Canadian Journal of Cardiology 30 (2014) S442eS454

Review

The Epidemic of Heart Failure: A Lucid Approach to Stemming the Rising Tide Eileen O’Meara, MD,a,* Nicolas Thibodeau-Jarry, MD,b,* Anique Ducharme, MD,a and Jean Lucien Rouleau, MDa,b a

Montreal Heart Institute, Montre al, Que bec, Canada

b

Universite de Montre al, Montre al, Que bec, Canada

ABSTRACT

  RESUM E

At least 1 in 5 Canadians will experience heart failure (HF) during their lifetimes, with an average 1-year mortality rate of 23.4%. Hospitalizations for HF are projected to increase 3-fold from 1996 to 2050. HF can be associated with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), with the latter becoming increasingly common. The prognosis of both groups is equally concerning, but clinical trials testing pharmacologic therapies for HFpEF have been disappointing. We briefly discuss established therapies for HF and then focus on emerging therapies, challenges, and opportunities. Areas covered include practical pathophysiology; health care organization; monitoring and new technologies; pharmacogenomics, biomarkers, and personalized therapy; novel pharmacologic approaches; special considerations in acutely decompensated HF; revascularization; managing valve dysfunction; refining cardiac resynchronization therapy and device therapies; and cell therapy for cardiac repair. Among the novel

veloppera une insuffisance cardiaque Au moins 1 Canadien sur 5 de  à 1 an de (IC) au cours de sa vie, avec un taux moyen de mortalite 23.4 %. Les projections suggèrent que les hospitalisations pour l’IC e à une fracdevraient tripler de 1996 à 2050. L’IC peut être associe jection re duite (HFrEF) ou à une fraction d’e jection pre serve e tion d’e (HFpEF), ce dernier devenant de plus en plus commun. Le pronostic de tant, mais les essais cliniques ces deux groupes est tout aussi inquie s à e valuer les the rapies pharmacologiques pour l’HFpEF destine cevants. Nous exposons brièvement les the rapies e tablies restent de mergents, les de fis et les pour l’IC et soulignons ensuite les traitements e s. Les domaines aborde s comprennent la physiopathologie opportunite ; le suivi et les nouvelles pratique; l’organisation des soins de sante nomique, les biomarqueurs et le traitement technologies; la pharmacoge ; les nouvelles approches pharmacologiques; les conpersonnalise rations particulières en IC aiguë de compense e; la revascularisation; side

Heart failure (HF) is an increasingly common disease that 1 in 5 or more Canadians
40 years of age will experience during their lifetimes. Although the therapy for HF and many of the risk factors leading to the development of HF have improved significantly over the past 3 decades, morbidity and mortality remain elevated. A striking 1% of the overall population is estimated to have HF in Canada.1 There is a projected 3-fold increase in HF hospitalizations from 1996 to 2050.2 Patients with HF have an average 1-year mortality rate of 23.4%.3 HF generally can be classified into 1 of 2 broad categories: patients with HF associated with reduced ejection fraction (HFrEF) and those with HF with a preserved ejection fraction (HFpEF). The prevalence of these 2 broad categories varies

with age, HFrEF being more common in younger patients and more frequently associated with a history of myocardial infarction.4 As a result of our progress in limiting the sequelae of coronary artery disease (CAD) and the increasing number of older individuals in Canada, the profile of patients with HF is changing, with an increasing number and proportion of patients having HFpEF as compared with HFrEF.5 Although one may instinctively expect the prognosis of patients with HFpEF to be better than that of patients with HFrEF, in actuality the prognosis of both groups is of equal concern, perhaps because of the multiple comorbidities associated with HFpEF, which also complicates the care of these patients. In this review, we only briefly discuss established therapies for HF and rather focus on emerging therapies, challenges, and opportunities. This includes modifications in the organization of the care of patients with HF. Indeed, innovative approaches to the improvement of care of these patients may offer the best opportunities for advancement because, at least in the short term, it would appear that (1) patients with HFrEF have myocardial damage that will be difficult to reverse, (2) we have few emerging new therapies on the

Received for publication September 18, 2014. Accepted September 30, 2014. *These authors contributed equally to this work. Corresponding author: Dr Jean L. Rouleau, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec, H1T 1C8, Canada. Tel.: þ1-514-3763330; fax: þ1-514-376-1355. E-mail: [email protected] See page S451 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2014.09.032 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

