the randomized cohort, there were 97deaths after CABG and 123 deaths after PCI during a 5-year follow-up. After CABG, 49.4% of deaths werecardiovascular, with the greatest cause being heartfailure, arrhythmia, or other causes (24.6%), whereasafter PCI, the majority of deaths were cardiovascular(67.5%) and as a result of MI (29.3%). The cumulativeincidence rates of all-cause death were notsignificantly different between CABG and PCI (11.4%vs. 13.9%, respectively; p ¼ 0.10), whereas there weresignificant differences in terms of cardiovascular(5.8% vs. 9.6%, respectively; p ¼ 0.008) and cardiacdeath (5.3% vs. 9.0%, respectively; p ¼ 0.003), whichwere caused primarily by a reduction in MI-relateddeath with CABG compared with PCI (0.4% vs. 4.1%,respectively; p <0.0001). Treatment with PCI versus


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CABG was an independent predictor of cardiac death(hazard ratio: 1.55; 95% confidence interval: 1.09 to2.33; p ¼ 0.045). The difference in MI-related deathwas seen largely in patients with diabetes, 3-vesseldisease, or high SYNTAX (TAXUS Drug-Eluting StentVersus Coronary Artery Bypass Surgery for theTreatment of Narrowed Arteries) trial scores.

CONCLUSIONS During a 5-year follow-up, CABG incomparison with PCI was associated with asignificantly reduced rate of MI-related death, whichwas the leading cause of death after PCI. Treatmentsfollowing PCI should target reducing post-revascularization spontaneous MI. Furthermore,secondary preventive medication remains essential inreducing events post-revascularization. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgeryfor the Treatment of Narrowed Arteries [SYNTAX];NCT00114972) (44).

Coronary Flow Reserve and MicrocirculatoryResistance in Patients With IntermediateCoronary Stenosis

J.M. Lee, et al.

BACKGROUND The prognostic impact of microvas-cular status in patients with high fractional flowreserve (FFR) is not clear.

OBJECTIVES The goal of this study was to investigatethe implications of coronary flow reserve (CFR) andthe index of microcirculatory resistance (IMR) in pa-tients who underwent FFR measurement.

METHODS Patients with high FFR (>0.80) were group-ed according to CFR (#2) and IMR ($23 U) levels: groupA, high CFR with low IMR; group B, high CFR with highIMR; group C, low CFR with low IMR; and group D, lowCFRwith high IMR. Patient-oriented composite outcome(POCO) of any death, myocardial infarction, andrevascularization was assessed. The median follow-upwas 658 days (interquartile range: 503.8 to 1,139.3 days).

RESULTS A total of 313 patients (663 vessels) wereassessed with FFR, CFR, and IMR. Correlation(r ¼ 0.201; p< 0.001) and categorical agreement (kappavalue ¼ 0.178; p < 0.001) between FFR and CFR weremodest. Low CFR was associated with higher POCOthan high CFR (p ¼ 0.034). There were no significantdifferences in clinical and angiographic characteristicsamong groups. Patients with high IMR with low CFRhad the highest POCO (p ¼ 0.002). Overt microvasculardisease (p ¼ 0.008), multivessel disease (p ¼ 0.033),and diabetes mellitus (p ¼ 0.033) were independentpredictors of POCO. Inclusion of a physiological indexsignificantly improved the discriminant function of a

predictive model (relative integrated discriminationimprovement 0.467 [p ¼ 0.037]; category-free netreclassification index 0.648 [p ¼ 0.007]).

CONCLUSIONS CFR and IMR improved the risk strat-ification of patients with high FFR. Low CFR with highIMR was associated with poor prognosis. (Clinical,Physiological and Prognostic Implication of Micro-vascular Status; NCT02186093) (45).

Cyclosporine A in Reperfused MyocardialInfarction: The Multicenter, Controlled,Open-Label CYCLE Trial

F. Ottani, et al.

BACKGROUND Whether cyclosporine A (CsA) hasbeneficial effects in reperfused myocardial infarction(MI) is debated.

OBJECTIVES This study investigated whether CsAimproved ST-segment resolution in a randomized,multicenter phase II study.

METHODS The authors randomly assigned 410 pa-tients from 31 cardiac care units, age 63 � 12 years,with large ST-segment elevation MI within 6 h ofsymptom onset, Thrombolysis In MyocardialInfarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primarypercutaneous coronary intervention, to 2.5 mg/kgintravenous CsA (n ¼ 207) or control (n ¼ 203)groups. The primary endpoint was incidenceof $70% ST-segment resolution 60 min after TIMIflow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4,left ventricular (LV) remodeling, and clinical eventsat 6-month follow-up.

RESULTS Time from symptom onset to first antegradeflow was 180 � 67 min; a median of 5 electrocardiog-raphy leads showed ST-segment deviation (quartile[Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior.ST-segment resolution $70% was found in 52.0% ofCsA patients and 49.0% of controls (p ¼ 0.55).Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l incontrols (p ¼ 0.85). The 2 groups did not differ in LVejection fraction on day 4 and at 6 months. Infarctsite did not influence CsA efficacy. There were noacute allergic reactions or nonsignificant excessesof 6-month mortality (5.7% CsA vs. 3.2% controls,p ¼ 0.17) or cardiogenic shock (2.4% CsA vs. 1.5%controls, p ¼ 0.33).

CONCLUSIONS In the CYCLE (CYCLosporinE A inReperfused Acute Myocardial Infarction) trial, asingle intravenous CsA bolus just before primary

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percutaneous coronary intervention had no effect onST-segment resolution or hs-cTnT, and did notimprove clinical outcomes or LV remodeling up to 6months. (CYCLosporinE A in Reperfused AcuteMyocardial Infarction [CYCLE]; NCT01650662;EudraCT number 2011-002876-18) (46).

Early Intravenous Beta-Blockers in Patients WithST-Segment Elevation Myocardial InfarctionBefore Primary Percutaneous CoronaryIntervention

V. Roolvink, et al.

BACKGROUND The impact of intravenous (IV) beta-blockers before primary percutaneous coronaryintervention (PPCI) on infarct size and clinicaloutcomes is not well established.

OBJECTIVES This study sought to conduct the firstdouble-blind, placebo-controlled internationalmulticenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segmentelevation myocardial infarction (STEMI) population.

METHODS STEMI patients presenting <12 h from symp-tom onset in Killip class I to II without atrioventricularblock were randomized 1:1 to IV metoprolol (2 � 5-mgbolus) or matched placebo before PPCI. Primaryendpoint was myocardial infarct size as assessed bycardiac magnetic resonance imaging (CMR) at 30 days.Secondary endpoints were enzymatic infarct size andincidence of ventricular arrhythmias. Safety endpointsincluded symptomatic bradycardia, symptomatichypotension, and cardiogenic shock.

