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On July 31, 2002, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) published the International Position Paper on Women’s Health and Menopause: A Comprehensive Approach .1 This landmark report was developed over a period of 4 years by an international, interdisciplinary team of experts in collaboration with the NHLBI, the Giovanni Lorenzini Medical Science Foundation, and the NIH Office of Research on Women’s Health (ORWH). There is need for a new, comprehensive approach to women’s health and menopause. Scientific evidence worldwide supports this redirection in the management of women’s health during and after the menopause transition. This perspective highlights some of the findings and conclusions in the executive summary. Comment is added regarding pivotal studies published subsequent to the completion of the International Position Paper . Women’s health and menopause is a rapidly expanding field of medical practice and scientific investigation. It has great social importance and economic impact nationally and globally, in both developed and developing countries. The International Position Paper is a joint effort to begin to address these challenges at the global level. This multidisciplinary monograph is designed to enhance the composite health of menopausal women on a global basis, with consideration of sociocultural concerns and economic issues. Importantly, a goal of this monograph is that the materials be reproduced and translated in individual countries for optimal global dissemination, which will be furthered by presentations at topic-related scientific meetings. This monograph represents the culmination of 7 years of cooperation between the NHLBI and the Giovanni Lorenzini Medical Science Foundation in a public/private partnership in the development and cosponsorship of 4 international conferences on Women’s Health and Menopause since the mid-1990s. These conferences have addressed not only cardiovascular disease, but other health issues such as cancer, osteoporosis, mental health, Alzheimer’s …

Although the number of cardiovascular deaths associated with environmental tobacco smoke cannot be predicted with absolute certainty, the available evidence indicates that environmental tobacco smoke increases the risk of heart disease. The effects of environmental tobacco smoke on cardiovascular function, platelet function, neutrophil function, and plaque formation are the probable mechanisms leading to heart disease. The risk of death due to heart disease is increased by about 30% among those exposed to environmental tobacco smoke at home and could be much higher in those exposed at the workplace, where higher levels of environmental tobacco smoke may be present. Even though considerable uncertainty is a part of any analysis on the health affects of environmental tobacco smoke because of the difficulty of conducting long-term studies and selecting sample populations, an estimated 35,000-40,000 cardiovascular disease-related deaths and 3,000-5,000 lung cancer deaths due to environmental tobacco smoke exposure have been predicted to occur each year. The AHA's Council on Cardiopulmonary and Critical Care has concluded that environmental tobacco smoke is a major preventable cause of cardiovascular disease and death. The council strongly supports efforts to eliminate all exposure of nonsmokers to environmental tobacco smoke. This requires that environmental tobacco smoke be treated as an environmental toxin, and ways to protect workers and the public from this health hazard should be developed. According to a 1989 Gallup survey commissioned by the American Lung Association, 86% of nonsmokers think that environmental tobacco smoke is harmful and 77% believe that smokers should abstain in the presence of nonsmokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

From an evidence-based perspective, cardiopulmonary exercise testing (CPX) is a well-supported assessment technique in both the United States (US) and Europe. The combination of standard exercise testing (ET) (ie, progressive exercise provocation in association with serial electrocardiograms [ECG], hemodynamics, oxygen saturation, and subjective symptoms) and measurement of ventilatory gas exchange amounts to a superior method to: 1) accurately quantify cardiorespiratory fitness (CRF), 2) delineate the physiologic system(s) underlying exercise responses, which can be applied as a means to identify the exercise-limiting pathophysiologic mechanism(s) and/or performance differences, and 3) formulate function-based prognostic stratification. Cardiopulmonary ET certainly carries an additional cost as well as competency requirements and is not an essential component of evaluation in all patient populations. However, there are several conditions of confirmed, suspected, or unknown etiology where the data gained from this form of ET is highly valuable in terms of clinical decision making.1 Several CPX statements have been published by well-respected organizations in both the US and Europe.1–5 Despite these prominent reports and the plethora of pertinent medical literature which they feature, underutilization of CPX persists. This discrepancy is at least partly attributable to the fact that the currently available CPX consensus statements are inherently complex and fail to convey succinct, clinically centered strategies to utilize CPX indices effectively. Likewise, current CPX software packages generate an overwhelming abundance of data, which to most clinicians are incomprehensible and abstract. Ironically, in contrast to the protracted scientific statements and dense CPX data outputs, the list of CPX variables that have proven clinical application is concise and uncomplicated. Therefore, the goal of this writing group is to present an approach of CPX in a way that assists in making meaningful decisions regarding a patient’s care. Experts from the European Association for Cardiovascular Prevention and Rehabilitation and American Heart Association have joined in this effort to distill easy-to-follow guidance on CPX interpretation based upon current scientific evidence. This document also provides a series of forms that are designed to highlight the utility of CPX in clinical decision-making. Not only will this improve patient management, it will also catalyze uniform and unambiguous data interpretation across laboratories on an international level. The primary target audience of this position paper is clinicians who have limited orientation with CPX but whose caregiving would be enhanced by familiarity and application of this assessment. The ultimate goal is to increase awareness of the value of CPX and to increase the number of healthcare professionals who are able to perform clinically meaningful CPX interpretation. Moreover, this document will hopefully lead to an increase in appropriate patient referrals to CPX with enhanced efficiencies in patient management. For more detailed information on CPX, including procedures for patient preparation, equipment calibration, and conducting the test, readers are encouraged to review other publications that address these and other topics in great detail.1–5