O’Meara et al. Heart Failure Epidemic

S443

pharmacologic directions we address are approaches to reducing oxidative stress, improving myocardial metabolism, new mineralocorticoid receptor antagonists, restoring vasoconstrictor-vasodilator balance, increasing cyclic guanosine monophosphate levels, and positive inotropic agents. Modifications in the organization of health care are particularly important, with an emerging hub-and-spokes model involving engaged patients cared for by primary care teams, with ready access to specialized HF clinics. Biomarkers have contributed to better understanding of the pathophysiology of HFrEF as well as HFpEF and will eventually allow much more effective and personalized management. Considering the vast array of areas in development, we can look forward to continuing improvements in the care and outcomes of patients with HF in the future.

rapies la gestion d’une dysfonction valvulaire; le raffinement des the de resynchronisation cardiaque et des traitements à l’aide de disrapie cellulaire pour la re paration cardiaque. positifs; et la the Parmi les nouvelles orientations pharmacologiques que nous voquons figurent les de marches de re duction du stress oxydatif, e lioration du me tabolisme du myocarde, les nouveaux antagl’ame cepteurs aux mine ralocorticoïdes, la restauration de onistes des re quilibre vasoconstriction/vasodilatation, l’augmentation des l’e niveaux de guanosine monophosphate cyclique et les agents inotropes positifs. Les modifications dans l’organisation des soins de  sont particulièrement importantes, avec un modèle e mergent sante seau en e toile impliquant des patients engage s et pris en de re quipes de soins primaires, avec un accès facilite  charge par des e cialise s dans l’IC. Les biomarqueurs ont contribue  à aux centres spe hension de la physiopathologie de l’HFrEF une meilleure compre ainsi que de l’HFpEF et permettront à terme une gestion plus e. Compte tenu de la large palette des efficace et personnalise veloppement, nous pouvons nous attendre à des domaines en de liorations continues dans les soins et des re sultats the rapeuame tiques pour les patients atteints d’IC dans le futur.

horizon to offer patients with HFpEF, and (3) the proportion of patients with HFpEF is increasing in Canada, becoming the dominant form of HF.

HF being the end point of multiple pathophysiological pathways, early diagnosis remains a challenge, but at least 1 large randomized trial was able to show promising results with brain natriuretic peptide (BNP) screening in a high-risk population.14 Whether this strategy will be applicable in the larger population and whether it will help to decrease the epidemic of HF remains to be seen.

Prevention As we try to move from a less reactive medical model to a more preventive one, earlier diagnosis in HF and risk factor modification appear to be very important goals.5 Known risk factors for the development of HF include CAD,6 hypertension,7 diabetes,8,9 obesity,10 age,11 and cigarette smoking.12 A large study demonstrated a decreased lifetime risk of HF developing, from 21% to 10%, in men adhering to healthy lifestyle habits.13 Early management of risk factors and healthy habits could thus help slow the HF epidemic. Although progress in controlling some of these risk factors has occurred over the past 25 years, the benefits are balanced by the aging of the Canadian population, increases in obesity and diabetes, and the improved survival of patients with CAD.6

Figure 1. Heterogeneous components of the syndrome of heart failure with reduced ejection fraction. BP, blood pressure; COPD, chronic obstructive pulmonary disease; ROS, reactive oxygen species. Adapted from Senni et al.17 with permission from xxx.

Pathophysiology from a Practical Perspective HFrEF is the result of myocardial damage, most frequently the result of loss of myocardial tissue and thus a result of loss of the pumping ability of the heart. The severity of HFrEF can be complicated by adverse left ventricular (LV) remodelling, mitral valve insufficiency, excessive neurohumoral activation, and comorbidities, the most important of which is renal dysfunction.15 Other important factors to consider in assessing how best to approach the therapy of patients with HFrEF include the level of dyssynchrony of the left ventricle, rhythm disturbances, and the extent of CAD. Except for renal dysfunction, significant progress in the care of patients with HFrEF has occurred as a result of advances in reversing many of the precipitating and complicating factors of HFrEF. In contrast, HFpEF is really a syndrome and not an entity as such. Indeed, apart from the symptoms and signs of HF, there are relatively few classic diagnostic findings, including imaging findings, that help secure a diagnosis of HFpEF.16 Rather, HFpEF appears to result from the convergence of multiple abnormalities that together result in clinical HF (Fig. 1). Some of the more frequent complicating comorbidities that contribute to the syndrome of HFpEF include renal dysfunction, mitral regurgitation, hypertension, LV hypertrophy, loss of vascular compliance, pulmonary hypertension, atrial fibrillation, conduction abnormalities, obesity, diabetes, aging, and paradoxically enough, relative hypotension or postural hypotension late in the course of HFpEF.17 Because of the relative importance of these and other comorbidities contributing to the syndrome of HFpEF, it has been difficult to find an effective therapy; interventions that can improve 1 patient profile can worsen that of the next.