RESULTS A total of 683 patients (mean age 62 � 12years; 75% male) were randomized to metoprolol(n ¼ 336) or placebo (n ¼ 346). CMR was performed in342 patients (54.8%). Infarct size (percent of leftventricle [LV]) by CMR did not differ betweenthe metoprolol (15.3 � 11.0%) and placebo groups(14.9 � 11.5%; p ¼ 0.616). Peak and area under thecreatine kinase curve did not differ between bothgroups. LV ejection fraction by CMR was 51.0 � 10.9%in the metoprolol group and 51.6 � 10.8% in the pla-cebo group (p ¼ 0.68). The incidence of malignantarrhythmias was 3.6% in the metoprolol group versus6.9% in placebo (p ¼ 0.050). The incidence of adverseevents was not different between groups.

CONCLUSIONS In a nonrestricted STEMI population,early intravenous metoprolol before PPCI was notassociated with a reduction in infarct size. Metoprololreduced the incidence of malignant arrhythmias in theacute phase and was not associated with an increase inadverse events. (Early-Beta blocker Administration

before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI];EudraCT no: 2010-023394-19) (47).

Heparin-Induced Thrombocytopenia:A Comprehensive Clinical Review

B.S. Salter, et al.

Heparin-induced thrombocytopenia is a profoundlydangerous, potentially lethal, immunologicallymediated adverse drug reaction to unfractionatedheparin or, less commonly, to low–molecular weightheparin. In this comprehensive review, the authorshighlight heparin-induced thrombocytopenia’s riskfactors, clinical presentation, pathophysiology,diagnostic principles, and treatment. The authorsplace special emphasis on the management ofpatients requiring procedures using cardiopulmonarybypass or interventions in the catheterizationlaboratory. Clinical vigilance of this disease process isimportant to ensure its recognition, diagnosis, andtreatment. Misdiagnosis of the syndrome, as well asmisunderstanding of the disease process, continues tocontribute to its morbidity and mortality (48).

Impact of the Timing of MetoprololAdministration During STEMI on Infarct Size andVentricular Function

J.M. García-Ruiz, et al.

BACKGROUND Pre-reperfusion administration ofintravenous (IV) metoprolol reduces infarct size inST-segment elevation myocardial infarction (STEMI).

OBJECTIVES This study sought to determine how thiscardioprotective effect is influenced by the timing ofmetoprolol therapy having either a long or shortmetoprolol bolus-to-reperfusion interval.

METHODS We performed a post hoc analysis ofthe METOCARD-CNIC (effect of METOprolol ofCARDioproteCtioN during an acute myocardial InfarCtion)trial, which randomized anterior STEMI patients to IVmetoprolol or control before mechanical reperfusion.Treated patients were divided into short- and long-interval groups, split by the median time from 15 mgmetoprolol bolus to reperfusion. We also performed acontrolled validation study in 51 pigs subjected to 45 minischemia/reperfusion. Pigs were allocated to IV metoprololwith a long (�25 min) or short (�5 min) pre-perfusioninterval, IV metoprolol post-reperfusion (þ60 min), or IVvehicle. Cardiac magnetic resonance (CMR) wasperformed in the acute and chronic phases in both clinicaland experimental settings.

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RESULTS For 218 patients (105 receiving IV meto-prolol), the median time from 15 mg metoprolol bolusto reperfusion was 53 min. Compared with patientsin the short-interval group, those with longermetoprolol exposure had smaller infarcts (22.9 g vs.28.1 g; p ¼ 0.06) and higher left ventricular ejectionfraction (LVEF) (48.3% vs. 43.9%; p ¼ 0.019) on day5 CMR. These differences occurred despite totalischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001).There was no between-group difference in the timefrom symptom onset to metoprolol bolus. Inthe animal study, the long-interval group (IVmetoprolol 25 min before reperfusion) had thesmallest infarcts (day 7 CMR) and highest long-termLVEF (day 45 CMR).

CONCLUSIONS In anterior STEMI patients undergoingprimary angioplasty, the sooner IV metoprolol isadministered in the course of infarction, the smallerthe infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicatedexperimental large animal study (49).

Invasive FFR and Noninvasive CFR in theEvaluation of Ischemia: What Is the Future?

N.P. Johnson, et al.

This review provides an integrative and forward-lookingperspective on the gamut of coronary physiology for thediagnosis and management of atherosclerosis. Becauseclinical events serve as the ultimate gold standard, thefuture of all diagnostic tests, including invasive fractionalflow reserve and noninvasive coronary flow reserve,depends on their ability to improve patient outcomes.Given the prominent role of acute coronary syndromesand invasive procedures in cardiology, we practicallyconsider 2 broad categories of patients with coronarydisease: acute and stable. For patients with acutecoronary disease, coronary physiology may potentiallyrefine treatment of the culprit lesion. For both patientswith stable and acute nonculprit disease, reducing hardendpoints with revascularization potentially occurs at thesevere end of the focal physiological spectrum, an areaunder-represented in existing trials. Nonepicardialdisease and diffuse atherosclerosis remain underexploredaspects of coronary physiology for testing of noveltreatments (50).

Kawasaki Disease

J.W. Newburger, et al.

Kawasaki disease is an acute, self-limited vasculitis ofunknown etiology that occurs predominantly in

infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 childrendevelop coronary artery aneurysms; this risk isreduced 5-fold if intravenous immunoglobulin isadministered within 10 days of fever onset. Coronaryartery aneurysms evolve dynamically over time,usually reaching a peak dimension by 6 weeks afterillness onset. Almost all the morbidity and mortalityoccur in patients with giant aneurysms. Risk ofmyocardial infarction from coronary arterythrombosis is greatest in the first 2 years after illnessonset. However, stenosis and occlusion progress overyears. Indeed, Kawasaki disease is no longer a rarecause of acute coronary syndrome presenting inyoung adults. Both coronary artery bypass surgeryand percutaneous intervention have been used totreat Kawasaki disease patients who developmyocardial ischemia as a consequence of coronaryartery aneurysms and stenosis (51).

Long-Term Mortality After CoronaryRevascularization in Nondiabetic Patients WithMultivessel Disease

M. Chang, et al.

BACKGROUND In diabetic patients with multivesselcoronary artery disease (CAD), the survival differencebetween coronary artery bypass graft (CABG) surgeryand percutaneous coronary intervention (PCI) favorsCABG. However, there are few data on the mortalitydifference between the 2 strategies in nondiabeticpatients.

