Progress in Cardiovascular Diseases

Anthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure, encapsulate anthracyclines in liposomes to reduce myocardial uptake, administer concurrently with the iron chelator dexrazoxane to reduce free iron-catalyzed reactive oxygen species formation; and modify anthracycline structure in an effort to reduce myocardial toxicity. Despite these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is, in part, due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death seems to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular "sarcopenia" characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore, up-regulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals.

Cardiac disease in patients with cancer is common and influences the longevity and quality of life both of patients in active treatment and of survivors of cancer. The disciplines of cardiology and oncology have increasingly recognized the benefits to patients of collaborating in the care of cancer patients with cardiac disease. This increased recognition arises from several factors: the aging population in which both cardiac and cancer diagnoses are common; the cellular and molecular therapeutic targets of newer medical treatments, and, in particular, the specific patient treatment choices and decisions that require careful, effective clinical interactions between these 2 disciplines. Responding to this need for an effective partnership between cardiology and oncology, the International CardiOncology Society was created and has set goals to develop and enhance our understanding and management of these clinical difficulties.

Since its first description in the 1950s, the pathophysiology of hypertrophic cardiomyopathy has been clarified by advanced echocardiographic technologies. Improved pharmacotherapy now successfully treats most afflicted individuals. Along with these advances, surgical management has also evolved, as the role of the mitral valve and the subvalvular structures in causing obstruction has been identified. Over the last 2 decades, a variety of options to surgically manage the complex patient with obstruction have been described. Successful surgical management is dependent on the complete evaluation of the causes of obstruction in the specific individual, as the heterogeneity of the anatomy may confound the direction of therapy. Mitral valve replacement may no longer be necessary in individuals who have a relatively thin septum and instead obstruct from an elongated mitral anterior leaflet or the presence of accessory papillary muscles and chords. Techniques for mitral valve plication have been successfully used with mid- to long-term success. A systematic strategy for the evaluation of obstruction in hypertrophic cardiomyopathy and the various surgical options are summarized in a procedure termed RPR for resection (extended myectomy), plication (mitral valve shortening), and release (papillary muscle manipulation).

Venous disease has long been recognized as a progressive, debilitating, and recurrent problem. Until recently, venous insufficiency was often undertreated due to a lack of therapeutic modalities. During the past decade, an explosion in the treatment options has occurred. Endovenous ablation therapy has nearly replaced the conventional surgical treatments for patients with superficial venous insufficiency. Dramatic changes in therapy are also available for deep venous thrombosis but are not the subject of this review. These newer techniques are much less invasive and consequently have reduced risks of wound complications or bleeding. In addition, they can be performed easily in the office setting with local anesthesia. Higher-risk patients can now be considered for these less invasive treatments to reduce their ambulatory venous hypertension. With the lower procedural risks and the dramatically shortened recovery times, earlier intervention can be entertained. This helps prevent the development of venous stasis ulceration and other sequelae of progressive venous insufficiency.

Sixty years on from its first publication, the Framingham study has made an historic impact in risk identification and prediction of cardiovascular disease (CVD) burden globally. The challenge for the 21st century is in finding practical and scalable methods for effective implementation of population-level interventions that are adaptable to low-, middle-, and high-income settings. Within its first 2 years, the Abu Dhabi Cardiovascular Program, "Weqaya," has delivered a Framingham Risk Score for almost every adult Emirati. This is complemented by a clear and progressive program including the health sector and societal approach to the delivery of interventions for CVD. The health sector response includes the use of clear, evidence-based standards of clinical care, customer-focused service innovation such as the use of mobile and wellness clinics, and attention to the patient experience, and improving compliance using a mixture of encourage, enable, and enforce mechanics. Components of the Abu Dhabi societal approach include "top-down" measures to align the civil sector response including use of policies and regulation, for example, for trade and urban planning. The "bottom-up" measures aim to empower individuals, groups, and populations. Key to the success of this approach lies in central coordination and routine monitoring and evaluation, incorporating the use of simple, shared metrics. The Abu Dhabi approach has created a solid platform for scalable intervention, and for "learning by doing," with impact being monitored at the level of individuals, groups and the whole population. The unique data architecture in Abu Dhabi will enable the first cardiovascular risk score to be developed for the region and the incorporation of novel, modifiable risk factors into the model. The last 2 years have seen huge progress in Abu Dhabi for CVD, but the coming 5 to 10 years promise to unearth real, large-scale solutions, building on the original Framingham model. Furthermore, the Abu Dhabi model is scalable and adaptable to low- and middle-income country settings. Local and global data on CVD risk are stark and raise a clear challenge for public health; the time for clear actions has arrived.