BACKGROUND Sinking prebeta lipoprotein is a putative marker for elevated levels of lipoprotein (a). Although prospective data suggest that increased plasma lipoprotein (a) is an independent risk factor for coronary heart disease in men, no prospective studies are available in women. METHODS AND RESULTS From 1968 through 1975, sinking prebeta lipoprotein was determined by paper electrophoresis in 3103 women Framingham Heart Study participants who were free of prevalent cardiovascular disease. A sinking prebeta lipoprotein band was detectable in 434 of the women (14%) studied. The median follow-up interval was approximately 12 years. Incident cardiovascular disease was associated with band presence using a proportional hazards model that included age, smoking, body mass index, systolic blood pressure, glucose intolerance, low- and high-density lipoprotein cholesterol, and ECG left ventricular hypertrophy. Multivariable adjusted relative risk estimates (with 95% confidence intervals) for outcomes in the band present versus absent groups were as follows: myocardial infarction (82 events), 2.37 (1.48 to 3.81); intermittent claudication (62 events), 1.94 (1.07 to 3.50); cerebrovascular disease (83 events), 1.88 (1.12 to 3.15); total coronary heart disease (174 events), 1.61 (1.13 to 2.29); and total cardiovascular disease (305 events), 1.44 (1.09 to 1.91). A subset analysis indicated that band presence was 50.9% sensitive and 95.4% specific for detecting plasma lipoprotein (a) levels of > 30 mg/dL, the threshold value linked to increased cardiovascular disease risk in men. CONCLUSIONS Sinking prebeta lipoprotein was a valid surrogate for elevated lipoprotein (a) levels in Framingham Heart Study women. Band presence and, equivalently, elevated plasma lipoprotein (a), was a strong, independent predictor of myocardial infarction, intermittent claudication, and cerebrovascular disease. Confirmation of these findings in other longitudinal studies of women is needed.

The cause of atherosclerosis and reason for its high incidence in diabetes are not known. In this study proteins and lipoids of serums of patients with diabetes or atherosclerosis are examined by paper electrophoresis to determine whether such changes may be a common factor for both of these conditions.

This article describes the case of a 10-year-old girl with generalized tortuosity and lengthening of all her major arteries-the carotid arteries, the aorta from the arcus to the bifurcation, and the iliac, femoral, splenic, hepatic, renal, and intercostal arteries. The condition appears to be a new entity. Pertinent abnormalities were as follows: gross pulsation of the arteries in the neck, telangiectasis of both cheeks, high palate, tortuosity of all the arteries, aortic valvular insufficiency, 1+ to 2+ capillary fragility on tourniquet test (lacet), 1+ Wassermann reaction, 4+ cephalin flocculation, and histological fragmentation of the internal elastic membrane of the arteries. Syphilis, arteriosclerosis, hypertension, mucopolysaccharidosis, and defects of amino acid metabolism were ruled out and the author concludes that the condition was most probably caused by a congenital defect of the elastic tissues of the arterial system.

Three patients with idiopathic orthostatic (postural) hypotension were infused over a 4-hr period with 104.6 µc of 3-hydroxytyramine-2- 14 C, the immediate precursor in the synthesis of the sympathetic neurohormone, that is, noradrenaline (norepinephrine). Urine was collected during the infusion period and at various intervals thereafter for a total of 5 days. By means of column fractionation, the various metabolic products of hydroxytyramine, including endogenous noradrenaline and its metabolic products, were separated, identified, and their radioactivity measured. From the comparison of the hydroxytyramine metabolic pattern of normal subjects to that of idiopathic orthostatic hypotensive patients, it was apparent that the greatest changes occurred in the formation of noradrenaline and 3-methoxy-4-hydroxymandelic acid (MOMA, VMA). The synthesis of noradrenaline was significantly reduced in the hypotensive patients, and there was also a marked reduction in the formation of MOMA, the principal metabolic product of noradrenaline. The implication of these findings is that the pathogenesis of idiopathic orthostatic hypotension is related to a defect in the neurogenic structures involved in the biosynthesis of noradrenaline. This conclusion is further supported by the fact that one of the subjects (M.Q.) at autopsy showed only degenerative changes in the sympathetic ganglia and neurons.

3 H-digitoxin and polyethylene glycol (nonabsorbable marker) were given orally to five subjects provided with a gastrointestinal tube. Of the radioactivity administered, approximately 15, 30, and 70% had been absorbed when the test solution was passing the stomach, the duodenum, and the upper jejunum, respectively. The absorption was rapid, and the plasma contained detectable amounts of radioactivity after 5 minutes. There was no evidence of a disposition of 3 H-digitoxin in intestinal aspirates. On a sixth subject labeled digitoxin was instilled in the mid-jejunum. The concentration of label in the plasma and the pattern of elimination of radioactivity in the urine and the feces in this subject indicated that the absorption of digitoxin was effective also in the more distal part of the gut. The combined results from the present study indicate that the absorption of orally administered digitoxin is complete. The biliary excretion of label 4 to 24 hours after the start of the experiments was calculated from the bilirubin turnover and the mean radioactivity per mg bilirubin in duodenal aspirates obtained after intravenous injections of cholecystokinin. Less than 10% of the administered dose appeared to be excreted with the bile. The radioactivity recovered in plasma showed less decomposition than that found in duodenal bile and urine.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non–vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non–vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Reports highlighting the problems with the standard practice of using bar graphs to show continuous data have prompted many journals to adopt new visualization policies. These policies encourage authors to avoid bar graphs and use graphics that show the data distribution; however, they provide little guidance on how to effectively display data. We conducted a systematic review of studies published in top peripheral vascular disease journals to determine what types of figures are used, and to assess the prevalence of suboptimal data visualization practices. Among papers with data figures, 47.7% of papers used bar graphs to present continuous data. This primer provides a detailed overview of strategies for addressing this issue by (1) outlining strategies for selecting the correct type of figure depending on the study design, sample size, and the type of variable; (2) examining techniques for making effective dot plots, box plots, and violin plots; and (3) illustrating how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. We also present solutions to other common problems identified in the systematic review. Resources include a list of free tools and templates that authors can use to create more informative figures and an online simulator that illustrates why summary statistics are meaningful only when there are enough data to summarize. Last, we consider steps that investigators can take to improve figures in the scientific literature.