OBJECTIVES This study performed a patient-levelmeta-analysis to compare the effect of CABG versusPCI with drug-eluting stents on long-term mortalityin 1,275 nondiabetic patients with multivessel CAD.

METHODS Individual patient data from the SYNTAX(Synergy between PCI with Taxus and Cardiac Surgery)and the BEST (Randomized Comparison of CoronaryArtery Bypass Surgery and Everolimus-Eluting StentImplantation in the Treatment of Patients withMultivessel Coronary Artery Disease) trials werepooled. The primary outcomewas death fromany cause.

RESULTS The median follow-up time was 61 months(interquartile range: 50 months to 62 months). Therisk of death from any cause was significantly lowerin the CABG group than in the PCI group (hazardratio [HR]: 0.65; 95% confidence interval [CI]: 0.43 to0.98; p ¼ 0.039). A similar finding was observed forthe risk of death from cardiac causes. The superiorityof CABG over PCI was consistent across the majorclinical subgroups. Likewise, the rate of myocardialinfarction was remarkably lower after CABG than



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after PCI (HR: 0.40; 95% CI: 0.24 to 0.65; p < 0.001).However, the rate of stroke was not differentbetween the 2 groups (HR: 1.13; 95% CI: 0.59 to 2.17;p ¼ 0.714). The need for repeat revascularization wassignificantly lower in the CABG group than in the PCIgroup (HR: 0.55; 95% CI: 0.40 to 0.75; p < 0.001).

CONCLUSIONS CABG, as compared with PCI withdrug-eluting stents, significantly reduced the long-term risk of mortality in nondiabetic patients withmultivessel CAD (52).

Long-Term P2Y12-Receptor Antagonists inPost-Myocardial Infarction Patients:Facing a New Trilemma?

D. Alexopoulos, et al.

Physicians considering prescription of P2Y12-receptorantagonist for long-term (>1 year) protection ofpatients post-myocardial infarction face the trilemmaof selecting between clopidogrel, prasugrel, orticagrelor. Differential ischemic benefits derived fromrelevant trials may assist in tailoring treatment,although the different bleeding definitions appliedmake any meaningful comparison of each agent’sbleeding potential very difficult. Considering theavailable data and recognizing the significantlimitation of observations obtained thus far fromsubgroup analyses, prasugrel appears to providehigher anti-ischemic protection than clopidogrel.Ticagrelor seems to be an attractive option for patientswith renal dysfunction, peripheral arterial disease,or following a brief P2Y12-receptor antagonistinterruption, whereas clopidogrel may be advised inthe presence of cost and availability issues. As head-to-head comparative trials between P2Y12-receptorantagonists are lacking, selection of a specific agent bythe clinician should be made on the basis of criticalappraisal of available large clinical datasets (53).

Long-Term Post-Discharge Risks in OlderSurvivors of Myocardial Infarction With andWithout Out-of-Hospital Cardiac Arrest

C.B. Fordyce, et al.

BACKGROUND Out-of-hospital cardiac arrest (OHCA)associated with acute myocardial infarction (MI)confers high in-hospital mortality; however, amongthose patients who survive, little is knownregarding their post-discharge mortality and healthcare use rates.

OBJECTIVES The purpose of this study was to deter-mine 1-year survival and readmission rates afterhospital discharge of older MI survivors with andwithout OHCA.

METHODS Using linked Acute Coronary Treatmentand Intervention Outcomes Network Registry-GetWith the Guidelines and Medicare data, this studyanalyzed 54,860 patients with MI who were olderthan 65 years of age and who had been dischargedalive from 545 U.S. hospitals between April 2011 andDecember 2012. Multivariable models examined theassociations between MI-associated OHCA and 1-yearpost-discharge mortality or all-cause readmissionrates. Patients discharged to hospice were excluded,given their known poor prognosis.

RESULTS Following hospital discharge, comparedwith older MI survivors without OHCA (n ¼ 54,219),those with OHCA (n ¼ 641, 1.2%) were more likely to beyounger, male, and smokers, but less likely to havediabetes, heart failure, or prior revascularization.OHCA patients presented more often with ST-segmentelevation myocardial infarction (63.2% vs. 29.6%) andcardiogenic shock (29.0% vs. 2.2%); however, amongin-hospital MI survivors, OHCA was not associatedwith 1-year post-discharge mortality (unadjusted13.8% vs. 15.8%, p ¼ 0.17, adjusted hazard ratio [HR]:0.89; 95% confidence interval [CI]: 0.68 to 1.15). Incontrast, MI survivors with OHCA actually had lowerunadjusted and adjusted risk of the compositeoutcome of 1-year mortality or all-cause readmissionthan patients without OHCA (44.0% vs. 50.0%,p ¼ 0.03, adjusted HR: 0.84; 95% CI: 0.72 to 0.97).

CONCLUSIONS Among older patients with MI whosurvived to hospital discharge and were not dis-charged to hospice, those presenting with OHCA didnot have higher 1-year mortality or health care userates compared with those MI survivors withoutOHCA. These findings show that the early risk ofadverse events in patients with OHCA does notpersist after hospital discharge, and they supportefforts to improve initial survival rates of olderpatients with MI and OHCA (54).

Management of Patients With NSTE-ACS:A Comparison of the Recent AHA/ACC andESC Guidelines

F. Rodriguez, et al.

Non–ST-segment elevation acute coronary syndromes(NSTE-ACS) are the leading cause of morbidity andmortality from cardiovascular disease worldwide. TheAmerican Heart Association/American College ofCardiology and the European Society of Cardiologyperiodically release practice guidelines to guideclinicians in the management of NSTE-ACS, mostrecently in in 2014 and 2015, respectively. The presentreview compares and contrasts the 2 guidelines, with a


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focus on the strength of recommendation and level ofevidence in the approach to initial presentation anddiagnosis of NSTE-ACS, risk assessment, treatments, andsystems of care. Important differences include the use ofa rapid rule-out protocol with high-sensitivity troponinassays, a preference for prasugrel/ticagrelor andfondaparinux for anticoagulation therapy, and apreference for radial arterial access in the EuropeanSociety of Cardiology guidelines compared with theAmerican Heart Association/American College ofCardiology guidelines. We also highlight the similaritiesand differences in the guidelines for special patientpopulations and suggest areas of further study (55).

Medical Therapy With Versus WithoutRevascularization in Stable Patients WithModerate and Severe Ischemia:The Case for Community Equipoise

G.W. Stone, et al.

