Showing papers in "Nature Reviews Cardiology in 2013"
TL;DR: Reassessment of assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.
Abstract: Remarkable progress has been made in understanding the genetic basis of dilated cardiomyopathy (DCM). Rare variants in >30 genes, some also involved in other cardiomyopathies, muscular dystrophy, or syndromic disease, perturb a diverse set of important myocardial proteins to produce a final DCM phenotype. Large, publicly available datasets have provided the opportunity to evaluate previously identified DCM-causing mutations, and to examine the population frequency of sequence variants similar to those that have been observed to cause DCM. The frequency of these variants, whether associated with dilated or hypertrophic cardiomyopathy, is greater than estimates of disease prevalence. This mismatch might be explained by one or more of the following possibilities: that the penetrance of DCM-causing mutations is lower than previously thought, that some variants are noncausal, that DCM prevalence is higher than previously estimated, or that other more-complex genomics underlie DCM. Reassessment of our assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted. Much about the genomic basis of DCM remains to be investigated, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.
728 citations
TL;DR: Findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality, have prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV.
Abstract: Blood pressure (BP) is characterized by marked short-term fluctuations occurring within a 24 h period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years). Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms. Although the adverse cardiovascular consequences of hypertension largely depend on absolute BP values, evidence from observational studies and post-hoc analyses of data from clinical trials have indicated that these outcomes might also depend on increased BP variability (BPV). Increased short-term and long-term BPV are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. Of particular interest are the findings from post-hoc analyses of large intervention trials in hypertension, showing that within-patient visit-to-visit BPV is strongly prognostic for cardiovascular morbidity and mortality. This result has prompted discussion on whether antihypertensive treatment should be targeted not only towards reducing mean BP levels but also to stabilizing BPV with the aim of achieving consistent BP control over time, which might favour cardiovascular protection.
601 citations
TL;DR: relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size are reviewed.
Abstract: The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection
538 citations
TL;DR: Advances in vascular tissue engineering technology—such as self-assembling cell sheets, as well as scaffold-guided and decellularized-matrix approaches—promise to produce responsive, living conduits with properties similar to those of native tissue.
Abstract: Vascular occlusion remains the leading cause of death in Western countries, despite advances made in balloon angioplasty and conventional surgical intervention. Vascular surgery, such as CABG surgery, arteriovenous shunts, and the treatment of congenital anomalies of the coronary artery and pulmonary tracts, requires biologically responsive vascular substitutes. Autografts, particularly saphenous vein and internal mammary artery, are the gold-standard grafts used to treat vascular occlusions. Prosthetic grafts have been developed as alternatives to autografts, but their low patency owing to short-term and intermediate-term thrombosis still limits their clinical application. Advances in vascular tissue engineering technology-such as self-assembling cell sheets, as well as scaffold-guided and decellularized-matrix approaches-promise to produce responsive, living conduits with properties similar to those of native tissue. Over the past decade, vascular tissue engineering has become one of the fastest-growing areas of research, and is now showing some success in the clinic.
380 citations
TL;DR: The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease.
Abstract: Cellular senescence, defined as arrest during the cell cycle (G₀), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed.
301 citations
TL;DR: How advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion is covered.
Abstract: Critical limb ischaemia (CLI) is the most-severe clinical manifestation of peripheral arterial disease (PAD), and is associated with a high risk of amputation and death. Therapeutic angiogenesis is an approach to stimulating blood vessel growth to improve tissue perfusion, and has the potential to benefit patients with CLI for whom revascularization is not an option. Here, Brian Annex reviews data from clinical trials of therapeutic angiogenesis in patients with PAD, and discusses how advances in systems biology, genetics, and gene therapy might be used in new approaches to this therapy.
245 citations
TL;DR: Public health efforts should urgently promote the understanding of current cigarette-smoke-induced cardiovascular pathology to encourage individuals to reduce their exposure to cigarette smoke and, therefore, the detrimental consequences of associated atherothrombotic disease.