Treatment of Heart Failure With Preserved Ejection Fraction: An Unmet Need In 2016, treatment of heart failure with preserved ejection fraction (HFpEF) remains a critical unmet need. A recent guideline publication (1) stated: "No treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF." This fact stands in stark contrast to the disease burden borne by HFpEF patients (2): It is estimated that > 50% of all HF patients have HFpEF; 5 year mortality is > 60%; 6 month re-hospitalization rate for decompensated HFpEF > 50%; many patients have profound disability, often comparable to patients with reduced EF (HFrEF) who are candidates for transplantation. A recent opinion paper by Shah et al (3) discussed phenotypic diversity in the HFpEF population and proposed an approach to treatment based on specific aspects of pathophysiology present in individual patients. The accompanying paper by Methawasin et al (4), with its focus on titin, is an example of how such an approach might ultimately work.

We read with interest the comments of Madias, Dandel et al, and Liu, in response to our paper entitled ‘Systolic and Diastolic Mechanics in Stress Cardiomyopathy’.1 We are gratified that the readers have given our paper such careful attention and were prompted to share their interesting and stimulating ideas on our work. Our group was indeed surprised by the similarities in hemodynamic profiles between stress cardiomyopathy (SCM) and LAD territory infarction (LAD-MI), disorders with very different pathophysiologic bases. Based on our clinical experience with well over 150 SCM patients and countless others with LAD-MI, we fully expected to find that diastolic filling pressures would be much lower in SCM patients than in LAD-MI patients. However, our data, as well those obtained from other studies, call into question previous notions that left …

We read with great interest the paper by Lavoie et al1 and congratulate the authors on this important and pioneering study. The paper shows encouraging evidence which adds to that from our lab2 and others,3 showing that vascular cells derived from adult stem cells (in this paper, blood outgrowth endothelial cells [BOECs]) can be used …

Whole exome sequencing (WES) is currently used to identify the genetic causes of many diseases, especially monogenic disorders. Ng et al,1 in 2009, completed the first proof-of-principle study demonstrating the feasibility of using exome sequencing to identify causal variants for diseases, specifically Freeman-Sheldon syndrome. Within 2 years, there was a marked increase in publications presenting WES data, and the pace continues to accelerate (Figure). In 2010, WES began to be used for clinical diagnoses, particularly for mendelian disorders. In early 2011, Worthey et al2 used exome sequencing to facilitate clinical diagnosis and modify treatment in a single case. Despite many of the successes resulting from exome sequencing, more than half of the approximately 7000 known or suspected mendelian disorders have not yet been discovered,3 which highlights the need for more genetic, mechanistic, and clinical studies, particularly if the data are to be used clinically. Moreover, as our knowledge of the genome increases, examples of some of the complexities associated with genotypic-phenotypic relationships further substantiate the need for both additional genomic annotation and many more sequenced genomes with phenotypic information. Some of these complexities include the following: (1) Variants in the same genes may lead to different clinical manifestations or phenotypes; (2) what appear to be similar phenotypic observations may result from different causal disease variants operating through distinct pathophysiological mechanisms; and (3) the recent ENCODE (Encyclopedia of DNA Elements) papers, which suggest that up to 80% of the human genome is functional.4 Figure. Number of exome sequencing publications by year. “Human exome sequencing” and “human patient exome sequencing” were searched in PubMed. Reviews, perspectives, and methodology papers were excluded. Article see p 1009 In this issue of Circulation , Crotti and colleagues5 use a …

Background— The purpose of this statement is to address the state of evidence on the routine use of pulse oximetry in newborns to detect critical congenital heart disease (CCHD). Methods and Results— A writing group appointed by the American Heart Association and the American Academy of Pediatrics reviewed the available literature addressing current detection methods for CCHD, burden of missed and/or delayed diagnosis of CCHD, rationale of oximetry screening, and clinical studies of oximetry in otherwise asymptomatic newborns. MEDLINE database searches from 1966 to 2008 were done for English-language papers using the following search terms: congenital heart disease, pulse oximetry, physical examination, murmur, echocardiography, fetal echocardiography, and newborn screening. The reference lists of identified papers were also searched. Published abstracts from major pediatric scientific meetings in 2006 to 2008 were also reviewed. The American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. In an analysis of pooled studies of oximetry assessment performed after 24 hours of life, the estimated sensitivity for detecting CCHD was 69.6%, and the positive predictive value was 47.0%; however, sensitivity varied dramatically among studies from 0% to 100%. False-positive screens that required further evaluation occurred in only 0.035% of infants screened after 24 hours. Conclusions— Currently, CCHD is not detected in some newborns until after their hospital discharge, which results in significant morbidity and occasional mortality. Furthermore, routine pulse oximetry performed on asymptomatic newborns after 24 hours of life, but before hospital discharge, may detect CCHD. Routine pulse oximetry performed after 24 hours in hospitals that have on-site pediatric cardiovascular services incurs very low cost and risk of harm. Future studies in larger populations and across a broad range of newborn delivery systems are needed to determine whether this practice should become standard of care in the routine assessment of the neonate.