All patients with stable ischemic heart disease (SIHD)should be managed with guideline-directed medicaltherapy (GDMT), which reduces progression ofatherosclerosis and prevents coronary thrombosis.Revascularization is also indicated in patients withSIHD and progressive or refractory symptoms, despitemedical management. Whether a strategy of routinerevascularization (with percutaneous coronaryintervention or coronary artery bypass graft surgeryas appropriate) plus GDMT reduces rates of death ormyocardial infarction, or improves quality of lifecompared to an initial approach of GDMT alone inpatients with substantial ischemia is uncertain.Opinions run strongly on both sides, and evidencemay be used to support either approach. Carefulreview of the data demonstrates the limitations ofour current knowledge, resulting in a state ofcommunity equipoise. The ongoing ISCHEMIA trial(International Study of Comparative HealthEffectiveness With Medical and Invasive Approaches)is being performed to determine the optimalapproach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can becontrolled medically. (International Study ofComparative Health Effectiveness With Medical andInvasive Approaches [ISCHEMIA]; NCT01471522) (56).

Medical Treatment and Revascularization Optionsin Patients With Type 2 Diabetes andCoronary Disease

G.B.J. Mancini, et al.

BACKGROUND There are scant outcomes data in pa-tients with type 2 diabetes and stable coronary artery

disease (CAD) stratified by detailed angiographic burdenof CAD or left ventricular ejection fraction (LVEF).

OBJECTIVES This study determined the effect ofoptimal medical therapy (OMT), with or withoutpercutaneous coronary intervention (PCI) or coronaryartery bypass grafting (CABG), on long-term outcomeswith respect to LVEF and number of diseased vessels,including proximal left anterior descending arteryinvolvement.

METHODS A patient-level pooled analysis wasundertaken in 3 federally-funded trials. The primaryendpoint was the composite of death, myocardialinfarction (MI), or stroke, adjusted for trial andrandomization strategy.

RESULTS Among 5,034 subjects, 15% had LVEF <50%,77% had multivessel CAD, and 28% had proximal leftanterior descending artery involvement. During amedian 4.5-year follow-up, CABG þ OMT was superiorto PCI þ OMT for the primary endpoint (hazard ratio[HR]: 0.71; 95% confidence interval [CI]: 0.59 to 0.85;p ¼ 0.0002), death (HR: 0.76; 95% CI: 0.60 to 0.96;p ¼ 0.024), and MI (HR: 0.50; 95% CI: 0.38 to 0.67;p ¼ 0.0001), but not stroke (HR: 1.54; 95% CI: 0.96 to2.48; p ¼ 0.074). CABG þ OMT was also superior toOMT alone for prevention of the primary endpoint(HR: 0.79; 95% CI: 0.64 to 0.97; p ¼ 0.022) and MI(HR: 0.55; 95% CI: 0.41 to 0.74; p ¼ 0.0001), and wassuperior to PCI þ OMT for the primary endpoint inpatients with 3-vessel CAD (HR: 0.72; 95% CI: 0.58 to0.89; p ¼ 0.002) and normal LVEF (HR: 0.71; 95% CI:0.58 to 0.87; p ¼ 0.0012). There were no significantdifferences in OMT versus PCI þ OMT.

CONCLUSIONS CABG þ OMT reduced the primaryendpoint during long-term follow-up in patients withtype 2 diabetes and stable CAD, supporting this asthe preferred management strategy (57).

Post-Hospital Outcomes of Patients With AcuteMyocardial Infarction With Cardiogenic Shock:Findings From the NCDR

R.U. Shah, et al.

BACKGROUND Many patients with acute myocardialinfarction (AMI) and cardiogenic shock survive hospitali-zation; little is known about their subsequent prognosis.

OBJECTIVES This study sought to evaluate the asso-ciations between cardiogenic shock and post-discharge mortality and all-cause hospitalizationamong hospital survivors.

METHODS We included patients $65 years of age withAMI from the ACTION Registry–GWTG (Acute Coro-nary Treatment and Intervention Outcomes Network




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Registry–Get With The Guidelines) who survivedhospitalization and linked these patients with Medi-care claims data. We used proportional hazardsmodels to test the association between cardiogenicshock and outcomes, adjusting for patient and hospi-tal characteristics. Hazard ratios (HRs) are reported forearly (1 to 60 days) and late (61 to 365 days) post-discharge time periods.

RESULTS Among 112,668 AMI survivors, 5% hadcardiogenic shock during hospitalization. The rate ofdeath was significantly higher among patients withcardiogenic shock at 60 days (9.6% vs. 5.5%) and 1 year(22.4% vs. 16.7%). After accounting for baseline char-acteristics, the risk of death remained higher forcardiogenic shock patients in the first 60 days afterdischarge (adjusted HR: 1.62; 95% confidence interval[CI]: 1.46 to 1.80), but was similar to nonshock pa-tients thereafter (adjusted HR: 1.08 for days 61 to 365;95% CI: 1.00 to 1.18). The rate of all-causehospitalization or death was significantly higheramong shock patients at 60 days (33.9% vs. 24.9%)and 1 year (59.1% vs. 52.3%). After adjustment, therisk of this outcome was also clustered in the first 60days (adjusted HR: 1.28; 95% CI: 1.21 to 1.35) and wassimilar thereafter (adjusted HR: 0.95 for days 61 to365; 95% CI: 0.89 to 1.01).

CONCLUSIONS Hospital survivors of AMI who hadcardiogenic shock have a higher risk of death and/orhospitalization during the first year after discharge. Therisk is time-dependent and is clustered in the early post-discharge period, after which the prognosis is similar inpatients with and without cardiogenic shock (58).

Proton-Pump Inhibitors Reduce GastrointestinalEvents Regardless of Aspirin Dose in PatientsRequiring Dual Antiplatelet Therapy

M. Vaduganathan, et al.

BACKGROUND The COGENT (Clopidogrel and the Opti-mization of Gastrointestinal Events Trial) showed thatproton-pump inhibitors (PPIs) safely reduced rates ofgastrointestinal (GI) events in patients requiring dualantiplatelet therapy (DAPT). However, utilization ofappropriate prophylactic PPI therapy remainssuboptimal, especially with low-dose aspirin.

OBJECTIVES The authors investigated the safety andefficacy of PPI therapy in patients receiving DAPT inlow- and high-dose aspirin subsets.

METHODS Randomized patients with availableaspirin dosing information in COGENT (N ¼ 3,752) weredivided into “low-dose” (#100 mg) and “high-dose”(>100 mg) aspirin groups. The primary GI

and cardiovascular endpoints were composite upper GIevents and major adverse cardiac events, respectively.All events were adjudicated by independent, blindedgastroenterologists and cardiologists.