S444

The past 3 decades have seen great advances in pharmacologic therapy for patients with HFrEF, but precious little progress has been made in such therapy for patients with HFpEF. The introduction of devices has also had an impressive impact on the prognosis of patients with HFrEF; however, again they have had little beneficial impact in patients with HFpEF.5 Newer expensive interventions, from implantable hearts to cell therapy, also are better adapted to patients with HFrEF than patients with HFpEF. The exception may be percutaneous valvular interventions, which as our population ages and the incidence of aortic stenosis increases, is helping a greater number of elderly patients. Acute HF is another HF syndrome for which we have had a difficult time finding ways of improving outcomes. As in HFpEF, acute HF is more of a syndrome than a disease entity and results from fluid overload associated with abnormalities related not only to HFrEF or HFpEF, or both, but also to arrhythmias, myocardial ischemia, uncontrolled hypertension, anemia, infection, valvular problems, or any combination of these factors. Because acute HF can result from multiple precipitating factors, it can take various forms, from hypotensive shock to uncontrolled hypertension, and is usually characterized by acute neurohumoral overactivation, which may serve to maintain adequate perfusion pressures. Again, finding therapies has been difficult because there is no unique intervention that can improve all cases of acute HF, with most interventions improving some patients but worsening others. Organization of the Health Care System The increasing number of patients with HF and their care is putting increasing pressure on our health care systems. The development of algorithms and quality promotion programs has helped increase the use of evidence-based care, and the development of HF clinics has helped ensure intense multidisciplinary care for patients in the greatest need. These gains notwithstanding, because of the sheer number of patients with HF and their complexity, the challenge that the delivery of optimal care to these patients at an affordable cost presents cannot be met without a paradigm shift. This paradigm shift must have 2 inter-related complementary aspectsdthat of greater patient and family engagement, and that of a greater shift in patient follow-up to primary care multidisciplinary teams associated with more specialized HF clinics in a huband-spokes configuration. Greater involvement of patients and their care is a key requirement of any strategy to optimize the care of patients with HF. The importance of educating patients and their families has been appreciated for some time, such that educational tools and programs have been developed for this purpose.18 The care of patients with HF must continue to evolve from one of patient-centred care to one in which patients and their families become true partners in their care. Such engagement of patients in their own care can only be reached with more intense and ongoing education and exchange between patients, their families, and health care professionals. Patient-directed tools and algorithms tailored to the follow-up and care of patients with HF need to be developed and tested so that patients can alter their habits and, in specified circumstances, their therapy to reduce instability and optimize outcomes. The intensity of involvement of health