Background—The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis that were last published in 1997.Methods and Results—A writing group was appointed by the AHA for their expertise in prevention and treatment of infective endocarditis, with liaison members representing the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on infective endocarditis. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and infective endocarditis, in vitro susceptibility data of the most common microorganisms that cause infective endocarditis, results of prophylactic studies in animal models of experimental endocarditis, and retrospective and prospective studies of prevention of infective endocarditis. MEDLINE database searches from 1950 to 2006 were done for English-language papers using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization, and bacteremia. The reference lists of the identified papers were also searched. We also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The paper was subsequently reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee.Conclusions—The major changes in the updated recommendations include the following: (1) The Committee concluded that only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. (2) Infective endocarditis prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. (3) For patients with these underlying cardiac conditions, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when infective endocarditis prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit–risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit–risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit–Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit–risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit–risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit–risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit–risk metric, may aid shared decision-making and enhance transparency of those decisions.

The discovery that end-diastolic volume regulates the work of the heart is generally credited to Ernest Henry Starling, who described this relationship in a series of papers between 1912 and 19141–4⇓⇓⇓ and in his Linacre Lecture, which was given at Cambridge University in 1915 and published in 1918.5 In these papers, Starling and his collaborators acknowledge that they were not the first to describe this relationship6; they cite the work of Blix7 and Evans and Hill8 on the length-dependence of energy release by skeletal muscle, Frank’s 1895 description of the influence of diastolic volume on the work of the frog ventricle,9 and contemporary descriptions in canine10 and feline hearts.11 The present article reviews evidence that what we now call “Starling’s Law of the Heart” or “The Frank-Starling Relationship” was widely appreciated by late 19th century physiologists. Starling’s Law of the Heart is a manifestation of the length-tension relationship seen in skeletal muscle, which was well known to physiologists during the second half of the 19th century. This relationship was discovered in 1832 by Schwann; Needham, who described this history,12 stated that Schwann’s discovery “caused a great sensation among physiologists of the time,” in part because this discovery was made at a time when muscle performance was being analyzed in terms of the then new science of thermodynamics. That contracting muscles liberate energy as both work and heat was first noted by Helmholtz, whose 1848 description of heat production by muscle “… lighted a flame which… burnt brightly in Germany till the end of the [19th] century.”13 Recognition of the role of rest length in determining energy release by skeletal muscle led to studies of cardiac energetics during the second half of the 19th century. ### Diastolic Volume and the Work of the Heart #### Early German Contributions Carl Ludwig …

Infective endocarditis (IE) is associated with substantial morbidity and mortality. Although it is relatively rare in children, its incidence may be increasing.1 This paper focuses on the features that are particularly relevant to infants and children, including important issues for the primary care physician. The epidemiology of heart disease in children has changed over the past 3 to 4 decades. With the increased survival rate of children with congenital heart disease (CHD) and the overall decrease in rheumatic valvular heart disease in developed countries, CHD now constitutes the predominant underlying condition for IE in children over the age of 2 years in these countries. The complexities of management of neonatal and pediatric intensive care unit patients have increased the risks of catheter-related IE. In addition, postoperative IE is a long-term risk following correction of complex CHD. The proper use of the diagnostic microbiology laboratory is critical in the diagnosis and management of children with IE. Moreover, newer diagnostic guidelines have improved sensitivity for making the diagnosis of clinically definite IE. In addition, advances in noninvasive techniques such as two-dimensional (2D) echocardiography have enhanced our ability to diagnose IE. Newer antibiotics have become available that can be used in children with IE, and home intravenous (IV) therapy has become an acceptable approach for stable patients who are at low risk for embolization. Additionally, approaches to the prevention of endocarditis have been recently modified and are reviewed in this paper. IE occurs less commonly in children than in adults and accounts for approximately 1 in 1280 pediatric admissions per year.2 Although the reported hospitalization rates for IE vary considerably among published series, the frequency of endocarditis among children appears to have increased in recent years.3 This is due in part to improved survival among children who are at risk … Address correspondence to Kathryn A. Taubert, PhD, Vice President, Department of Science and Medicine, American Heart Association, 7272 Greenville Ave, Dallas, TX 75231. E-mail: ktaubert{at}heart.org

Over half a century ago, heart specialists – there were no board certified cardiologists yet – began to report unusual phenotypes like very long QT intervals or extraordinary left ventricular hypertrophy that ran in families and caused sudden death in the young. In the 1980s and 90s, linkage analysis in large families identified the first disease genes, landmark discoveries that have been critical for understanding basic physiologic and pathophysiologic processes in the heart, counselling families, defining penetrance that is so often incomplete, and identifying phenotype positive patients in whom coding region variants in these first disease genes were absent. In those patients, disease pathways defined by early rigorous linkage-based studies implicated new candidate genes for mediating these cardiovascular genetic phenotypes. So, for example, once beta-myosin heavy chain mutations were identified in hypertrophic cardiomyopathy (HCM), genes encoding other contractile proteins became logical candidates; similarly, ion channel genes or modifiers were candidates in channelopathies and desmosomal proteins in arrhythmogenic right ventricular cardiomyopathy (ARVC). As a result, we now have long lists of disease genes for major cardiovascular genetic diseases, and dramatic improvements in sequencing costs and efficiencies have enabled widespread application of panel-based sequencing. While these advances have improved care of affected patients and their families, two papers in the current issue of Circulation highlight potential flaws in the logic that underlies increasing use of these panels across large patient populations.(1,2)