RESULTS Median duration of follow-up was 110 days.Low-dose aspirin users (n ¼ 2,480; 66.1%) were morelikely to be older, female, and have higher rates ofperipheral artery disease, prior stroke, and hyperten-sion, whereas high-dose aspirin users (n ¼ 1,272;33.9%) had higher rates of hyperlipidemia, smoking, ahistory of percutaneous coronary intervention, andwere more than twice as likely to be enrolled fromsites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-dayKaplan-Meier estimates of adjudicated composite GIevents (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95%confidence interval: 0.46 to 1.66) and major adversecardiac events (4.8% vs. 5.5%; adjusted hazard ratio:0.73; 95% confidence interval: 0.48 to 1.11) comparedwith low-dose aspirin. Randomization to PPI therapyreduced 180-day Kaplan-Meier estimates of theprimary GI endpoint in low-dose (1.2% vs. 3.1%) andhigh-dose aspirin subsets (0.9% vs. 2.6%; p forinteraction ¼ 0.80), and did not adversely affect theprimary cardiovascular endpoint in either group.

CONCLUSIONS Gastroprotection with PPI therapyshould be utilized in appropriately selected patients withcoronary artery disease requiring DAPT, even if the pa-tients are on low-dose aspirin. (Clopidogrel and theOptimization of Gastrointestinal Events Trial[COGENT]; NCT00557921) (59).

Radial Artery as a Coronary Artery BypassConduit: 20-Year Results

M. Gaudino, et al.

BACKGROUND There is a lack of evidence for thechoice of the second conduit in coronary surgery. Theradial artery (RA) is a possible option, but few data onvery-long-term outcomes exist.

OBJECTIVES This study describes 20-year resultsof RA grafts used for coronary artery bypassgrafting and the effects of RA removal on forearmcirculation.

METHODS We report the results of the prospective 20-year follow-up of the first 100 consecutive patientswho received the RA as a coronary bypass conduit atour institution.

RESULTS Follow-up was 100% complete. There were 64deaths, 23 (35.9%) from cardiovascular causes. Kaplan-Meier 20-year survival was 31%. Of the 36 survivors, 33(91.6%) underwent RA graft control at a mean of 19.0 �



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2.5 years after surgery. The RA was found to be patent in24 cases (84.8% patency). In the overall population,probability of graft failure at 20 years was 19.0 � 0.2%for the left internal thoracic artery (ITA), 25.0 � 0.2% forthe RA, and 55.0 � 0.2% for the saphenous vein(p ¼ 0.002 for RA vs. saphenous vein, 0.11 for RA vs.ITA, and p < 0.001 for ITA vs. saphenous vein). Targetvessel stenosis >90%, but not location of distalanastomosis, significantly influenced long-term RA graftpatency. No patients reported hand or forearmsymptoms. The ulnar artery diameter was increased inthe operated arm (2.44 � 0.43 mm vs. 2.01 � 0.47 mm;p < 0.05) and correlated with the peak systolic velocityof the second palmar digital artery (Pearson coefficient:0.621; p < 0.05).

CONCLUSIONS The 20-year patency rate of RA graftsis good, and not inferior to the ITA, especially whenthe conduit is used to graft a vessel with >90%stenosis. RA harvesting does not lead to hand orforearm symptoms, even at a very-long-term follow-up (60).

Safety and Efficacy of Everolimus- VersusSirolimus-Eluting Stents: 5-Year Results FromSORT OUT IV

L.O. Jensen, et al.

BACKGROUND Long-term safety and efficacy foreverolimus-eluting stents (EES) versus those ofsirolimus-eluting stents (SES) are unknown.

OBJECTIVES This study compared 5-year outcomesfor EES with those for SES from the SORT OUT IV(Scandinavian Organization for Randomized Trialswith Clinical Outcome) trial.

METHODS Five-year follow-up was completed for2,771 patients (99.9%). Primary endpoint was acomposite of major adverse cardiac events (MACE),including cardiac death, myocardial infarction (MI),target vessel revascularization (TVR), and definitestent thrombosis.

RESULTS At 5-years, MACE occurred in 14.0% and17.4% in the EES and SES groups, respectively(hazard ratio [HR]: 0.80, 95% confidence interval[CI]: 0.66 to 0.97; p ¼ 0.02). The MACE rate did notdiffer significantly within the first year (HR: 0.96,95% CI: 0.71 to 1.19; p ¼ 0.79), but from years 1through 5, the MACE rate was lower with EES(HR: 0.71, 95% CI: 0.55 to 0.90; p ¼ 0.006;p interaction ¼ 0.12). Definite stent thrombosis waslower with EES (0.4%) than with SES (2.0%; HR:0.18, 95% CI: 0.07 to 0.46), with a lower risk of verylate definite stent thrombosis in the EES group

(0.2% vs. 1.4%, respectively; HR: 0.16, 95% CI: 0.05to 0.53). When censoring the patients at the time ofstent thrombosis, we found no significant differencesbetween the 2 stent groups for MACE rates (HR: 0.89,95% CI: 0.73 to 1.08; p ¼ 0.23), target lesion revas-cularization (HR: 0.90, 95% CI: 0.64 to 1.27; p ¼ 0.55),and MI (HR: 0.93, 95% CI: 0.64 to 1.36; p ¼ 0.72).

CONCLUSIONS At 5-year follow-up, MACE rate wassignificantly lower with EES- than with SES-treatedpatients, due largely due to a lower risk of very latedefinite stent thrombosis. (Randomized ClinicalComparison of the Xience V and the Cypher CoronaryStents in Non-selected Patients With Coronary HeartDisease [SORT OUT IV]; NCT00552877) (61).

Single-Staged Compared With Multi-StagedPCI in Multivessel NSTEMI Patients:The SMILE Trial

G. Sardella, et al.

BACKGROUND A lack of clarity exists about the role ofcomplete coronary revascularization in patients pre-senting with non–ST-segment elevation myocardialinfarction.

OBJECTIVES The aim of our studywas to compare long-term outcomes in terms of major adverse cardiovascularand cerebrovascular events of 2 different completecoronary revascularization strategies in patientswith non–ST-segment elevation myocardial infarctionand multivessel coronary artery disease: 1-stagepercutaneous coronary intervention (1S-PCI) during theindex procedure versus multistage percutaneouscoronary intervention (MS-PCI) complete coronaryrevascularization during the index hospitalization.

METHODS In the SMILE (Impact of Different Treatmentin Multivessel Non ST Elevation Myocardial InfarctionPatients: One Stage Versus Multistaged PercutaneousCoronary Intervention) trial, 584 patients wererandomly assigned in a 1:1 manner to 1S-PCI or MS-PCI.The primary study endpoint was the incidence of majoradverse cardiovascular and cerebrovascular events,which were defined as cardiac death, death,reinfarction, rehospitalization for unstable angina,repeat coronary revascularization (target vesselrevascularization), and stroke at 1 year.