Abstract: Cigarette smoke is an aerosol that contains >4,000 chemicals, including nicotine, carbon monoxide, acrolein, and oxidant compounds. Exposure to cigarette smoke induces multiple pathological effects in the endothelium, several of which are the result of oxidative stress initiated by reactive oxygen species, reactive nitrogen species, and other oxidant constituents of cigarette smoke. Cigarette-smoke exposure interferes adversely with the control of all stages of plaque formation and development and pathological thrombus formation. The reactive oxygen species in cigarette smoke contribute to oxidative stress, upregulation of inflammatory cytokines, and endothelial dysfunction, by reducing the bioavailability of nitric oxide. Plaque formation and the development of vulnerable plaques also result from exposure to cigarette smoke via the enhancement of inflammatory processes and the activation of matrix metalloproteases. Moreover, exposure to cigarette smoke results in platelet activation, stimulation of the coagulation cascade, and impairment of anticoagulative fibrinolysis. Many cigarette-smoke-mediated prothrombotic changes are quickly reversible upon smoking cessation. Public health efforts should urgently promote our understanding of current cigarette-smoke-induced cardiovascular pathology to encourage individuals to reduce their exposure to cigarette smoke and, therefore, the detrimental consequences of associated atherothrombotic disease.
244 citations
TL;DR: Existing barriers to RF and RHD control are reviewed and existing actions required to change the trajectory of control for these diseases are identified.
Abstract: In the 21(st) century, rheumatic fever (RF) and rheumatic heart disease (RHD) are neglected diseases of marginalized communities. Globally, RHD remains the most-common cardiovascular disease in young people aged <25 years. Although RF and RHD have been almost eradicated in areas with established economies, migration from low-income to high-income settings might be responsible for a new burden of RHD in high-income countries. The World Heart Federation (WHF) and its Working Group on RF and RHD unites global experts, combines their experience and enthusiasm, and provides a platform for RHD control. This paper is a declaration of the WHF institutional strategic goal--a 25% reduction in premature deaths from RF and RHD among individuals aged <25 years by the year 2025. The position statement affirms WHF commitments to five key strategic targets: comprehensive register-based control programmes, global access to benzathine penicillin G, identification and development of public figures as 'RHD champions', expansion of RHD training hubs, and support for vaccine development. In this paper, we also review existing barriers to RF and RHD control and identify the actions required to change the trajectory of control for these diseases. This approach provides the foundation for governments, civil society, patient advocates, clinicians, researchers, and funding agencies to develop partnerships and unify global efforts to control RF and RHD. The WHF plans to expand this position statement to an operational plan that will be founded on science, research, and quantifiable progress indicators to impact positively on the millions of people who are affected by RHD and its long-term sequelae.
230 citations
TL;DR: The biological characterization of VEGF is outlined, and the evidence for its potential therapeutic application is examined, including the novel concept of V EGF as adjuvant therapy to stem cell transplantation, in patients with heart failure.
Abstract: Heart failure is a devastating condition, the progression of which culminates in a mismatch of oxygen supply and demand, with limited options for treatment. Heart failure has several underlying causes including, but not limited to, ischaemic heart disease, valvular dysfunction, and hypertensive heart disease. Dysfunctional blood vessel formation is a major problem in advanced heart failure, regardless of the aetiology. Vascular endothelial growth factor (VEGF) is the cornerstone cytokine involved in the formation of new vessels. A multitude of investigations, at both the preclinical and clinical levels, have garnered valuable information on the potential utility of targeting VEGF as a treatment option for heart failure. However, clinical trials of VEGF gene therapy in patients with coronary artery disease or peripheral artery disease have not, to date, demonstrated clinical benefit. In this Review, we outline the biological characterization of VEGF, and examine the evidence for its potential therapeutic application, including the novel concept of VEGF as adjuvant therapy to stem cell transplantation, in patients with heart failure.
195 citations
TL;DR: An overview of the many causes and the prognostic importance of the release of cardiac troponins not related to ACS is provided, and strategies to discriminate between ischaemic and nonischaemic cTn elevation are recommended.