We are grateful to Stiermaier et al, Sacha and Feusette, and Bulluck and Hausenloy for their interest and comments on our article,1 in which we showed that myocardial edema in the week after ST-segment–elevation myocardial infarction in humans is a bimodal phenomenon. We concur with Stiermaier et al on the implications of our findings, and the need to put these data into perspective. Indeed, in the discussion of our paper, we speculated on the potential explanations for divergent findings in the literature. It is important to note that our clinical study was specifically designed to validate the hypothesis generated in previous experimental studies,2,3 and thus the timing for each cardiac magnetic resonance (CMR) was exquisitely chosen. Thus, we first analyzed the dynamics of the initial wave of edema (online-only Data Supplement Figure I from Fernandez-Jimenez et al)1 to define the optimal timing for the first CMR scan in patients and not miss the initial wave of edema. The fact that this initial wave of edema peaks very early, and is significantly attenuated …

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient’s genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.

This paper is the first of a series of three which will deal with the relationship between the voltages in electrocardiographic leads and the electromotive forces of the heart. The general purpose of this series is to discuss various experimental and theoretic technics which can be used in the analysis of a given lead, and in the building up, or "synthesis," of leads having desired characteristics. The procedures used are based on a fundamental theorem which takes into account not only the irregular shape and conductivity of the body but also the spatial dispersion of the electromotive forces within the heart. It is closely related to the "lead vector" concept of Burger and van Milaan. In this first paper the basic definitions and theorems are developed. The second paper discusses various methods of analysing leads. The third and last presents a number of systematic procedures for designing leads, both vectorcardiographic and unipolar. Such leads can have substantially higher accuracies than those now in use, because their design takes into account the shape and conductivity of the body and its tissues, and the eccentric and extended location of the heart.

Spurred by advances in processing power, memory, storage, and an unprecedented wealth of data, computers are being asked to tackle increasingly complex learning tasks, often with astonishing success. Computers have now mastered a popular variant of poker, learned the laws of physics from experimental data, and become experts in video games − tasks that would have been deemed impossible not too long ago. In parallel, the number of companies centered on applying complex data analysis to varying industries has exploded, and it is thus unsurprising that some analytic companies are turning attention to problems in health care. The purpose of this review is to explore what problems in medicine might benefit from such learning approaches and use examples from the literature to introduce basic concepts in machine learning. It is important to note that seemingly large enough medical data sets and adequate learning algorithms have been available for many decades, and yet, although there are thousands of papers applying machine learning algorithms to medical data, very few have contributed meaningfully to clinical care. This lack of impact stands in stark contrast to the enormous relevance of machine learning to many other industries. Thus, part of my effort will be to identify what obstacles there may be to changing the practice of medicine through statistical learning approaches, and discuss how these might be overcome.

Good afternoon, and welcome to the Scientific Sessions. On behalf of all of the American Heart Association’s (AHA) clinicians, scientists, lay volunteers, and staff, I extend a warm welcome and offer my thanks for your efforts to understand, prevent, and treat cardiovascular diseases. We are inspired by your dedication to saving and improving lives. The burden of these diseases is something we all share, no matter where we live or work. So let us make the most of our opportunities to learn from one another throughout the Scientific Sessions. For these next 4 days, Chicago is home to the latest in cardiovascular and stroke research. Chicago is also home to significant cardiovascular history. Ninety years ago, Chicago resident Dr James B. Herrick joined Dr Paul Dudley White and 4 other pioneering physicians at Chicago’s Drake Hotel to create the AHA.1 They started this lifesaving organization just 4 miles away from where we are sitting right now. Yet, it was worlds away when we consider what we can offer patients today. We now have tools at our disposal that we could barely imagine only a few years ago. New diagnostic and therapeutic options are being discovered at a pace unseen in human history. We have an unprecedented opportunity to harness these advances to save and improve lives, and that is what I would like to talk to you about. But first, I would like to share a quick illustration of just how much our tools have changed. This 28-pound box is the actual ECG machine Paul Dudley White used in his office decades ago.2 It was considered state of the art back then. With the patient lying supine and connected to the device, a paper recording of the ECG could be obtained, a single lead at a time. Now, …

Therapeutic options for patients with chronic thromboembolic pulmonary hypertension (CTEPH) have expanded significantly with the development of catheter-based interventional therapy, namely percutaneous transluminal pulmonary angioplasty (PTPA) or so-called balloon pulmonary angioplasty (BPA). Conventionally, surgical pulmonary endarterectomy has been the first-line treatment for operable CTEPH. Several teams, including our own, have developed PTPA procedures, and some important reports have been published.1–4 Extrapolating from the published papers, about one third of patients with confirmed CTEPH in Japan have been treated with PTPA over the past decade. It is important to note that according to updated guidelines for the diagnosis and treatment of pulmonary hypertension published in 2016 by the European Society of Cardiology and the European Respiratory Society,5 this catheter-based therapy has been accepted as a therapeutic strategy (Class IIb recommendation for patients with technically inoperable disease or with unfavorable risk-to-benefit ratio for surgery). Because PTPA has only recently been developed, long-term outcomes have not been reported thus far. Therefore, the purpose of the present observational study was to clarify the long-term outcomes for PTPA. The performance of PTPA and analysis of clinical data in the present study were approved by the institutional review boards of Kyorin University Hospital, and all patients …