Canadian Journal of Cardiology Volume 30 2014

care professionals in these algorithms would need to vary according to the patient’s capacity and will to engage in their own care, as well as family involvement and the complexity of the health care problems being addressed. Already evidence exists that patient engagement can significantly improve outcomes and quality of life of patients with HF, and consensus is building that this is where we should be focusing more attention if we are to stem the tide of the increasing burden of HF.19,20 Different approaches to optimizing the follow-up and care of patients with HF have been and are being developed and tested.21 The impact of these strategies has varied, so apart from multidisciplinary HF clinics, there are no universally accepted approaches to optimizing the follow-up of these patients. HF clinics have been shown to improve patient outcomes and to reduce hospitalizations22; however, even when directed by HF specialists, the type of services offered and the types of patients cared for varies remarkablydfrom young and reasonably well patients to elderly and more severely compromised patientsdunderlying the need to develop guidelines even for these clinics. If optimal resource use is to be limited, specialist-led HF clinics should focus on high-risk patients who have had multiple episodes of decompensated HF or who have comorbidities. The majority of patients with HF require much less intensive care and should be cared for by multidisciplinary primary health care teams that focus on optimizing patient and family engagement tailored to the needs and competencies of individual patients, such as ease of use of newer information technologies. The organizational scheme should take a hub-and-spokes form, with engaged patients cared for by primary care teams with ready access to specialized HF clinics (Fig. 2). Monitoring and the Use of New Technologies The ultimate goal of monitoring and the use of new technologies is to have more sensitive markers of HF status and the risk of decompensation to allow earlier diagnosis, time to intervene, and prevent the progression of HF or a costly admission for HF. New strategies include implantable devices that allow continuous monitoring of hemodynamics in patients with HF.23 Three types of devices have been studied so far. The first is the right ventricular (RV) pressure monitor. This device resembles a single-lead RV pacemaker and can monitor RV pressure, which correlates with pulmonary artery diastolic pressure.24 A multicentre study using the device demonstrated a nonsignificant 21% reduction in the primary efficacy end point of reduction in HF events (hospitalizations and emergency or urgent care visits requiring intravenous therapy) in the RV sensor group compared with the control group.23 The CardioMEMS device (St. Jude Medical, St. Paul, MN) is a pulmonary artery pressure sensor composed of a coil- and pressure-sensitive capacitor encased in a capsule implanted into the pulmonary artery. The device is interrogated using an antenna that transmits information to a website available to clinicians.24 A study of 550 patients comparing this device with standard of care demonstrated a 37% relative risk reduction in hospitalizations for HF compared with the control group.25 The third type of implantable device is the left atrial pressure monitor, which consists of a sensor lead

O’Meara et al. Heart Failure Epidemic

S445

Figure 2. Optimal organization of health care delivery for patients with heart failure (HF). The organizational scheme should take a hub-and-spokes form, with engaged patients cared for by primary care teams with ready access to specialized HF clinics.

implanted through a transeptal puncture into the left atrium linked to a subcutaneous antenna coil.24 Despite some encouraging results, at this time more trials documenting its risks and benefit, and describing its exact role in the care of patients with HF are required.23 A large randomized controlled study is under way to evaluate this device (NCT01121107). Finally, Telehome monitoring of patients with HF has been evaluated and some reports have been favourable,26 whereas others have not, so again, larger more definitive trials that test the efficacy of the algorithms proposed, the costs of such strategies, and their outcomes are required. Pharmacogenomics, Biomarkers, and Personalized Therapy Given the complexity of the treatment regimens offered and the numerous comorbid conditions affecting patients with HF, thinking that a single solution would apply to all is clearly unrealistic. A personalized approach is long overdue, but the big question is how? What are the ideal tools, when should we use them and how many lives (or hospitalizations) could a personalized strategy save, and at what cost? In 2020, we would ideally be able to not only predict the risks of hospitalizations for HF and mortality in a given patient (in a given clinical situation) but also to predict which patients would have adverse reactions to HF therapies and which ones would benefit most. We offer a brief overview of the tools in development, or needed, toward reaching this goal.

The individual response of a patient with HF to medications or various treatments is an example of complex mechanisms, being influenced by both environmental and genetic factors. Environmental factors consist predominantly of the comorbidities and lifestyle habits of the individual as well as nonpharmacologic and pharmacologic therapies, including in some instances over-the-counter agents. Genetic factors include polymorphisms scattered throughout the human genome, generally with high frequency. When coupled with other factors, such as environmental factors, polymorphisms could have an impact on the occurrence of HF (susceptibility genes) and could also influence the process of cardiac remodelling, exercise tolerance, responses to therapy, or prognosis (modifying genes), or a combination of these factors. In recent years, researchers have turned their attention toward genomics and pharmacogenomics (PGx) to discover potentially useful biomarkers to identify patients most likely to benefit or experience side effects from a given drug or to predict prognosis. The number of clinical applications of PGx and personalized medicine has grown exponentially, with many clinically useful PGx markers having been validated in other therapeutic fields, particularly in oncology.27 In fact, more than 100 drugs in the United States carry PGx information in their prescribing information. As reviewed by de Denus et al.,28 this includes widely prescribed cardiovascular drugs such as warfarin and clopidogrel. Despite these successes, the clinical implementation of PGx has been slow outside the field of oncology. Data from our group and others show that the limited knowledge of health care professionals about PGx and