Abstract: Over the past 2 decades, cardiac troponins (cTn) have emerged as the preferred biomarkers for the noninvasive detection of myocardial injury. In conjunction with typical clinical findings of ischaemia, elevated cTn levels in blood confirm a diagnosis of myocardial infarction. However, neither cTnT or cTnI are exclusively released as a result of ischaemic myocardial cell necrosis, but also with numerous nonischaemic acute and chronic cardiac conditions, such as myopericarditis, toxic injury, or severe cardiac overload. With the advent of high-sensitivity assays, causes of cTn elevation not related to an acute coronary syndrome (ACS) have become common findings in patients with chest pain and in those with acute or chronic systemic disorders. Elevated cTn levels in blood are associated with increased rates of cardiac events and mortality, independently of the underlying disease. However, the clinical conditions leading to cTn release in patients who do not have ACS, and the appropriate diagnostic and therapeutic strategies for these individuals, are largely unknown. Here, we provide an overview of the many causes and the prognostic importance of the release of cTn not related to ACS. We also recommend strategies to discriminate between ischaemic and nonischaemic cTn elevation, and describe the clinical evaluation of these patients.
193 citations
TL;DR: Post-hoc analyses of phase II–III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents, but the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven.
Abstract: Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II-III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile.
TL;DR: The current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies are described.
Abstract: Over the past 2 decades, investigators in the field of cardiac genetics have evolved a complex understanding of the pathophysiological basis of inherited cardiac diseases, which predispose individuals to sudden cardiac death. In this Review, we describe the current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies. The various indications for genetic testing and its utility in the clinic are assessed in relation to diagnosis, cascade testing, guiding management, and prognosis. Some common problems exist across all phenotypes: the variable penetrance and expressivity of genetic disease, and the difficulty of assessing the functional and clinical effects of novel mutations. These issues will be of particular importance as the next-generation sequencing technologies are used by genetics laboratories to provide results from large panels of genes. The accurate interpretation of these results will be the main challenge for the future.
TL;DR: Data clearly support the use of statins for primary prevention in high-risk individuals, in whom the strategy is cost-effective and the benefits exceed the risks, but whether primary prevention is beneficial in individuals at low or moderate risk is not certain.
Abstract: Statins are widely used in the evidence-based lowering of cardiovascular disease (CVD) risk. The use of these drugs for secondary prevention of CVD is well founded, but their expanding use in primary prevention--in individuals without documented CVD--has raised some concerns. Firstly, evidence suggests that, in primary prevention, statins substantially decrease CVD morbidity, but only moderately reduce CVD mortality. Secondly, long-term statin use might cause adverse effects, such as incident diabetes mellitus. Thirdly, the cost-effectiveness of such a strategy is unclear, and has to be balanced against the risk of 'overmedicating' the general population. Data clearly support the use of statins for primary prevention in high-risk individuals, in whom the strategy is cost-effective and the benefits exceed the risks. Whether primary prevention is beneficial in individuals at low or moderate risk is not certain. Therefore, the prescription of statins for primary prevention should be individualized on the basis of clinical judgment, particularly for low-risk individuals. In appropriately selected individuals, statins should also be used for primary prevention of ischaemic stroke and transient ischaemic attack.
TL;DR: The fundamental elements of coronary physiology in the absence or presence of coronary artery disease are revisit and the characteristics and role of FFR as a surrogate for noninvasively assessed myocardial ischaemia are revisited.
Abstract: Fractional flow reserve is routinely used to estimate the extent of myocardial ischaemia caused by the narrowing of a coronary artery. In this Review, the physiological basis of this measurement, its limitations, and its clinical use are discussed.
TL;DR: It is believed that no failure of immune system and, possibly, no molecular mimicry occur in rheumatic fever, and this alternative hypothesis shares similarity with collagen involvement in both Goodpasture syndrome and Alport syndrome.