RESULTS The occurrence of the primary endpoint wassignificantly lower in the 1-stage group (1S-PCI: n ¼ 36[13.63%] vs. MS-PCI: n ¼ 61 [23.19%]; hazard ratio [HR]:0.549 [95% confidence interval (CI): 0.363 to 0.828];p ¼ 0.004). The 1-year rate of target vessel revasculariza-tion was significantly higher in the MS-PCI group (1S-PCI:n ¼ 22 [8.33%] vs. MS-PCI: n ¼ 40 [15.20%]; HR: 0.522

https://clinicaltrials.gov/ct2/show/NCT00552877?term=NCT00552877&rank=1



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[95% CI: 0.310 to 0.878]; p ¼ 0.01; p log-rank ¼ 0.013).When the analyses were limited to cardiac death (1S-PCI: n ¼ 9 [3.41%] vs. MS-PCI: n ¼ 14 [5.32%]; HR: 0.624[95% CI: 0.270 to 1.441]; p ¼ 0.27) and myocardialinfarction (1S-PCI: n ¼ 7 [2.65%] vs. MS-PCI: n ¼ 10[3.80%]; HR: 0.678 [95% CI: 0.156 to 2.657]; p ¼ 0.46),no significant differenceswere observed between groups.

CONCLUSIONS In multivessel non–ST-segment eleva-tion myocardial infarction patients, complete 1-stagecoronary revascularization is superior to multistage PCIin terms of major adverse cardiovascular andcerebrovascular events. (Impact of Different Treatmentin Multivessel Non ST Elevation Myocardial Infarction[NSTEMI] Patients: One Stage Versus MultistagedPercutaneous Coronary Intervention [PCI] [SMILE]:NCT01478984) (62).

The Hybrid Algorithm for TreatingChronic Total Occlusions in Europe:The RECHARGE Registry

J. Maeremans, et al.

BACKGROUND The hybrid algorithm for chronic totalocclusion (CTO) percutaneous coronary intervention(PCI) was developed to improve procedural outcomes.Large, prospective studies validating the algorithm ina broad multicenter setting with operators of differentexperience levels are lacking.

OBJECTIVES The RECHARGE (REgistry of Crossbossand Hybrid procedures in FrAnce, the NetheRlands,BelGium and UnitEd Kingdom) registry aims to reportachievable results using the hybrid algorithm.

METHODS Between January 2014 and October 2015,consecutive patients undergoing hybrid CTO-PCI wereprospectively enrolled in 17 centers. Proceduraltechniques, outcomes, and in-hospital complicationswere analyzed.

RESULTS A total of 1,253 CTO-PCIs were performed in1,177 patients, of which 86% were men. Mean age was66 � 11 years. The average Japanese CTO score was2.0 � 1.0, and was higher in the failure group (2.6 �0.6 vs. 1.9 � 1.0; p < 0.001). Overall procedure successwas 86% and major in-hospital complicationsoccurred in 2.6%. Antegrade wire escalation was thepreferred primary strategy in 77%, followed byretrograde (17%) and antegrade dissection re-entrystrategies (7%). Primary strategies were successful in60%. Consecutive strategies were applied in 34% andwere successful in 74%. Antegrade dissection re-entryand retrograde strategies were the most commonbailout strategies and were successful in 67% and62%, respectively. Median procedure and fluoroscopy

time were 90 (interquartile range [IQR]: 60 to 120)min and 35 (IQR: 21 to 55) min, contrast volume was250 (IQR: 180 to 340) ml, and radiation doses (airkerma and dose area product) were 1.6 (IQR: 1.0 to2.7) Gy and 98 (IQR: 57 to 168) Gy$cm2, respectively.

CONCLUSIONS High procedure and patient successrates, combined with a low event rate and improvedprocedural characteristics, support further use of thehybrid algorithm for a broad community of appropri-ately trained CTO operators (63).

The Prognostic Value of Residual CoronaryStenoses After Functionally CompleteRevascularization

Y. Kobayashi, et al.

BACKGROUND The residual SYNTAX score (RSS) andSYNTAX revascularization index (SRI) quantitativelyassess angiographic completeness of revascularizationfor patients with multivessel coronary artery disease.Whether residual angiographic disease remains ofprognostic importance after “functionally” completerevascularization with fractional flow reserve (FFR)guidance is unknown.

OBJECTIVES This study sought to investigate theprognostic value of the RSS and SRI after FFR-guidedfunctionally complete revascularization.

METHODS From the FFR-guided percutaneous coronaryintervention (PCI) cohort of the FAME (Fractional FlowReserve Versus Angiography for Multivessel Evaluation)trial, the RSS and SRI were calculated in 427 patientsafter functionally complete revascularization. The RSSwas defined as the SYNTAX score (SS) recalculated afterPCI. The SRI was calculated as: 100 � (1 � RSS/baselineSS) (%). We compared differences in 1- and 2-yearoutcomes among patients with RSS of 0, >0 to 4, >4 to8, and >8, and with SRI of 100%, 50% to <100%, and0 to <50%.

RESULTS The mean baseline SS, RSS, and SRI were14.4 � 7.2, 6.5 � 5.8, and 55.1 � 32.5%, respectively.Major adverse cardiac events (MACE) at 1 yearoccurred in 53 patients (12.4%). Patients with MACEhad higher SS than those without (18.0 [interquartilerange (IQR): 11.0 to 21.0] vs. 12.0 [IQR: 9.0 to 18.0],p ¼ 0.001), but had similar RSS and SRI after PCI (RSS:6.0 [IQR: 3.0 to 10.0] vs. 5.0 [IQR: 2.0 to 9.5], p ¼ 0.51and SRI: 60.0% [IQR: 40.9% to 78.9%] vs. 58.8%[IQR: 26.7% to 81.8%], p ¼ 0.24, respectively). Kaplan-Meier analysis showed similar 1-year incidence ofMACE with RSS/SRI stratifications (log-rank p ¼ 0.55and p ¼ 0.54, respectively). Results were similarwith 2-year outcome data analysis.



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CONCLUSIONS After functionally complete revascu-larization with FFR guidance, residual angiographiclesions that are not functionally significant do notreflect residual ischemia or predict a worse outcome,supporting functionally complete, rather than angio-graphically complete, revascularization. (FractionalFlow Reserve Versus Angiography for MultivesselEvaluation [FAME]; NCT00267774) (64).