S446

the lack of decision-support tools are major obstacles to its implementation,29,30 which will need to be addressed if we are to evolve toward effectively using PGx in practice. Metabolomic analyses, the systematic study of smallmolecule metabolite profiles, has been used to identify potential biomarkers that may provide new insights into biological processes. There are significant metabolic differences in serum and urine samples between patients with HF and control participants, or a so-called metabolomics fingerprint of HF.31,32 For example, myocardial energy expenditure (MEE), which is related to left ventricular ejection fraction (LVEF), has been identified as an independent predictor of cardiovascular mortality.33 MEE can be evaluated by calculating the amount of O2 extracted by the left ventricle from arterial blooddusing echocardiography or advanced imaging techniques such as positron emission tomography, singlephoton emission tomography, and phosphorus-31 magnetic resonance imaging, which have allowed the noninvasive measurement of cardiac metabolism.34,35 In a study of 46 patients with HF and 15 age-matched controls, metabolomics testing was performed through nuclear magnetic resonance spectrometry,36 and MEE was calculated using colour Doppler echocardiography. The mean MEE levels of patients with HF and controls were 139.61  58.18 calories/min and 61.09  23.54 calories/min, respectively. Serum metabolomics varied with MEE changes, and 3-hydroxybutyrate, acetone, and succinate were significantly elevated with increasing MEE. Levels of these 3 metabolites were independent of administration of angiotensin-converting enzyme inhibitor, b-blockers, diuretic agents, and statins (P > 0.05). Although we are only at the beginning of the journey with metabolomics, we can foresee its role in further understanding the pathophysiology of HF and eventually in refining the application of therapeutics through the identification of novel (and perhaps unexpected) biomarkers. Several clinical characteristics have long been identified as prognostic markers in HF, eg, age, New York Heart Association (NYHA) functional class, systolic blood pressure, LVEF, and QRS duration. These are routinely being used in decision making for the management of patients with HF. Various circulating biomarkers (serum sodium, glomerular filtration rate, proteinuria, hemoglobin) have also been largely incorporated into clinical practice. However, they are not consistently included in clinical decision making or at least not in a standardized manner. The natriuretic peptides (NPs) BNP and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) are the most established biomarkers in HF, increasingly being used for their diagnostic and prognostic value and with accumulating evidence for the role of NPguided therapy.37,38 Recent studies have suggested that cardiac troponins and high-sensitivity troponins in combination with BNP measurements in patients with HF might provide additional value for risk stratification in patients with HF.39,40 The costs associated with additional biomarkers are of concern. Although myriad circulating biomarkers are becoming increasingly attractive regarding prognostication for patients with HF, integrating the data from numerous studies on this topic is challenging.41 The incremental value of novel biomarkers above and beyond what is obtained from established HF risk prediction models must be clearly demonstrated before considering their clinical application, and cost-benefit analyses

Canadian Journal of Cardiology Volume 30 2014

need to be performed. Moreover, the clinical impact of using such biomarkers should then be tested “in the real world” when applied to decision making in various clinical HF conditions. This step also needs to involve both ethical and health economics perspectives. For example, the decision to implant a defibrillator for primary prevention of sudden death may benefit from the aid of biomarkers, and research is under way to achieve this goal.42,43 In that case, even more expensive markers (such as those obtained from advanced cardiac imaging) may prove cost-effective. International groups of investigators are now working together to move research faster and in a more organized manner to evolve from prognostication with biomarkers toward optimization of HF management using biomarkers. The latter will most likely involve a multimarker approach (clinical, imaging, and circulating biomarkers, as well as genetic determinants) that would be part of a personalized medicine approach. Novel Pharmacologic approaches for the Treatment of Chronic HF The quest for old and new drugs to reduce the burden of HF continues relentlessly. We highlight a few recent and ongoing studies assessing novel therapeutic avenues in HF. Reducing oxidative stress Oxidative stress is thought to play a significant role in ventricular and vascular remodelling, leading to progression of HF. Xanthine oxidase (XO) is involved in oxidative stress pathways,44 so oxypurinol and allopurinol, both potent XO inhibitors, have been tested in patients with HF. In the Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure (OPT-CHF) trial, in which patients with moderate to severe HF were randomized to 6 months of treatment with oxypurinol or placebo, no clinical benefits were observed in the overall study population, but there was a signal of benefit in hyperuricemic participants (uric acid level
565 mmol/L).45 Unfortunately, the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACTHF) trial, which tested high-dose (300-600 mg) allopurinol for 24 weeks in 253 high-risk patients with symptomatic HFrEF and elevated serum uric acid levels failed to show benefit. Although discouraging, both of these trials included only a small number of patients followed for only a short time. Considering the somewhat divergent results of these 2 studies, it may still be worthwhile to test allopurinol in a larger population and for a longer time. Improving Myocardial Metabolism Cardiac metabolism is abnormal in patients with HF, with patients with normal coronary arteries being global lactate producers.46 There is a growing body of evidence demonstrating beneficial effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on cardiovascular risk factors such as body weight, blood pressure, and lipid profiles, as well as their potential consequences on cardiovascular events, including HF.47 Indeed, it appears that these agents promote natriuresis and diuresis and improve endothelial function.47 The Functional Impact of GLP-1 for Heart Failure Treatment