Rapid reperfusion in patients with ST-elevation myocardial infarction (STEMI) is associated with lower mortality. Reduction in door-to-balloon (D2B) time for percutaneous coronary intervention requires multidisciplinary cooperation, process analysis, and quality improvement methodology. Six Sigma methodology was used to reduce D2B times in STEMI patients presenting to a tertiary care center. Specific steps in STEMI care were determined, time goals were established, and processes were changed to reduce each step's duration. Outcomes were tracked, and timely feedback was given to providers. After process analysis and implementation of improvements, mean D2B times decreased from 128 to 90 minutes. Improvement has been sustained; as of June 2010, the mean D2B was 56 minutes, with 100% of patients meeting the 90-minute window for the year. Six Sigma methodology and immediate provider feedback result in significant reductions in D2B times. The lessons learned may be extrapolated to other primary percutaneous coronary intervention centers.

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.

Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion in patients with ST-elevation myocardial infarction (STEMI). Therefore, increasing timely access to PCI is a major national focus. The majority of United States hospitals are not PCI capable, which has stimulated the development of regional STEMI programs using standardized protocols and organized transfer systems. These regional STEMI systems have improved treatment times and clinical outcomes, leading to a recent class I recommendation in the American College of Cardiology/American Heart Association guidelines to develop STEMI systems of care. Despite this, less than 15% of patients transferred from non-PCI hospitals to PCI centers have total door-to-balloon times less than 2 hours. We review the therapeutic options for the STEMI patient with expected delay to PCI focusing on recent pharmacoinvasive trials. Based on these trial results, recent guidelines recommend early transfer and cardiac catheterization for patients treated with fibrinolytic therapy.

Sudden cardiac death is a major cause of mortality in the United States of America (Circulation 2008;117:e25-146) with approximately 310000 deaths related to coronary heart disease occurring in emergency departments or in the prehospital environment annually. Several organizations have directed resources toward the treatment of sudden cardiac arrest through a paradigm that has come to be known as the "chain of survival"-prompt activation of emergency response by telephone 911, early bystander cardiopulmonary resuscitation, early defibrillation, and timely advanced cardiac life support (Circulation 1991;83:1832-1847). The ready availability of automated external defibrillators (AEDs) has been advocated as a key component of this chain. Some authors have suggested a "fire extinguisher model" for AED deployment (Circulation 1998;98:2334-2351; Resuscitation 1995;30:151-156; Ann Intern Med 2001;135:990-998). In this model, AEDs are prominently displayed in public places for use by laypersons, much like fire extinguishers. For example, in Chicago's O'Hare Airport, AEDs are placed alongside fire extinguishers in the public concourse (N Engl J Med 2002;347:1242-1247). Advocates of this model suggest that advancing this practice would be a means to widely disbourse life-saving technology that is easy to use. Several experts have questioned this model, suggesting that the cost-effectiveness of distributing AEDs this widely would be prohibitive (BMJ 2002;325:515; Curr Opin Cardiol 2007;22:5-10; BMJ 2003;326:162; Int J Technol Assess Health Care 2007;23:362-367) and may not be more effective than more targeted distribution of AEDs. This literature review will examine the available data on both AEDs and fire extinguishers to determine if these comparisons are reasonable as a means of guiding public policy.

This paper provides an overview of key achievements of the Framingham Heart Study and identifies areas and approaches for future research in cardiovascular disease epidemiology and prevention. There is a need for a range of different studies using diverse designs (i.e. case-control, cohort, multi-community, birth cohort, family-based cohorts and randomized trials) in different settings and involving multiple ethnic groups. Incorporation of a range of new disciplines, such as genetics, behavioural sciences, social epidemiology, measures of the environment, geography, and health policy are required to understand the root determinants of cardiovascular diseases.

The association between fish consumption and risk of cardiovascular disease (CVD) has been extensively studied. Although the results are inconsistent, the majority of studies are in favor of cardioprotective effects of fish consumption. There is little doubt that long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) in fish are the key nutrients responsible for the benefits and are important for CVD prevention. Although fish is valued as a source of these fatty acids, it also provides other nutrients that may have cardioprotective effects. It is likely that the beneficial effects of fish consumption on the risk of CVD are the synergistic effects among nutrients in fish, and the integrative effects of fish consumption may reflect the interactions of nutrients and contaminants in fish. This review summarizes the epidemiology of fish or LCn-3PUFAs with major CVD risk factors as well as coronary heart disease mortality and stroke. This review also discusses the possible difference between whole fish as a nutrient package and fish oil supplements as a source of LCn-3PUFAs with respect to CVD prevention. Further studies are needed to investigate the potential adverse effects of contaminants in fish and the possible different effects from different types of fish and cooking methods.