The Risk Continuum of Atherosclerosis and itsImplications for Defining CHD byCoronary Angiography

A. Arbab-Zadeh, et al.

Patients undergoing coronary angiography for suspectedcoronary heart disease who are found to have coronaryatherosclerotic disease with <50% diameter stenosismay carry a risk of adverse cardiac events similar tothat in patients with single-vessel obstructive disease.Yet clinical practice guidelines offer no direction formanaging symptomatic patients with nonobstructivecoronary atherosclerosis because current diagnosticcriteria for coronary heart disease are not met.Accordingly, secondary preventive measures are notendorsed, and their role is not defined in this setting.Available data suggest that we are missing theopportunity to provide effective preventive measures inmillions of patients with nonobstructive coronary heartdisease. The emergence of noninvasive coronaryangiography in patients with suspected coronary heartdisease provides the opportunity to transition from acategorical perspective on the presence or absence ofcoronary heart disease to accepting the risk continuumfrom atherosclerosis and its implications for diagnosisand management (65).

Transatlantic Comparison of ST-SegmentElevation Myocardial Infarction Guidelines:Insights From the United States and Europe

K.R. Bainey, et al.

ST-segment elevation myocardial infarction (STEMI)remains a significant global public health concern.Practice guidelines in both the United States and Europehave been major contributors to providing evidence-based care. Rapid advances in contemporary therapiesmandate regular and timely updates to guidelinerecommendations. In the fall of 2012, the EuropeanSociety of Cardiology published their latest guidelines forthe management of STEMI. In 2013 (w3 months later),the American College of Cardiology Foundation and theAmerican Heart Association jointly published their mostrecent STEMI guideline statements. In this review, we

compare the transatlantic guidelines, highlightingdifferences in their recommendations and the interpreta-tion of evidence addressing STEMI care (66).

C
VD PREVENTION & HEALTH PROMOTION
A Comprehensive Lifestyle Peer Group–BasedIntervention on Cardiovascular Risk Factors:The Randomized Controlled Fifty-Fifty Program

E. Gómez-Pardo, et al.

BACKGROUND Cardiovascular diseases stem frommodifiable risk factors. Peer support is a provenstrategy for many chronic illnesses. Randomized trialsassessing the efficacy of this strategy for global car-diovascular risk factor modification are lacking.

OBJECTIVES This study assessed the hypothesis that apeer group strategy would help improve healthy behav-iors in individuals with cardiovascular risk factors.

METHODS A total of 543 adults 25 to 50 years of agewith at least 1 risk factor were recruited; risk factorsincluded hypertension (20%), overweight (82%),smoking (31%), and physical inactivity (81%). Subjectswere randomized 1:1 to a peer group–basedintervention group (IG) or a self-management controlgroup (CG) for 12 months. Peer-elected leadersmoderated monthly meetings involving role-play,brainstorming, and activities to address emotions,diet, and exercise. The primary outcome was meanchange in a composite score related to bloodpressure, exercise, weight, alimentation, and tobacco(Fuster-BEWAT score, 0 to 15). Multilevel modelswith municipality as a cluster variable were appliedto assess differences between groups.

RESULTS Participants’ mean age was 42 � 6 years, 71%were female, and they had a mean baseline Fuster-BEWAT score of 8.42 � 2.35. After 1 year, the meanscores were significantly higher in the IG (n ¼ 277) thanin the CG (n ¼ 266) (IG mean score: 8.84; 95%confidence interval [CI]: 8.37 to 9.32; CG mean score:8.17; 95% CI: 7.55 to 8.79; p ¼ 0.02). The increase in theoverall score was significantly larger in the IG comparedwith the CG (difference: 0.75; 95% CI: 0.32 to 1.18;p ¼ 0.02). The mean improvement in the individualcomponents was uniformly greater in the IG, with asignificant difference for the tobacco component.

CONCLUSIONS The peer group intervention had bene-ficial effects on cardiovascular risk factors, with signifi-cant improvements in the overall score and specificallyon tobacco cessation. A follow-up assessment will beperformed 1 year after the final assessment reportedhere to determine long-term sustainability of the




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improvements associated with peer group intervention.(Peer-Group-Based Intervention Program [Fifty-Fifty];NCT02367963) (67).

Aspirin and Cancer

P. Patrignani, et al.

The place of aspirin in primary prevention remainscontroversial, with North American and Europeanorganizations issuing contradictory treatment guidelines.More recently, the U.S. Preventive Services Task Forcerecommended “initiating low-dose aspirin use for theprimary prevention of cardiovascular disease (CVD) andcolorectal cancer in adults aged 50 to 59 years who havea 10% or greater 10-year CVD risk, are not at increasedrisk for bleeding, have a life expectancy of at least 10years, and are willing to take low-dose aspirin daily forat least 10 years.” This recommendation reflectsincreasing evidence for a chemopreventive effect of low-dose aspirin against colorectal (and other) cancer. Theintent of this paper is to review the evidence supportinga chemopreventive effect of aspirin, discuss its potentialmechanism(s) of action, and provide a conceptualframework for assessing current guidelines in the light ofongoing studies (68).

Assessing the Impact of Medication Adherenceon Long-Term Cardiovascular Outcomes

S. Bansilal, et al.

BACKGROUND Although guideline-recommendedtherapies reduce major adverse cardiovascularevents (MACE) in patients after myocardial infarction(MI) or those with atherosclerotic disease (ATH),adherence is poor.

OBJECTIVES The goal of this study was to determinethe association between medication adherence levelsand long-term MACE in these patients.

METHODS We queried the claims database of a largehealth insurer for patients hospitalized for MI or withATH. The primary outcome measure was a composite ofall-cause death, MI, stroke, or coronary revascularization.Using proportion of days covered for statins andangiotensin-converting enzyme inhibitors, patientswere stratified as fully adherent ($80%), partiallyadherent ($40% to #79%), or nonadherent (<40%).Per-patient annual direct medical (ADM) costs wereestimated by using unit costs from 2 national files.

RESULTS Data were analyzed for 4,015 post-MI patientsand 12,976 patients with ATH. In the post-MI cohort, thefully adherent group had a significantly lower rate ofMACE than the nonadherent (18.9% vs. 26.3%; hazardratio [HR]: 0.73; p ¼ 0.0004) and partially adherent

(18.9% vs. 24.7%; HR: 0.81; p ¼ 0.02) groups at 2 years.The fully adherent group had reduced per-patient ADMcosts for MI hospitalizations of $369 and $440 comparedwith the partially adherent and nonadherent groups,respectively. In the ATH cohort, the fully adherent grouphad a significantly lower rate of MACE than thenonadherent (8.42% vs. 17.17%; HR: 0.56; p < 0.0001)and the partially adherent (8.42% vs. 12.18%; HR: 0.76;p < 0.0001) groups at 2 years. The fully adherent grouphad reduced per-patient ADM costs for MIhospitalizations of $371 and $907 compared with thepartially adherent and nonadherent groups.