O’Meara et al. Heart Failure Epidemic

(FIGHT) trial (ClinicalTrials.gov Identifier: NCT01800968) is currently enrolling patients after an acute HF episode to assess the effect of liraglutide on mortality, HF hospitalization, and change in NT-proBNP levels (baseline-180 days). Patients require a previous diagnosis of HF and an LVEF 40% and already be receiving evidence-based medication for HF and at least 80 mg of furosemide total daily dose (or equivalent) before admission. Secondary end points include changes in cardiac structure and function, quality of life, and exercise tolerance. Mineralocorticoid Receptor Antagonists, Old and New Mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcome in patients with HFrEF and in patients with HF or LV dysfunction after myocardial infarction. Although the Treatment Of Preserved Cardiac function heart Failure With an Aldosterone antagonist Trial (TOPCAT),48 which evaluated spironolactone in patients with HFpEF, did not reduce the composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization in the whole of the included population, it reduced it in patients enrolled on the basis of an elevated natriuretic peptide level and also significantly reduced the rates of recurrent hospitalizations for HF in the overall population. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia, defined as serum Kþ
5.5 mmol/L (18.7% vs 9.1% in the placebo group), but these side effects were generally not serious. Nevertheless, the prevalence of diabetes mellitus and chronic kidney disease (CKD) in patients with acute decompensated HF (ADHF) is 40% and 50% of patients, respectively, in clinical trials and approximately 35% and 26%, respectively, in observational studies.49-51 These patients are at greater risk of hyperkalemia and deterioration of renal function with the addition of an MRA,52 such that BAY 94-8662, a next-generation nonsteroidal MRA that has shown improved selectivity for the heart over the kidney and thus may provide the structural benefits of an MRA while minimizing the risk of hyperkalemia and renal dysfunction, has been developed and tested.53 In patients with HFrEF and moderate CKD, the safety and tolerability of BAY 94-8862 was at least as effective as spironolactone in decreasing biomarkers of hemodynamic stress and was associated with lower incidences of hyperkalemia and worsening renal function (n ¼ 65).54 The ongoing phase IIb Safety and Efficacy Study of Different Oral Doses of BAY94-8862 in Subjects With Worsening Chronic Heart Failure and Left Ventricular Systolic Dysfunction and Either Type 2 Diabetes Mellitus With or Without Chronic Kidney Disease or Chronic Kidney Disease, the ARTS-HF trial (NCT01807221) is a randomized, double-blind study to assess safety and efficacy of BAY 94-8862 (vs eplerenone) in participants with acute decompensation of chronic HFrEF and either type 2 diabetes mellitus with or without CKD or moderate CKD alone. Efficacy will be defined as the proportion of participants with a relative decrease in NT-proBNP of more than 30% from baseline at 90 days. Restoring the Vasoconstrictor-Vasodilator Balance Combining established treatments with newer drugs is also of interest. LCZ696 is an angiotensin-receptor neprilysin