The Framingham study was a landmark study that, already in the 1960s, gave strong evidence as to the likely causal role of several lifestyle-linked factors in the development of cardiovascular diseases (CVDs). Men in Finland had at that time the highest mortality rates of coronary heart disease in the world, a finding that raised much local concern. In 1972, a pioneering project by a young leadership team and with many partners, including World Health Organization, was started to change the situation. The project was based on the results for Framingham and some other classical studies to carry out a comprehensive prevention program to reduce the risk factor levels in the population through general lifestyle changes in the pilot area of North Karelia. Later on, the work was transferred to national level. Over the years, great reductions in the population levels of the risk factors took place, associated with dramatic reduction in age-adjusted CVD mortality rates and improvement in public health. The experience of diminishing the prevalence of risk factors in the population is a powerful demonstration of how the CVD epidemic can be successfully confronted-thatis, how the Framingham results can effectively be used for major progress in public health.

Annually, more than 100 million tourists are attracted by the mountainous areas around the world. On the one hand, leisure time activities at altitude may well contribute to the well-established beneficial effects of exercise; on the other hand, these activities are also associated with a relatively high risk of death. Sudden cardiac death (SCD) is the most frequent cause of nontraumatic death in males older than 34 years at altitude during leisure time activities such as downhill skiing and hiking. Whereas prior myocardial infarction is the most important risk factor for SCD, particularly relevant in downhill skiers, the unusual physical activity during the first days at altitude and the prolonged abstinence from food and fluid intake during exercise at altitude are the most important triggers. Unaccustomed physical activity seems more likely to trigger SCD than altitude per se. The detection of subjects at risk, evidence-based therapy, and advice on adequate behavior during the altitude sojourn will help to prevent SCD and to increase the health benefits generated by mountaineering activities.

Cardiovascular magnetic resonance (CMR) imaging is a recognized technique for characterization of myocardial tissue in stable ischemic heart disease. In addition, CMR is emerging as a noninvasive imaging tool that can provide supporting information to guide treatment in acute coronary syndromes (ACSs). The advantages of using CMR acutely could potentially include triage/differential diagnosis in patients presenting with chest pain and troponin rise but without diagnostic electrocardiogram changes, assessment of severity of myocardial injury (irreversible vs reversible damage) in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, and risk stratification and assessment of prognosis in patients with ACS. This review evaluates a potential clinical role of CMR in the acute setting, highlighting its advantages and limitations. This critical approach emphasizes areas of uncertainty and ongoing controversies but aims to equip the reader to evaluate the potential clinical application and the practicalities of CMR in patients presenting with ACS.

Several randomized trials and meta-analyses have shown that primary angioplasty is superior to thrombolysis in the treatment of ST-segment elevation myocardial infarction (MI) in terms of death, reinfarction, and stroke. However, primary angioplasty should be regarded as the preferred strategy as long as it can not be applied with a reasonable time delay to treatment, as compared with the administration of thrombolysis. In fact, time-to-treatment has been shown to be a determinant of survival not only for thrombolysis but also for primary angioplasty. Recent guidelines consider a time from first medical contact to PCI of 90 minutes or a PCI-related delay of 60 minutes as reasonable cutoffs to identify the best reperfusion strategy. The beneficial effects of primary angioplasty could be expected particularly after the first 3 hours from symptom onset, when thrombolysis, particularly streptokinase, may be less effective, whereas within the first 3 hours, thrombolysis (started in the prehospital setting, preferably) may represent a valid therapeutic option. Because the survival benefits of primary angioplasty depends on the patient's risk profile and timely application of reperfusion, we would suggest, among patients in the first hours from symptom onset, a strategy of early pharmacologic reperfusion and transfer to primary PCI centers, where the decision of performing angiography acutely may be based on the assessment of myocardial reperfusion and risk profile, whereas after the first 3 hours from symptoms onset, primary angioplasty should be considered the preferred strategy if applicable, particularly in regions when streptokinase still represents the only available lytic therapy. However, even though primary angioplasty is able to achieve thrombolysis and TIMI 3 flow in most patients, a still relevant proportion of patients experience poor myocardial reperfusion, with negative impact on acute and long-term survival. The use of platelet glycoprotein IIb/IIIa complex inhibitors has significantly improved survival, with additional benefits obtained by early administration aiming at early reperfusion, which are to be recommended, particularly among high-risk patients and those presenting within the first hours from symptom onset. The use of adjunctive mechanical devices has reduced the incidence of distal embolization without any apparent benefit in survival. Until the results of larger randomized trials become available, these devices may be considered in patients at high risk for distal embolization, such as those with large thrombotic burden. The use of coronary stenting has significantly reduced restenosis, as compared with balloon angioplasty. Several randomized trials have recently been conducted on drug-eluting stents in ST-segment elevation MI, showing the safety and significant benefits of these devices in terms of restenosis, as compared with bare metal stents (BMSs). However, because of unpredictable compliance to long-term double oral antiplatelet therapy in acute patients, caution should be taken with extensive use of drug-eluting stents in primary angioplasty.