We are delighted to see Maltais and colleagues express interest in our efforts to enhance depiction of clinical outcomes in the field of mechanical circulatory support. We welcome this opportunity to help clarify several misconceptions that may have arisen from perhaps a perfunctory review of our collective work as referenced by our colleagues.1,2 When the notion of hemocompatibility was first alluded to by Mehra,1 it was designed to develop a clinical definition for this rather complex weave of intersection between bleeding and clotting disorders that form the Achilles heel of clinical application of left ventricular assist systems. The concept paper alluded to the challenges and provided the algorithm for tiered outcomes assessment, which …

Background: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. Methods: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation Results: There were 11 529 participants in the preimplementation phase (range, 284–3465) and 19 803 in the postimplementation phase (range, 395–5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%–37.7%) to 18.4% (6.8%–43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3–2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4–3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P =0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. Conclusions: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. Clinical Trial Registration: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

We read with great interest the paper by Jolly et al1 on thrombus aspiration in ST elevation myocardial infarction. The authors performed an individual patient meta-analysis of the 3 larger randomized controlled trials in the field (ie, TAPAS [Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study], TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia], and TOTAL [Thrombectomy with PCI versus PCI Alone in Patients with STEMI]) with a total number of 18 306 patients. There was no difference on clinical outcome (cardiovascular death, …

We thank Drs Downey and Cohen and Dr Fernandez-Jimenez et al for their comments and interest on our article, 1 where we demonstrate in pigs and by 3T-cardiac magnetic resonance (CMR) analysis that ticagrelor protects against myocardial injury to a greater extent than clopidogrel. It is important to note that we report for the first time that ticagrelor cardioprotective effects are associated with the attenuation in myocardial edema formation after myocardial infarction (MI) through adenosine-related mechanisms. Drs Downey and Cohen have made major contributions to our understanding on the role of antiplatelet agents in cardioprotection by carrying out studies in rabbits and rodents.2,3 In this regard, the discrepancies found between their studies2,3 and Ye et al4 and ours may rely on species-related differences and methodological approaches used. It is worth mentioning that the same group which published the Ye et al4 paper has demonstrated, in contrast with Dr Downey and Cohen’s findings,2,3 that ticagrelor but not clopidogrel …

We read with great interest the paper by Bernard et al1 recently published in Circulation . The authors conducted a multicenter, randomized controlled trial to demonstrate the neuroprotective effect of induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline. However, therapeutic hypothermia failed to improve outcomes at hospital discharge but decreased the rate of return of spontaneous circulation in adults with out-of-hospital cardiac arrest. The findings of this randomized trial indicate …

We read with interest the article by Fordyce et al1 about the on-treatment outcomes in patients with worsening renal function treated with rivaroxaban compared with those on warfarin from the ROCKET AF trial (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) data. In this substudy, worsening renal function was defined as a decrease of >20% from screening creatinine clearance measurement at any time point during the study. The main conclusion of this paper was that, among patients with on-treatment worsening renal function, rivaroxaban was associated with lower rates of stroke compared …

In today’s healthcare environment, terms such as value-based, transparent, efficient, evidence-based, accountable, and cost-effective are used frequently when talking about new care delivery models and models of physician and hospital reimbursement. Within the context of this environment, accreditation is increasingly being looked to as a means of helping hospitals and physicians successfully prepare for and participate in these new models. “Organizations that participate in accreditation confirm their commitment to quality improvement, risk mitigation, patient safety, improved efficiency, and accountability; it sends a powerful message to key decision-makers and the public. This performance measure contributes to the sustainability of the health care system,” wrote Wendy Nicklin, president and chief executive officer of Accreditation Canada, in an updated 2015 review of scholarly papers related to hospital accreditation.1 In a 2010 Presidential Advisory, the American Heart Association (AHA) identified the need, opportunity, and responsibility for the cardiovascular community to provide greater leadership in the design, development, and offering of accreditation services with the potential to provide clinical care. As stated in …

Background and Purpose— The guidelines presented in this consensus statement are intended to serve researchers, clinicians, reviewers, and regulators in the selection of the most appropriate primary outcome for a clinical trial of cardiac arrest therapies. The American Heart Association guidelines for the treatment of cardiac arrest depend on high-quality clinical trials, which depend on the selection of a meaningful primary outcome. Because this selection process has been the subject of much controversy, a consensus conference was convened with national and international experts, the National Institutes of Health, and the US Food and Drug Administration. Methods— The Research Working Group of the American Heart Association Emergency Cardiovascular Care Committee nominated subject leaders, conference attendees, and writing group members on the basis of their expertise in clinical trials and a diverse perspective of cardiovascular and neurological outcomes (see the online-only Data Supplement). Approval was obtained from the Emergency Cardiovascular Care Committee and the American Heart Association Manuscript Oversight Committee. Preconference position papers were circulated for review; the conference was held; and postconference consensus documents were circulated for review and comments were invited from experts, conference attendees, and writing group members. Discussions focused on (1) when after cardiac arrest the measurement time point should occur; (2) what cardiovascular, neurological, and other physiology should be assessed; and (3) the costs associated with various end points. The final document underwent extensive revision and peer review by the Emergency Cardiovascular Care Committee, the American Heart Association Science Advisory and Coordinating Committee, and oversight committees. Results— There was consensus that no single primary outcome is appropriate for all studies of cardiac arrest. The best outcome measure is the pairing of a time point and physiological condition that will best answer the question under study. Conference participants were asked to assign an outcome to each of 4 hypothetical cases; however, there was not complete agreement on an ideal outcome measure even after extensive discussion and debate. There was general consensus that it is appropriate for earlier studies to enroll fewer patients and to use earlier time points such as return of spontaneous circulation, simple “alive versus dead,” hospital mortality, or a hemodynamic parameter. For larger studies, a longer time point after arrest should be considered because neurological assessments fluctuate for at least 90 days after arrest. For large trials designed to have a major impact on public health policy, longer-term end points such as 90 days coupled with neurocognitive and quality-of-life assessments should be considered, as should the additional costs of this approach. For studies that will require regulatory oversight, early discussions with regulatory agencies are strongly advised. For neurological assessment of post–cardiac arrest patients, researchers may wish to use the Cerebral Performance Categories or modified Rankin Scale for global outcomes. Conclusions— Although there is no single recommended outcome measure for trials of cardiac arrest care, the simple Cerebral Performance Categories or modified Rankin Scale after 90 days provides a reasonable outcome parameter for many trials. The lack of an easy-to-administer neurological functional outcome measure that is well validated in post–cardiac arrest patients is a major limitation to the field and should be a high priority for future development.