S447

inhibitor that both reduces neurohumoral vasoconstrictor overactivation with the angiotensin-receptor blocker valsartan and enhances endogenous vasodilation by blocking neprilysin and thus increasing natriuretic peptide and adrenomedullin. In patients with HFrEF, LCZ696 has recently been shown to reduce cardiovascular mortality by 20%, to reduce hospitalizations for HF by 21%, to reduce overall mortality by 16%, and to improve symptoms and signs of HF (P ¼ 0.001) over optimal doses of enalapril.55 The results of the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (PARADIGM-HF) trial will likely result in the replacement of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as a first-line therapy in patients with HFrEF.55 The Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial (ClinicalTrials.gov NCT01920711) has just gotten under way and will test whether LCZ will have similarly beneficial effects in patients with HFpEF. Increasing Cyclic Guanosine Monophosphate Levels Patients with HF have endothelial dysfunction that can lead not only to vascular dysfunction, stiffness, and fibrosis but also to ventricular dysfunction, hypertrophy, and fibrosis and worsen the ventriculoarterial coupling mismatch that is characteristic of HF, particularly HFpEF.56 Sildenafil is a potent selective inhibitor of type 5 phosphodiesterase (PDE5), a widespread enzyme in the pulmonary bed that induces smooth muscle cell relaxation and causes vasodilation through an increase in cyclic guanosine monophosphate (cGMP) levels. This agent was shown to improve pulmonary hemodynamics and functional capacity in patients with advanced HF awaiting heart transplantation.57,58 However, sildenafil administered orally for 24 weeks in 206 patients with HFpEF did not result in significant improvement in exercise capacity (peak oxygen consumption) or clinical status in the PDE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial.59 Moreover, the Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure (PITCHHF) trial, testing parent drug tadalafil in systolic HF, was recently stopped (NCT01910389) for undisclosed reasons. Agents such as the oral soluble guanylate cyclase stimulator vericiguat, which increases cGMP, are now being evaluated in phase II dose ranging studies in patients with HFrEF (NCT01951625) and in patients with HFpEF (NCT01951638). Inotropic Agents Are we overusing inotropic agents? They are often our last resource to improve symptoms and hemodynamics in patients with advanced HF, despite an increase in adverse events.60 Previous trials of inotropic agents in patients with HFrEF have all shown them to be at best neutral and all too often detrimental. Nevertheless, trials using new approaches to increasing inotropy are under investigation. Omecamtiv mecarbil is a cardiac myosin activator, which binds directly to the myosin catalytic domain, stabilizing an actin-bound conformation of myosin and increasing fractional shortening

S448

Canadian Journal of Cardiology Volume 30 2014

Figure 3. Pathophysiological schema for mechanisms underlying acutely decompensated heart failure. Volume overload plays a central role. Reproduced from Koniari K, et al.61 Treating volume overload in acutely decompensated heart failure: established and novel therapeutic approaches.

in cardiomyocytes in the absence of any increase in calcium transients.62 In a dose-ranging trial of 45 patients with stable HF, omecamtiv mecarbil increased LVEF and stroke volume and decreased end-systolic and end-diastolic volumes.63 These findings led to the Acute Treatment With Omecamtiv Mecarbil to Increase ContractilityeAcute Heart Failure (ATOMIC-AHF; NCT01300013) study, completed in September 2013 (results not yet published). The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) trial is now enrolling patients with HFpEF (NCT01786512). This phase II multicenter clinical trial is designed to assess the pharmacokinetics and tolerability of oral dosing of omecamtiv mecarbil in this population of patients. Reducing the diastolic leak of calcium from the sarcoplasmic reticulum (SR) through the ryanodine receptor 2 (RyR2) is another potential means of improving myocardial contractility, and RyR2 stabilizers, or “rycals” are now being investigated as inotropic agents.64 SR calcium uptake is mediated by Ca(2þ)-ATPase (SERCA2), whose activity is reversibly regulated by phospholamban. Modulation of cardiac inotropy could also be achieved through targeting of the SERCA2/phospholamban system.65 Newer Therapeutic Approaches to Therapy for ADHF and Relieving Acute Volume Overload As previously emphasized, the pathophysiologic mechanisms involved in ADHF are complex (Fig. 3), so there is currently not much evidence-based therapy for the treatment of ADHF and its well-recognized relationship with mortality in chronic HF, despite this being the number 1 cause for