The revolution in cardiac care over the past two decades, characterized by emergent revascularization, drug eluting stents, anti-platelet medications, and advanced imaging has had little impact on overall ACS recurrence, or ACS prevention. The "Perfect Storm" refers to a confluence of events and processes, including atherosclerotic plaque, coronary flow dynamics, hemostatic and fibrinolytic function, metabolic and inflammatory conditions, neurohormonal dysregulation, and environmental events that give rise to, and result in an ACS event. In this article we illustrate the limits of the traditional main effect research model, giving a brief description of the current state of knowledge regarding the development of atherosclerotic plaque and the rupturing of these plaques that defines an ACS event. We then apply the Perfect Storm conceptualization to describe a program of research concerning a psychosocial vulnerability factor that contributes to increased risk of recurrent ACS and early mortality, and that has defied our efforts to identify underlying pathophysiology and successfully mount efforts to fully mitigate this risk.

The current study investigates the association of estimated personal exposure to traffic-related air pollution and acute myocardial infarction (AMI). Cases of AMI were interviewed in the Augsburg KORA Myocardial Infarction Registry from February 1999 through December 2003, and 960 AMI survivors were included in the analyses. The time-varying component of daily personal soot exposure (the temporally variable contribution due to the daily area level of exposure and daily personal activities) was estimated using a linear combination of estimated mean ambient soot concentration, time spent outdoors, and time spent in traffic. The association of soot exposure with AMI onset was estimated in a case-crossover analysis controlling for temperature and day of the week using conditional logistic regression analyses. Estimated personal soot exposure was associated with AMI (relative risk, 1.30 per 1.1 m(-1) × 10(-5) [95% confidence interval, 1.09-1.55]). Estimated ambient soot and measured ambient PM(2.5) particulate matter 2.5 µm and smaller in aerodynamic diameter were not significantly associated with AMI onset. Our results suggest that an increase in risk of AMI in association with personal soot exposure may be in great part due to the contribution of personal soot from individual times spent in traffic and individual times spent outdoors. As a consequence, estimates calculated based on measurements at urban background stations may be underestimations. Health effects of traffic-related air pollution may need to be updated, taking into account individual time spent in traffic and outdoors, to adequately protect the public.

This review begins by discussing the importance of clinical congestion as the dominant presenting manifestation of acute heart failure syndromes (AHFS). The pathophysiology of the cardiorenal syndrome is reviewed, including its relationship to the use of current therapy, that is, loop diuretics. The review then summarizes results from recent clinical trials evaluating therapy for AHFS, with a focus on those studies investigating ultrafiltration and vasopressin antagonists, and also, but more briefly, vasodilators and inotropic agents. Possible reasons for the success and failure of various therapeutic strategies directed at the congested state are discussed. The review concludes with recommendations for possible new strategies and specific investigations designed to benefit from the lessons learned from both the recent successful trials and the more numerous failures.

Clinical trials in acute myocardial infarction (AMI) and other urgent or emergent conditions present special challenges regarding informed consent. Available data suggest patients often poorly understand such research when they are offered enrollment, and unalterable factors such as time constraints and emotional and physical distress create barriers to informed consent on the part of patients and surrogates. We examine the challenges to informed consent in AMI trials in particular and suggest that full informed consent may not be a realistic goal. We propose instead a model of informed refusal, offering patients an informed opportunity to refuse participation rather than requesting a positive commitment to participate. Informed refusal may be both more achievable and more respectful of patients, and we describe how such a process might be implemented and evaluated. We also suggest a need for regulatory change in order to maximize effective patient participation in decisions for clinical research in AMI and other acute illnesses.

The management of patients with acute coronary syndromes (ACS) has evolved dramatically over the past decade and, in many respects, represents a rapidly moving target for the cardiologist and internist who seek to integrate these recent advances into contemporary clinical practice. Unstable angina and non-ST-segment elevation myocardial infarction (MI) comprise a growing percentage of patients with ACS and is emerging as a major public health problem worldwide, especially in Western countries, despite significant improvements and refinements in management over the past 20 years. Against this backdrop of a multitude of randomized, controlled clinical trials that have established the scientific foundation upon which evidence-based treatment strategies have emerged and become increasingly refined, the clinician is frequently confronted with panoply of choices that can create uncertainty or confusion regarding "optimal management". While the debate about the ideal approach to the management of non-ST-segment elevation (NSTE) ACS (i.e., routine "early invasive strategy" versus an "ischemia-guided", or "conservative", strategy) has been ongoing for over a decade, clinical trials results provide compelling evidence that intermediate- and high-risk ACS patients derived significant reductions in both morbidity and mortality with mechanical or surgical intervention, especially when revascularization is coupled with aggressive, multifaceted (anti-platelet, antithrombin, anti-ischemic and anti-atherogenic) medical therapy along with risk factor modification. For these reasons, it seems especially timely and appropriate to present a state-of-the-art paper that reviews the latest advances in the management of NSTE ACS, mindful of the fact that even this noble effort to synthesize and integrate a prodigious amount of scientific information and cardiovascular therapeutics is destined to evolve still further as our full-scale assault on optimizing clinical outcomes by harmonizing the advances in mechanical and pharmacologic interventions continues unabated.