During the past 40 years, knowledge has accumulated that survival increases significantly if the OHCA is quickly recognized and responded to with prompt activation of 911, bystander-initiated cardiopulmonary resuscitation (CPR), lay application of an automated external defibrillator (AED) before arrival of emergency medical services (EMS) providers on scene, advanced life support, and postresuscitation care.1 Recent analyses of a multicenter observational study have demonstrated that multiple components of CPR process are associated with survival in patients with OHCA.2,3 However, there are significant and important variations in the process and outcome for care for patients with OHCA.4–6 These differences appear to be much larger than variations associated with care of other acute cardiovascular conditions such as ST-elevation myocardial infarction.7 Despite advances in resuscitation knowledge, many communities have not achieved significant improvements in outcomes after OHCA over time.8 This lack of improvement in survival has led some skeptics to conclude that the glass is half empty and that patients with OHCA have a dismal prognosis. Articles see pp 1868, 1876, and 1883 Recently, tantalizing suggestions that outcomes after OHCA can improve over time have emerged from multicenter observational studies, including Arizona9 and Denmark.10 The relative contribution of interventions to increased survival in these communities is difficult to tease out because multiple changes in resuscitation care were implemented contemporaneously. Three important papers published in this issue of Circulation provide compelling evidence that the nation and the world is improving resuscitation care over time.11–13 Each of these large cohort studies demonstrates that OHCA is indeed a treatable condition and that a community can improve outcomes after OHCA. The first analysis described temporal changes in risk-adjusted survival after OHCA.12 Included were patients with OHCA of noncardiac cause who were …

The salient characteristics of the Lipid Research Clinics (LRC) Program Prevalence Study are presented, including an overview of its structure, the populations included and the common procedures used. Highlighted are the two sequential screening examinations that included 68,317 participants in 12 LRCs in the U.S. Canada and the U.S.S.R. for the first examination and 15,816 for the second. Several thousand more will be added as the thirteenth LRC completes its screening in Israel. Major data items are described briefly, as are data quality enhancement procedures. Procedures for plasma lipid determination, lipoprotein cholesterol, other clinical chemistries, nutritional intake assessment, and resting and stress electrocardiography are discussed. A discussion of the methodologic strengths and weaknesses of the findings of the LRC Program Prevalence Study is also included. This paper provides a frame of reference for the individual papers in this volume.

This paper describes a method of analyzing electrocardiograms that detects and identifies nonfibrillatory atrial, A-V junctional, and ventricular pacemakers in atrial fibrillation, measures the ventricular beat intervals produced by the detected pacemaker, and estimates the block between pacemaker and ventricle. The identification and measurements are made with a known degree of assurance which may be increased or diminished since it depends entirely upon the number of heart beats analyzed. By applying the method to 61 recordings of 31 patients, we detected 18 instances of A-V junctional tachycardia and escape rhythm of which only three had been identified by ordinary electrocardiographic interpretation. The procedure consists of recording the electrocardiogram on magnetic tape, reducing the contained information to certain displays, and testing statistically the hypotheses suggested by them. The displays employed are: (1) A plot of the duration or the reciprocal of the duration of successive electrocardiographic R-R intervals against elapsed time (tachogram); (2) a plot of the number of R-R intervals in the recording within each duration class against the duration of the class (interval histogram); (3) a plot of the number of beat-to-beat interval sequences formed by intervals with equal durations, successively diminishing durations, and durations representing multiples of a common time segment against the duration of the identifying interval of each sequence (sequence histogram); and (4) a graphic presentation of the averaged electrocardiographic presystolic potential. The paper also presents evidence that A-V junctional escape rhythm in atrial fibrillation is due to pathological A-V block and should be considered to be the result of digitalis excess when this drug is exhibited.

Rabbits were injected with saline suspensions of fibers of filter paper and of mixtures of filter paper and human fibrin or filter paper and rabbit whole blood. The emboli became impacted in the pulmonary arteries or adhered to the intima. In one rabbit an embolus adhered to the endocardium of the right ventricle. An acute arteritis resulted which was finally organized leaving a diffuse or eccentric scar on the intima. The filter paper fibers were surrounded by a foreign body granuloma and localized in either the intima or adventitia. Frequently they passed entirely through the wall clausing varying amounts of injury and were found in the adventitia or perivascular lung tissue. This is interpreted as indicating the existence of a mechanism for ridding the circulation of foreign material in the blood.