Abstract: Rheumatic fever is one of the most-neglected ailments, and its pathogenesis remains poorly understood. The major thrust of research has been directed towards cross-reactivity between streptococcal M protein and myocardial α-helical coiled-coil proteins. M protein has also been the focus of vaccine development. The characteristic pathological findings suggest that the primary site of rheumatic-fever-related damage is subendothelial and perivascular connective tissue matrix and overlying endothelium. Over the past 5 years, a streptococcal M protein N-terminus domain has been shown to bind to the CB3 region in collagen type IV. This binding seems to initiate an antibody response to the collagen and result in ground substance inflammation. These antibodies do not cross-react with M proteins, and we believe that no failure of immune system and, possibly, no molecular mimicry occur in rheumatic fever. This alternative hypothesis shares similarity with collagen involvement in both Goodpasture syndrome and Alport syndrome.
TL;DR: This research presents a large number of novel and exciting findings in the field of cardiovascular medicine, which have the potential to improve the quality of care and provide new insights into the causes of death and disease.
Abstract: Nat. Rev. Cardiol. 9, 439–453 (2012); doi:10.1038/nrcardio.2012.64 In the version of this article originally published online and in print, the following sentence should have been included in the Figure 3 legend: Parts c, e, and h were previously published in Guagliumi, G. et al. Images in cardiovascular medicine.
TL;DR: The natural history of RHD in children with subclinical abnormalities detected by echocardiographic screening remains unknown, and long-term follow-up studies are needed to evaluate the significance of detecting these changes at an early stage.
Abstract: Rheumatic heart disease (RHD) is a leading cause of cardiac disease among children in developing nations, and in indigenous populations of some industrialized countries. In endemic areas, RHD has long been a target of screening programmes that, historically, have relied on cardiac auscultation. The evolution of portable echocardiographic equipment has changed the face of screening for RHD over the past 5 years, with greatly improved sensitivity. However, concerns have been raised about the specificity of echocardiography, and the interpretation of minor abnormalities poses new challenges. The natural history of RHD in children with subclinical abnormalities detected by echocardiographic screening remains unknown, and long-term follow-up studies are needed to evaluate the significance of detecting these changes at an early stage. For a disease to be deemed suitable for screening from a public health perspective, it needs to fulfil a number of criteria. RHD meets some, but not all, of these criteria. If screening programmes are to identify additional cases of RHD, parallel improvements in the systems that deliver secondary prophylaxis are essential.
TL;DR: Improvements in stent performance have made detecting statistically robust and clinically relevant differences between contemporary devices difficult, and the wide array of available stents enables the choice of device to be tailored to the individual patient.
Abstract: Drug-eluting stents (DES) have revolutionized the practice of interventional cardiology over the past decade. Although their efficacy has never been called into question, concerns have been raised regarding their safety, particularly with respect to very late stent thrombosis. These valid concerns have prompted extensive research into improving stent safety, with particular interest in modifying the permanent polymer used on first-generation DES. Subsequently, various new types of coronary stent have been developed, including DES with biocompatible polymers, DES with biodegradable polymers, polymer-free DES, and completely bioresorbable scaffolds. Some of these new DES are already available in clinical practice, and others are currently undergoing clinical evaluation. Improvements in stent performance have made detecting statistically robust and clinically relevant differences between contemporary devices difficult. The wide array of available stents enables the choice of device to be tailored to the individual patient.
TL;DR: In this article, the authors discuss aspects of the epidemiology, pathophysiology, and diagnosis of cardiovascular disease in patients with kidney disease, and propose specific, evidence-based recommendations for pharmacological and surgical treatment.
Abstract: The burden of cardiovascular disease is high in patients with chronic kidney disease or end-stage renal disease. The presence of kidney dysfunction affects the cardiovascular system in multiple ways, including accelerated progression of atherosclerosis and valvular disease, the exacerbation of congestive heart failure, and the development of pericardial disease. This comorbidity results not only from the concordance of shared risk factors, but also from other issues specific to this population, such as systemic inflammation and vascular calcification. Furthermore, both the sensitivity and specificity of noninvasive testing modalities, and the efficacy of several pharmacotherapeutic strategies, are diminished in this population. The exclusion of patients with severe kidney disease from many clinical trials of cardiac interventions raises various therapeutic uncertainties, and kidney disease itself is likely to alter the underlying cardiovascular physiology. In this Review, we discuss aspects of the epidemiology, pathophysiology, and diagnosis of cardiovascular disease in patients with kidney disease, and propose specific, evidence-based recommendations for pharmacological and surgical treatment.