Barometric pressure falls with increasing altitude and consequently there is a reduction in the partial pressure of oxygen resulting in a hypoxic challenge to any individual ascending to altitude. A spectrum of high altitude illnesses can occur when the hypoxic stress outstrips the subject's ability to acclimatize. Acute altitude-related problems consist of the common syndrome of acute mountain sickness, which is relatively benign and usually self-limiting, and the rarer, more serious syndromes of high-altitude cerebral edema and high-altitude pulmonary edema. A common feature of acute altitude illness is rapid ascent by otherwise fit individuals to altitudes above 3000 m without sufficient time to acclimatize. The susceptibility of an individual to high-altitude syndromes is variable but generally reproducible. Prevention of altitude-related illness by slow ascent is the best approach, but this is not always practical. The immediate management of serious illness requires oxygen (if available) and descent of more than 300 m as soon as possible. In this article, we describe the setting and clinical features of acute mountain sickness and high-altitude cerebral edema, including an overview of the known pathophysiology, and explain contemporary practices for both prevention and treatment exploring the comprehensive evidence base for the various interventions.

About 30 million people live above 2500 m in the Andean Mountains of South America. Among them are 5.5 million Aymaras, an ethnic group with its own language, living on the altiplano of Bolivia, Peru, and northern Chile at altitudes of up to 4400 m. In this high altitude region traces of human population go back for more than 2000 years with constant evolutionary pressure on its residents for genetic adaptation to high altitude. Aymaras as the assumed direct descendents of the ancient cultures living in this region were the focus of much research interest during the last decades and several distinctive adaptation patterns to life at high altitude have been described in this ethnic group. The aim of this article was to review the physiology and pathophysiology of circulatory adaptation and maladaptation to longtime altitude exposure in Aymaras and Caucasians.

Altitude exposure is associated with major changes in cardiovascular function. The initial cardiovascular response to altitude is characterized by an increase in cardiac output with tachycardia, no change in stroke volume, whereas blood pressure may temporarily be slightly increased. After a few days of acclimatization, cardiac output returns to normal, but heart rate remains increased, so that stroke volume is decreased. Pulmonary artery pressure increases without change in pulmonary artery wedge pressure. This pattern is essentially unchanged with prolonged or lifelong altitude sojourns. Ventricular function is maintained, with initially increased, then preserved or slightly depressed indices of systolic function, and an altered diastolic filling pattern. Filling pressures of the heart remain unchanged. Exercise in acute as well as in chronic high-altitude exposure is associated with a brisk increase in pulmonary artery pressure. The relationships between workload, cardiac output, and oxygen uptake are preserved in all circumstances, but there is a decrease in maximal oxygen consumption, which is accompanied by a decrease in maximal cardiac output. The decrease in maximal cardiac output is minimal in acute hypoxia but becomes more pronounced with acclimatization. This is not explained by hypovolemia, acid-bases status, increased viscosity on polycythemia, autonomic nervous system changes, or depressed systolic function. Maximal oxygen uptake at high altitudes has been modeled to be determined by the matching of convective and diffusional oxygen transport systems at a lower maximal cardiac output. However, there has been recent suggestion that 10% to 25% of the loss in aerobic exercise capacity at high altitudes can be restored by specific pulmonary vasodilating interventions. Whether this is explained by an improved maximum flow output by an unloaded right ventricle remains to be confirmed. Altitude exposure carries no identified risk of myocardial ischemia in healthy subjects but has to be considered as a potential stress in patients with previous cardiovascular conditions.

Approximately 50% of patients with cardiovascular disease and/or its major risk factors have poor adherence to their prescribed medications. Finding novel methods to help patients improve their adherence to existing evidence-based cardiovascular drug therapies has enormous potential to improve health outcomes while potentially reducing health care costs. The goal of this report is to provide a review of the current understanding of adherence to cardiovascular medications from the point of view of prescribing clinicians and cardiovascular researchers. Key topics addressed include: 1) definitions of medication adherence; 2) prevalence and impact of non-adherence; 3) methods for assessing medication adherence; 4) reasons for poor adherence; and 5) approaches to improving adherence to cardiovascular medications. For each of these topics, the report seeks to identify important gaps in knowledge and opportunities for advancing the field of cardiovascular adherence research.