The background of basic conceptions underlying this paper is familiar to everyone by experience. The powerful automobile, when the light turns from red to green, can make a "jack-rabbit start" which leaves the less powerful cars far behind. If the engine of the big car is weakened, as by a cylinder gone dead, it can still do 50 miles per hour on the parkway and get you to your destination, but the jack-rabbit start is no longer possible. The first sign of weakness manifests itself more conspicuously in differences in acceleration than in differences in speed or in the distance that can be traveled; indeed the effect on acceleration may be the only manifestation of weakness. There is every reason to expect that this analogy would hold for the cardiac performance also and that the first sign of a weakening myocardium might well manifest itself by a change in acceleration of the ejected blood. This paper is chiefly concerned with the development of a simple method, available to clinicians, which would aid in the detection of changes in the acceleration of the aortic blood. This opportunity has also been used to answer certain criticisms of our previously published work, some, we believe, due to misunderstanding of the mathematical background of statistical procedures, and others due to a frank difference of opinion concerning the accuracy of the Fick method used to test the results secured by one of our formulas published previously.

In this second paper of a series of three on electrocardiographic leads, presented primarily from the standpoint of an electrical engineer or physicist, the concept of the lead field introduced in the first paper is considered in detail and several necessarily indirect methods for the estimation of these fields are presented.

▪ Abstract Atrial fibrillation is frequently disabling and resistant to antiarrhythmic drugs. Curative treatment by catheter-based ablation has been shown to be feasible either by achieving long linear lesions, mainly in the left atrium, or by targeting the initiating focus, most frequently in the pulmonary veins. This paper reviews the different ablation approaches, their results, potential complications, and relative merits.

Neurocardiology has many dimensions, but it may be conceptualized as divided into 3 major categories: the heart’s effects on the brain (eg, cardiac source embolic stroke), the brain’s effects on the heart (eg, neurogenic heart disease), and neurocardiac syndromes (eg, Friedreich disease). The present review deals with the nervous system’s capacity to injure the heart. This subject is inherently important but also represents an example of a much more widespread and conceptually fascinating area of neurovisceral damage in general. In 1942, at the culmination of his distinguished career as Professor of Physiology at Harvard Medical School, Walter B. Cannon published a remarkable paper entitled “‘Voodoo’ Death,”1 in which he recounted anecdotal experiences, largely from the anthropology literature, of death from fright. These often remote events, drawn from widely disparate parts of the world, had several features in common. They were all induced by an absolute belief that an external force, such as a wizard or medicine man, could, at will, cause demise and that the victim himself had no power to alter this course. This perceived lack of control over a powerful external force is the sine qua non for all the cases recounted by Cannon, who postulated that death was caused “by a lasting and intense action of the sympathico-adrenal system.” Cannon believed that this phenomenon was limited to societies in which the people were “so superstitious, so ignorant, that they feel themselves bewildered strangers in a hostile world. Instead of knowledge, they have fertile and unrestricted imaginations which fill their environment with all manner of evil spirits capable of affecting their lives disastrously.” Over the years since Cannon’s observations, evidence has accumulated to support his concept that “voodoo” death is, in fact, a real phenomenon but, far from being limited to ancient peoples, may be a basic …

The coronary heart disease (CHD) epidemic peaked in the 1960s. Since that time age-adjusted mortality declined steadily in the United States and many other industrialized countries 1 . Hospitalization for CHD also fell, particularly in the past two decades with CHD severity decreasing as NSTEMIs increased, indicating milder forms of CHD 1 . Finally, lifestyle factors and associated risk factors improved such as smoking, hypertension and cholesterol 1 . These changes and the trends over time lead naturally to the question of causality. Are changes in lifestyles, risk factors, or acute and chronic clinical care playing roles in this evolving picture and how does each influence the desired outcomes? In this issue of Circulation , the paper by Mannsverk and colleagues 2 in Norway provides insights into the evolving cardiovascular disease epidemic.

Objective— To review the literature systematically to determine whether noninvasive or invasive risk stratification, such as with an electrophysiological study of patients with asymptomatic pre-excitation, reduces the risk of arrhythmic events and improves patient outcomes. Methods— PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (all January 1, 1970, through August 31, 2014) were searched for randomized controlled trials and cohort studies examining noninvasive or invasive risk stratification in patients with asymptomatic pre-excitation. Studies were rejected for low-quality design or the lack of an outcome, population, intervention, or comparator of interest or if they were written in a language other than English. Results— Of 778 citations found, 9 studies met all the eligibility criteria and were included in this paper. Of the 9 studies, 1 had a dual design—a randomized controlled trial of ablation versus no ablation in 76 patients and an uncontrolled prospective cohort of 148 additional patients—and 8 were uncontrolled prospective cohort studies (n=1594). In studies reporting a mean age, the range was 32 to 50 years, and in studies reporting a median age, the range was 19 to 36 years. The majority of patients were male (range, 50% to 74%), and P 250 ms) developed in 0% to 16%, malignant atrial fibrillation (shortest RR interval ≤250 ms) in 0% to 9%, and ventricular fibrillation in 0% to 2%, most of whom were children in the last case. Conclusions— The existing evidence suggests risk stratification with an electrophysiological study of patients with asymptomatic pre-excitation may be beneficial, along with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. Given the limitations of the existing data, well-designed and well-conducted studies are needed.