TL;DR: This Review assesses the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identifies gaps in the literature that need to be addressed in future research efforts.
Abstract: Scientific interest in ischaemic heart disease (IHD) in women has grown considerably over the past 2 decades. A substantial amount of the literature on this subject is centred on sex differences in clinical aspects of IHD. Many reports have documented sex-related differences in presentation, risk profiles, and outcomes among patients with IHD, particularly acute myocardial infarction. Such differences have often been attributed to inequalities between men and women in the referral and treatment of IHD, but data are insufficient to support this assessment. The determinants of sex differences in presentation are unclear, and few clues are available as to why young, premenopausal women paradoxically have a greater incidence of adverse outcomes after acute myocardial infarction than men, despite having less-severe coronary artery disease. Although differential treatment on the basis of patient sex continues to be described, the extent to which such inequalities persist and whether they reflect true disparity is unclear. Additionally, much uncertainty surrounds possible sex-related differences in response to cardiovascular therapies, partly because of a persistent lack of female-specific data from cardiovascular clinical trials. In this Review, we assess the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identify gaps in the literature that need to be addressed in future research efforts.
TL;DR: Patients with hypertriglyceridaemia usually present with obesity, insulin resistance, hepatic steatosis, ectopic fat deposition, and diabetes mellitus, and patients with a diagnosis of genetic lipoprotein lipase deficiency might benefit from LPL gene replacement therapy.
Abstract: Hypertriglyceridaemia (typical triglyceride level 1.7-5.0 mmol/l) is caused by interactions between many genetic and nongenetic factors, and is a common risk factor for atherosclerotic cardiovascular disease (CVD). Patients with hypertriglyceridaemia usually present with obesity, insulin resistance, hepatic steatosis, ectopic fat deposition, and diabetes mellitus. Hypertriglyceridaemia reflects the accumulation in plasma of proatherogenic lipoproteins, triglyceride-rich lipoprotein (TRL) remnants, and small, dense LDL particles. Mendelian randomization studies and research on inherited dyslipidaemias, such as type III dysbetalipoproteinaemia, testify that TRLs are causally related to atherosclerotic CVD. Extreme hypertriglyceridaemia (a triglyceride level >20 mmol/l) is rare, often monogenic in aetiology, and frequently causes pancreatitis. Treatment of hypertriglyceridaemia relies on correcting secondary factors and unhealthy lifestyle habits, particularly poor diet and lack of exercise. Pharmacotherapy is indicated for patients with established CVD or individuals at moderate-to-high risk of CVD, primarily those with metabolic syndrome or diabetes. Statins are the cornerstone of treatment, followed by fibrates and n-3 fatty acids, to achieve recommended therapeutic levels of plasma LDL cholesterol, non-HDL cholesterol, and apolipoprotein (apo) B-100. The case for using niacin has been weakened by the results of clinical trials, but needs further investigation. Extreme hypertriglyceridaemia requires strict dietary measures, and patients with a diagnosis of genetic lipoprotein lipase deficiency might benefit from LPL gene replacement therapy. Several therapies for regulating TRL metabolism, including inhibitors of diacylglycerol O-acyltransferase and microsomal triglyceride transfer protein, and apoC-III antisense oligonucleotides, merit further investigation in patients with hypertriglyceridaemia.
TL;DR: A host of novel strategies, including cardiac contractility modulation, implantable haemodynamic-monitoring devices, and phrenic and vagus nerve stimulation, are under investigation and might have an impact on the future care of patients with chronic HF.
Abstract: Medical devices are often life-saving therapies in patients with advanced heart failure whose condition worsens despite optimal medical therapy. Drs Abraham and Smith expertly review the development of cardiac resynchronization therapy and left ventricular assist devices, describe the current challenges associated with these treatment strategies, and speculate on future advances in this fast-moving field.