Adiponectin is a protein secreted by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. Obesity-related disorders characterized by insulin resistance including the metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with both decreased adiponectin levels and endothelial dysfunction. Recent studies demonstrate that adiponectin has insulin-sensitizing effects as well as antiatherogenic properties. Lifestyle modifications and some drug therapies to treat atherosclerosis, hypertension, diabetes, and coronary heart disease have important effects in increasing adiponectin levels, decreasing insulin resistance, and improving endothelial dysfunction. In this review, we discuss insights into the relationships between adiponectin levels, insulin resistance, and endothelial dysfunction that are derived from various therapeutic interventions. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that may be important for understanding and treating atherosclerosis and coronary heart disease.

The recent explosion of scientific knowledge and technological progress has led to the discovery of a large array of circulating molecules commonly referred to as biomarkers. Biomarkers in heart failure (HF) research have been used to provide pathophysiologic insights, aid in establishing the diagnosis, refine prognosis, guide management, and target treatment. However, beyond diagnostic applications of natriuretic peptides, there are currently few widely recognized applications for biomarkers in HF. This represents a remarkable discordance considering the number of molecules that have been shown to correlate with outcomes, refine risk prediction, or track disease severity in HF in the past decade. In this article, we use a broad framework proposed for cardiovascular risk markers to summarize the current state of biomarker development for patients with HF. We use this framework to identify the challenges of biomarker adoption for risk prediction, disease management, and treatment selection for HF and suggest considerations for future research.

Adults with congenital heart disease (CHD) have unique medical and psychosocial needs. They require lifelong cardiac surveillance from medical providers with training and expertise in the care of adults with CHD. Patients with CHD must recognize the importance of ongoing surveillance and must not be lost to care in childhood, adolescence, or adulthood. This can be accomplished with the implementation of a comprehensive transition program with the collaboration of patients, parents, and both pediatric and adult health care providers. Finally, consideration of the "whole" patient demands recognition of the unique medical and psychosocial challenges of adults with CHD.

The number of adults with congenital heart disease (CHD) has steadily increased as medical and surgical treatment of congenital heart lesions--whether simple or complex--continues to improve. Over the past half century advances in surgical technique have continued with the evolution of traditional surgical repair and introduction of new surgical procedures for complex lesions previously considered to be irreparable. This article describes the rich history of surgical repair, important surgical considerations specific to the adult undergoing primary or reoperative cardiac repair or palliation, the most common types congenital heart lesions and associated cardiac procedures (including cardiac transplantation) performed in the adult population, as well as considerations regarding the optimal surgical environment and current surgical training and education.

Although "congenital heart disease" incorporates a broad and diverse spectrum of inborn cardiac disorders, one shared feature is the propensity for cardiac arrhythmias, albeit to varying degrees. The magnitude of this issue is underscored by its high prevalence, major impact on morbidity and disability, considerable consummation of healthcare resources, and loss of life at ages well below normative population values. Moreover, with changing demographics, arrhythmias increasingly afflict the aging and growing population of survivors with congenital heart disease. Nevertheless, the field of cardiac electrophysiology has, auspiciously, greatly matured over the past 2 decades. The fruits of this progress are largely applicable to adults with congenital heart disease. This review focuses on recent advances and emerging therapeutic options that are providing safer solutions and increasing the effectiveness with which arrhythmias may be managed in adults with congenital heart disease, spanning pharmacotherapy to innovative interventions.

The success of modern therapies in congenital heart disease has produced a large and growing population of adults with congenital heart disease as a chronic condition. Such success increasingly raises a host of ethical issues, from resource utilization to end of life decision-making. The importance of a multidisciplinary approach to the care of adult congenital heart disease (ACHD) patients has been emphasized for some time, but addressing the challenges in this population requires a broad range of ethical expertise as well. This paper is based on a conference entitled "Ethical and Policy Challenges in Pediatric and Adult Congenital Heart Disease" held in March of 2012. Herein, we present a compilation of the ethics priorities in ACHD discussed at the conference, including ethical aspects of clinical care, ethics research and policy development in the areas of providing clinical care for challenging ACHD patients, improving transitions from pediatric to adult healthcare systems, advance care planning, and addressing costs.

Recent advances in pediatric cardiology have dramatically changed the landscape of the field of congenital heart disease. This changing field is placing new demands on imaging to plan medical management as well as identify the need for, and timing of, reintervention. There are a number of imaging modalities available to the clinician when it comes to these evaluations, including echocardiography, computed tomography, and cardiac magnetic resonance imaging; each having their strengths and unique contributions. This article will discuss the advances in the aforementioned imaging modalities over the past decade and highlight how these tools can provide guidelines on the management of adults with congenital heart disease.

Prevalence of congenital heart disease in the adult population has increased out of proportion to that of the pediatric population as survival has improved, and adult congenital heart disease patients make up a growing percentage of pediatric and adult cardiac intensive care unit admissions. These patients often develop complex multiorgan system disease as a result of long-standing altered cardiac physiology, and many require reoperation during adulthood. Practitioners who care for these patients in the cardiac intensive care unit must have a strong working knowledge of the pathophysiology of complex congenital heart disease, and a full team of specialists must be available to assist in the care of these patients. This chapter will review some of the common multiorgan system effects of long-standing congenital heart disease (eg, renal and hepatic dysfunction, coagulation abnormalities, arrhythmias) as well as some of the unique cardiopulmonary physiology of this patient population.