CONCLUSIONS Full adherence to guideline-recommended therapies was associated with a lowerrate of MACE and cost savings, with a thresholdeffect at >80% adherence in the post-MI population;at least a 40% level of long-term adherence needs tobe maintained to continue to accrue benefit. Novelapproaches to improve adherence may significantlyreduce cardiovascular events (69).

Association Between a Social-Business EatingPattern and Early AsymptomaticAtherosclerosis

J.L. Peñalvo, et al.

BACKGROUND The importance of a healthy diet inrelation to cardiovascular health promotion is widelyrecognized. Identifying specific dietary patterns relatedto early atherosclerosis would contribute greatly toinform effective primary prevention strategies.

OBJECTIVES This study sought to quantify the asso-ciation between specific dietary patterns and presenceand extent of subclinical atherosclerosis in a popula-tion of asymptomatic middle-aged adults.

METHODS The PESA (Progression of Early SubclinicalAtherosclerosis) study enrolled 4,082 asymptomaticparticipants 40 to 54 years of age (mean age 45.8years; 63% male) to evaluate the presence of subclin-ical atherosclerosis in multiple vascular territories. Afundamental objective of this cohort study was toevaluate the life-style–related determinants,including diet, on atherosclerosis onset and develop-ment. We conducted a cross-sectional analysis ofbaseline data, including detailed information ondietary habits obtained as part of the overalllife-style and risk factor assessment, as well as acomplete vascular imaging study that was performedblinded to the clinical information.

RESULTS Most PESA participants follow a Mediterra-nean (40% of participants) or a Western (41%) dietarypattern. A new pattern, identified among 19% of partici-pants, was labeled as a social-business eating pattern,



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characterized by a high consumption of red meat, pre-made foods, snacks, alcohol, and sugar-sweetenedbeverages and frequent eating-out behavior.Participants following this pattern presented asignificantly worse cardiovascular risk profile and, afteradjustment for risk factors, increased odds of presentingsubclinical atherosclerosis (odds ratio: 1.31; 95%confidence interval: 1.06 to 1.63) compared withparticipants following a Mediterranean diet.

CONCLUSIONS A new social-business eating pattern,characterized by high consumption of red andprocessed meat, alcohol, and sugar-sweetenedbeverages, and by frequent snacking and eating outas part of an overall unhealthy life-style, isassociated with an increased prevalence, burden,and multisite presence of subclinical atherosclerosis.(Progression of Early Subclinical Atherosclerosis[PESA]; NCT01410318) (70).

Exercise at the Extremes: The Amount of Exerciseto Reduce Cardiovascular Events

T.M.H. Eijsvogels, et al.

Habitual physical activity and regular exercise trainingimprove cardiovascular health and longevity. Aphysically active lifestyle is, therefore, a key aspect ofprimary and secondary prevention strategies. Anappropriate volume and intensity are essential tomaximally benefit from exercise interventions. Thisdocument summarizes available evidence on therelationship between the exercise volume and riskreductions in cardiovascular morbidity and mortality.Furthermore, the risks and benefits of moderate- versushigh-intensity exercise interventions are compared.Findings are presented for the general populationand cardiac patients eligible for cardiac rehabilitation.Finally, the controversy of excessive volumes ofexercise in the athletic population is discussed (71).

Family-Based Approaches to CardiovascularHealth Promotion

R. Vedanthan, et al.

Cardiovascular disease is the leading cause of mortalityin the world, and the increasing burden is largely aconsequence of modifiable behavioral risk factors thatinteract with genomics and the environment.Continuous cardiovascular health promotion anddisease prevention throughout the lifespan is critical,and the family is a central entity in this process.In this review, we describe the potential rationaleand mechanisms that contribute to the importanceof family for cardiovascular health promotion,

focusing on: 1) mutual interdependence of thefamily system; 2) shared environment; 3) parentingstyle; 4) caregiver perceptions; and 5) genomics.We conclude that family-based approaches thattarget both caregivers and children, encouragecommunication among the family unit, and addressthe structural and environmental conditions inwhich families live and operate are likely to be themost effective approach to promote cardiovascularhealth. We describe lessons learned, futureimplications, and applications to ongoing andplanned studies (72).

Heavy Metals, Cardiovascular Disease, and theUnexpected Benefits of Chelation Therapy

G.A. Lamas, et al.

This review summarizes evidence from 2 lines ofresearch previously thought to be unrelated: theunexpectedly positive results of TACT (Trial toAssess Chelation Therapy), and a body ofepidemiological data showing that accumulation ofbiologically active metals, such as lead and cadmium,is an important risk factor for cardiovascular disease.Considering these 2 areas of work together may leadto the identification of new, modifiable risk factorsfor atherosclerotic cardiovascular disease. Weexamine the history of chelation up through thereport of TACT. We then describe work connectinghigher metal levels in the body with the future risk ofcardiovascular disease. We conclude by presenting abrief overview of a newly planned National Institutesof Health trial, TACT2, in which we will attempt toreplicate the findings of TACT and to establish thatremoval of toxic metal stores from the body is aplausible mechanistic explanation for the benefits ofedetate disodium treatment (73).

Testosterone and Cardiovascular Disease

R.A. Kloner, et al.

Testosterone (T) is the principal male sex hormone.As men age, T levels typically fall. Symptoms oflow T include decreased libido, vasomotor instability,and decreased bone mineral density. Other symptomsmay include depression, fatigue, erectile dysfunction,and reduced muscle strength/mass. Epidemiologystudies show that low levels of T are associatedwith more atherosclerosis, coronary artery disease,and cardiovascular events. However, treatinghypogonadism in the aging male has resulted indiscrepant results in regard to its effect oncardiovascular events. Emerging studies suggest that




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T may have a future role in treating heart failure,angina, and myocardial ischemia. A large,prospective, long-term study of T replacement, with aprimary endpoint of a composite of adversecardiovascular events including myocardial infarction,

stroke, and/or cardiovascular death, is needed. TheFood and Drug Administration recently put additionalrestrictions on T replacement therapy labeling andcalled for additional studies to determine its cardiacsafety (74).

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Editor-in-Chief sTopPicksFrom2016: Part One filethe hearts of patients with a primary diagnosis of AD, affecting myocardial function. METHODS The authors examined myocardial function