TL;DR: A substantial, unmet need remains in patients who have HF with preserved ejection fraction (HFpEF), and new data on spironolactone and LCZ696 (a combined ARB and neprilysin inhibitor) show promise for these patients.
Abstract: The renin–angiotensin–aldosterone system (RAAS) is well established as a therapeutic target in patients with heart failure. Professors Lang and Struthers discuss new indications for existing drugs—angiotensin-converting-enzyme inhibitors, angiotensin II-receptor blockers, and mineralocorticoid-receptor antagonists—as well as novel ways of targeting the RAAS—direct inhibition of renin or dual blockade of the angiotensin II-receptor and neprilysin—in patients who have heart failure with or without reduced ejection fraction.
TL;DR: The next decade will be an exciting time for advances in the understanding and management of RV failure, as promising new targeted therapies are under development and mechanical support is becoming increasingly feasible.
Abstract: Right ventricular (RV) failure is a complex problem with poor outcomes. Diagnosis requires a high degree of clinical suspicion, because many of the signs and symptoms of this condition are nonspecific and can be acute or chronic. Identification of the underlying aetiology, which can include pulmonary hypertension, cardiomyopathy, myocardial infarction, congenital or valvular heart disease, and sepsis, is essential. Echocardiography is the technique of choice for first-line assessment, but cardiac MRI is the current gold standard for anatomical and functional assessment of the right ventricle. Therapy for RV failure should be directed at the underlying cause, although management of symptoms is also important. Therapeutic options range from pharmacological treatment to mechanical RV support and heart transplantation. The complex 3D geometry of the right ventricle and its intricate interactions with the left ventricle have left many questions about RV failure unanswered. However, promising new targeted therapies are under development and mechanical support is becoming increasingly feasible. The next decade will be an exciting time for advances in our understanding and management of RV failure.
TL;DR: Evidence is discussed that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF, and the need for appropriately designed, genotype-directed clinical trials is apparent.
Abstract: Atrial fibrillation (AF) is the most-common sustained arrhythmia observed in clinical practice, but response to therapy is highly variable between patients. Current drug therapies to suppress AF are incompletely and unpredictably effective and carry substantial risk of proarrhythmia and noncardiac toxicities. The limited success of therapy for AF is partially the result of heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to therapies in individual patients. In this Review, we discuss the evidence that variability in response to drug therapy is also conditioned by the underlying genetic substrate for AF. Increased susceptibility to AF is mediated through diverse genetic mechanisms, including modulation of the atrial action-potential duration, conduction slowing, and impaired cell-to-cell communication, as well as novel mechanisms, such as regulation of signalling proteins important in the pathogenesis of AF. However, the translation of genetic data to the care of the patients with AF has been limited because of poor understanding of the underlying mechanisms associated with common AF-susceptibility loci, a dearth of prospective, adequately powered studies, and the challenges associated with determining efficacy of antiarrhythmic drugs. What is apparent, however, is the need for appropriately designed, genotype-directed clinical trials.
TL;DR: Findings from five drug-development programs are discussed to shed light on common themes in clinical trials conducted in patients hospitalized for HF and the importance of selecting the 'right' patient population, drug, and clinical end points to optimize the trial design is discussed.
Abstract: Hospitalization for heart failure (HF) is a clinical entity associated with high postdischarge morbidity and mortality, yet few therapies are available to improve outcomes in patients with this condition. In the past decade, large phase III studies of HF treatments have failed to demonstrate drug efficacy, safety, or both, despite encouraging results from preceding phase II trials. This Review is focused on this disconnect between the results of phase II and phase III trials of drugs for HF and discusses findings from five drug-development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) to shed light on common themes in clinical trials conducted in patients hospitalized for HF. In particular, the importance of selecting the 'right' patient population, drug, and clinical end points to optimize the trial design is discussed. Areas that require further investigation are highlighted and we suggest possible directions that will help to guide future clinical trials in these patients. Large, expensive phase III trials should not be initiated without adequate phase II evidence or on the basis of overly optimistic interpretation of phase II data. Additionally, drug development programs should be targeted not only to change short-term symptoms, but also to improve the postdischarge event rate.