Cardiac catheterization in the adult patient with congenital heart disease clearly is now its own field. The history of the field is closely tied to pediatric cardiac catheterization, in large part because of the individual histories of its patients, and as such, at least for the foreseeable future, these two fields appear inexorably linked. For both, the pace of progress has been swift. This chapter provides a broad review of the important advances in cardiac catheterization that have occurred over the past decade as they pertain to the adult with congenital heart disease, with an emphasis on recent interventional tools and techniques that have revolutionized this exciting field.

The clinical use of the implantable cardioverter-defibrillator (ICD) is well established to prevent sudden death in patients with left ventricular dysfunction due to coronary artery disease and dilated cardiomyopathy, and its use has saved thousands of lives. More recently, its use has been extended to other patients at risk for sudden cardiac arrest due to ventricular fibrillation: patients with structural heart diseases such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia and patients with normal cardiac anatomy and function except for electrophysiologic abnormalities that predispose to cardiac arrest: Brugada syndrome and long QT syndrome. A distinguishing feature of these patients may be the young age when they present for either primary or secondary prevention. This contrasts with the "first wave" of adult ICD implantations that were usually performed in elderly or middle aged patients. An important consideration in favor of ICD implantation in young patients with sudden death risk is the long and cumulative period of their risk. Similarly, after implantation, these patients will experience the long-term risks of ICD implantation. This review focuses on the unique challenges presented by device implantation in young patients 16 to 45 years of age who may have 4 to 7 decades of life with their devices. Although devices may prolong life, they come with problems that will pose unique challenges for both patients and their physicians. Moreover, because of the long durations, these problems may accelerate as patients age.

The comprehensive coverage and versatility of cardiovascular magnetic resonance (CMR), providing functional as well as anatomical information, make it an important facility in a center specializing in the care of adults with congenital heart disease. Imaging specialists using CMR to investigate acquired heart disease should also be able to recognize and evaluate previously unsuspected congenital malformations. Conditions that may present or be picked up during imaging in adulthood include atrial septal defect, anomalously connected pulmonary veins, double-chambered right ventricle, congenitally corrected transposition of the great arteries, aortic coarctation, and patent arterial duct. To realize its full potential and to avoid pitfalls, CMR of adults with congenital heart disease requires specific training and experience. Appropriate pathophysiological understanding is needed to evaluate cardiovascular function after surgery for tetralogy of Fallot, after transposition of the great arteries, and after Fontan operations. For these and other more complex cases, CMR should ideally be undertaken by specialists committed to long-term collaboration with the clinicians and surgeons managing the patients in a tertiary referral center.

Considerable progress in pediatric cardiac surgery has led to more patients with congenital heart disease surviving into adulthood. However, progressive cardiopulmonary dysfunction often occurs late after palliative or corrective surgeries to the point where transplantation becomes the only treatment option. Adult congenital heart disease represents a growing population of patients being referred for heart, lung, and combined heart-lung transplantation. This group of patients presents multiple unique surgical and medical challenges to transplantation owing to their complex anatomy, multiple prior palliative and corrective procedures, frequently increased pulmonary vascular resistance, and often debilitated condition. Consequently, transplantation in adults with congenital heart disease is associated with a relatively high operative mortality secondary to increased bleeding, infection, and graft failure rates compared with noncongenital heart disease transplant recipients. However, those who survive of the first posttransplant year enjoy an excellent long-term prognosis.

Inotropic agents are administered to improve cardiac output and peripheral perfusion in patients with systolic dysfunction and low cardiac output. However, there is evidence of increased mortality and adverse effects associated with current inotropic agents. These adverse outcomes may be ascribed to patient selection, increased myocardial energy expenditure and oxygen consumption, or to specific mechanisms of action. Both sympathomimetic amines and type III phosphodiesterase inhibitors act through an increase in intracellular cyclic adenosine monophoshate and free calcium concentrations, mechanisms that increase oxygen consumption and favor arrhythmias. Concomitant peripheral vasodilation with some agents (phosphodiesterase inhibitors and levosimendan) may also lower coronary perfusion pressure and favor myocardial damage. New agents with different mechanisms of action might have a better benefit to risk ratio and allow an improvement in tissue and end-organ perfusion with less untoward effects. We have summarized the characteristics of the main inotropic agents for heart failure treatment, the data from randomized controlled trials, and future perspectives for this class of drugs.

Over the past decade, emerging clinical trial data supported the usefulness of implanted therapeutic cardiac devices (pacemakers and defibrillators) for the treatment of heart failure (HF). Interest has now developed in evaluating the potential of device diagnostics to identify HF patients at risk for clinical events and to be used in the management of HF patients. Initial studies have provided inconsistent results. A number of trial design elements have likely played a role in the lack of positive results, including cohort risk determination, intensity of usual care, intensity of the intervention, and selection of end points for the study. These issues will be important to understand when evaluating future clinical trial results and developing new studies, particularly in other HF patient cohorts such as HF with preserved left ventricular function.

Advanced heart failure (HF) is a disease process that carries a high burden of symptoms, suffering, and death. Palliative care can complement traditional care to improve symptom amelioration, patient-caregiver communication, emotional support, and medical decision making. Despite a growing body of evidence supporting the integration of palliative care into the overall care of patients with HF and some recent evidence of increased use, palliative therapies remain underused in the treatment of advanced HF. Review of the literature reveals that although barriers to integrating palliative care are not fully understood, difficult prognostication combined with caregiver inexperience with end-of-life issues specific to advanced HF is likely to contribute. In this review, we have outlined the general need for palliative care in advanced HF, detailed how palliative measures can be integrated into the care of those having this disease, and explored end-of-life issues specific to these patients.

Although orthotopic heart transplantation is the gold standard for definitive surgical treatment of end-stage heart failure, other operative therapies exist for dealing with severe systolic left ventricular dysfunction. The choice of surgical intervention depends on the etiology and functional characteristics of the patient's ventricular dysfunction. In patients with ischemic cardiomyopathy, surgical revascularization improves survival. Patients with mitral regurgitation experience significant functional improvement from mitral valve repair and replacement. In patients with aortic valve dysfunction, aortic valve replacement results in improved survival and functional status. Although surgical ventricular reconstruction is controversial, significant data exist suggesting that it is an effective therapy in a subset of patients with left ventricular dysfunction. Finally, passive restraint devices are effective at halting further ventricular dilation. Although cardiac surgery in patients with severe ventricular dysfunction can be complicated by significant morbidity and mortality, experienced centers have demonstrated acceptable outcomes in carefully selected patients.

The public health impact and the need to intervene upon the worsening heart failure (HF) epidemic are currently a matter of national interest. The greater than $39 billion annual cost of caring for the 5.8 million patients living with HF in the United States places a considerable burden on the health care system. In 2006, HF was a contributing factor in more than 250,000 deaths. HF is the primary cause of more than 1 million and a contributing cause for more than 3 million hospitalizations. Because of lack of uniform definition, defining advanced HF precisely and, in turn, specifically assessing its epidemiology are difficult. However, with availability of more therapeutic options available for patients with advanced HF, the need to precisely define this entity is becoming ever more important. In general, patients with advanced HF have an extremely high mortality and morbidity and poor health status and quality of life. With the aging of the population and the worsening risk factor profile at large, for example, diabetes mellitus and obesity, the current epidemiological trends in advanced HF will likely get worse. Newer medical and device therapies as well as regenerative techniques hold considerable promise for these patients in future.

In this communication we review those trials that have contributed in recent years to improving our knowledge on the management (diagnosis and treatment) of syncope. In this regard, most recent trials focus on vasovagal syncope (VVS) and consequently these will be the focus of this manuscript. In essence, from a diagnostic perspective the ISSUE studies demonstrate the value of insertable loop recorders (ILR), while in terms of treatment, in the case of VVS current data strongly support use of non-pharmacologic treatment as a primary approach. There is no clear evidence supporting pharmacologic treatment with the possible exception of midodrine. Further, the most recent ISSUE trials suggest that in older very symptomatic patients with VVS in whom an asystole has been documented during spontaneous episode or possibly after ATP administration, implantation of a permanent pacemaker (PPM) can be effective. Which pacing or programming mode will be the more beneficial has not been completely clarified. Management of other forms of neurally-mediated syncope (e.g., carotid sinus syndrome) or other causes of syncope has not been addressed by clinical trials. In those cases, direction is provided by older evidence, the vast majority of which is based on observational reports or small non-randomized patient series.

Cardiovascular magnetic resonance (CMR) has a recognized role in diagnosing and monitoring coronary artery disease (CAD). Multiple studies have shown that CMR can predict adverse outcomes. We reviewed contemporary available literature to establish the role of CMR with late gadolinium enhancement (LGE) in predicting mortality and major adverse cardiac events (MACEs) in patients with CAD. Meta-analysis of available prospective studies showed that the presence of LGE increases the hazards of death by more than 4 times and of MACE by almost 4 times. The size of LGE (per gram or percent) increases the hazards of death and MACE by 4% and 5%, respectively. The presence and size of LGE predict mortality and MACE in CAD. Various parameters derived from LGE images enhance the predictive value. Large randomized controlled trials are needed to establish the actual value of LGE and other derived parameters in the wider population.