TL;DR: For patients with acute pulmonary oedema, vasodilatation is important to reduce cardiac filling pressures, and removing the fluid, using either diuretics or mechanical means, is the most important consideration.
Abstract: Oedema is one of the fundamental features of heart failure, but the pathophysiology of oedema varies. Patients present along a spectrum ranging from acute pulmonary oedema to gross fluid retention and peripheral oedema (anasarca). In patients with pure pulmonary oedema, the problem is one of acute haemodynamic derangement; the patient does not have excess fluid, but pulmonary venous pressure rises such that the rate of fluid transudation into the interstitium of the lung exceeds the capacity of the pulmonary lymphatics to drain away the fluid. Conversely, in patients with peripheral oedema, the problem is one of fluid retention. Understanding the causes of oedema will enable straightforward, correct management of the condition. For patients with acute pulmonary oedema, vasodilatation is important to reduce cardiac filling pressures. For patients with fluid retention, removing the fluid, using either diuretics or mechanical means, is the most important consideration.
TL;DR: This Review is a critical overview of cost-effectiveness studies on key areas of HF management, involving pharmacological and nonpharmacological clinical therapies, including device-based and surgical therapeutic strategies.
Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Management of HF involves accurate diagnosis and implementation of evidence-based treatment strategies. Costs related to the care of patients with HF have increased substantially over the past 2 decades, partly owing to new medications and diagnostic tests, increased rates of hospitalization, implantation of costly novel devices and, as the disease progresses, consideration for heart transplantation, mechanical circulatory support, and end-of-life care. Not surprisingly, HF places a huge burden on health-care systems, and widespread implementation of all potentially beneficial therapies for HF could prove unrealistic for many, if not all, nations. Cost-effectiveness analyses can help to quantify the relationship between clinical outcomes and the economic implications of available therapies. This Review is a critical overview of cost-effectiveness studies on key areas of HF management, involving pharmacological and nonpharmacological clinical therapies, including device-based and surgical therapeutic strategies.
TL;DR: Control studies in patients with mild-to-moderate, nonresistant hypertension and comorbid conditions such as heart failure, diabetes mellitus, sleep apnoea, and arrhythmias are needed to investigate the capability of renal sympathetic denervation to improve cardiovascular outcomes.
Abstract: Increased sympathetic activity is associated with a number of diseases, including resistant hypertension Renal denervation is becoming increasingly prevalent throughout Europe as a treatment for this condition The pathophysiology of this technique, its use in treating hypertension, and its potential to treat other conditions are discussed in this Review
TL;DR: Cardiac contractility modulation device therapy might benefit symptomatic patients with reduced left ventricular ejection fraction who are not candidates for cardiac resynchronization therapy and ongoing studies are attempting to identify the ideal target population and accumulate additional outcome data.
Abstract: Cardiac contractility modulation (CCM) is the application of nonexcitatory electrical signals to the myocardium, during the absolute refractory period of the action potential, to elicit a positive inotropic effect without increasing myocardial oxygen consumption. These effects are independent of QRS duration; consequently, CCM device therapy might benefit symptomatic patients with reduced left ventricular ejection fraction who are not candidates for cardiac resynchronization therapy. Preclinical studies have demonstrated a rapid positive inotropic effect of CCM, which seems to be mediated by modulation of cardiomyocyte Ca(2+) fluxes and alterations in the phosphorylation of cardiac phospholamban. In vivo translational and clinical studies that utilized double biphasic voltage pulses to the right ventricular aspect of the interventricular septum have demonstrated positive global effects on cardiac reverse remodelling and contractility. Long-term application of CCM seems to improve patients' exercise tolerance and quality of life. These benefits are apparently accomplished with an acceptable safety profile; however, to date, no data have demonstrated reductions in hospitalizations for heart failure or mortality. CCM is currently available in Europe and ongoing studies are attempting to identify the ideal target population and accumulate additional outcome data.