hospital admissions in North America.66,67 Unfortunately, results from randomized clinical trials evaluating various interventions, such as the adenosine A1 receptor antagonist rolofylline.68 the recombinant human BNP nesiritide,69 or the cardiac inotropic agent dobutamine, which has renal effects, all had disappointing results.70 Nevertheless, a trial with ularitide, a synthetic form of urodilatinda human NP produced in the kidneys that induces natriuresis and diuresis by binding to specific NP receptors, thereby increasing intracellular cGMP, relaxing smooth muscle cells, and leading to vasodilation and increased renal blood flowdremains under investigation. Early studies have shown that ularitide lowered cardiac filling pressures and improved dyspnea without apparent early deleterious effects on renal function in AHF.71 The Trial of Ularitide’s Efficacy and Safety in Patients With Acute Heart Failure (TRUE-AHF) is currently ongoing to evaluate the role of this agent as an intravenous infusion in addition to conventional therapy in patients with ADHF (NCT01661634). Relaxin is an endogenous peptide initially discovered as an active hormone in pregnancy. Through stimulation of the relaxin receptor, relaxin decreases inflammation, decreases fibrosis, increases vasodilation, promotes renal blood flow, and increases vascular endothelial growth factor and angiogenesis.72 The Relaxin in Acute Heart Failure (RELAX-AHF) study enrolled 1161 patients with ADHF within 16 hours of presentation,73 and they were randomly assigned to receive an infusion of seralaxin or placebo for 48 hours. Compared with placebo, seralaxin significantly improved the primary end point of dyspnea at 5 days, but it had no significant effect on the secondary end point of death or readmission for HF at 60 days. However, it was associated with reduced 180-day

O’Meara et al. Heart Failure Epidemic

mortality (P ¼ 0.02). These findings need to be confirmed in larger studies. Congestion leads to further neurohormonal activation, adverse LV remodelling, pulmonary hypertension, right ventricular dysfunction, and renal damage.74 Although the underlying mechanisms leading to congestion are still being debated (Fig. 3), relief of symptoms starts with treatment of congestion. Multiple precipitating factors leading to ADHF have been proposed, yet in a significant proportion of patients, a specific cause cannot be found. Unfortunately, since the publication of the Canadian Recommendations for the treatment of HF in 2012, there has been little recent progress in the development of agents and techniques to achieve decongestion.75 Loop diuretics remain the first pharmacologic treatment for decongestion, despite their inherent short-term risks for deterioration of renal function. Data from metaanalyses suggest that functional status and mortality may be improved with torsemide when compared with furosemide.76 However, a majority of patients are receiving furosemide, which should probably be re-evaluated against torsemide in clinical trials.77 The Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE) trial demonstrated that no difference in the efficacy of furosemide in reducing congestion existed whether given in infusion or by bolus and that larger doses tended to reduce congestive symptoms faster with only a transient increase in creatinine levels.78 Generally, nondiuretic approaches to relieving volume overload have been disappointing. Although venovenous ultrafiltration may be of benefit in relieving congestion, particularly in diuretic-resistant patients, this technology may potentially lead to more renal dysfunction than pharmacologic therapy does.79 Optimal diuresis is likely to vary in each patient, and this is where we could use circulating biomarkers to prevent renal injury. Vasopressin receptor antagonists (eg, tolvaptan) can rapidly and effectively reduce body weight and restore serum sodium levels in patients with hyponatremic congestion, but short-term morbidity (hospitalizations) or mortality benefits have not yet been demonstrated.80 Limited data exist regarding treatment with hypertonic saline for decongestion. Although the results of a recent meta-analysis suggest that in patients with advanced HF this therapy could improve weight loss, preserve renal function, and decrease length of hospitalization, mortality, and rehospitalization for HF,81 large clinical trial evidence to support this intervention is lacking. Revascularization Because HFrEF is most frequently the result of CAD, much interest has focused on how best to address coronary revascularization. The recent publication of the Surgical Treatment for Ischemic Heart Failure (STICH) trial demonstrated that coronary artery bypass grafting (CABG) in patients with CAD and LV dysfunction (EF  35%) reduced cardiovascular mortality and cardiovascular hospitalizations.82 The more severe the LV dysfunction, the greater the LV dilatation and the more advanced CAD, the greater was the benefit of CABG.83 Interestingly, the presence of viable myocardium or reversible ischemia did not identify patients who would improve most with CABG.84 Whether novel imaging technology and better standardization of reporting

S449

formats could improve decision making regarding revascularization (leading to better outcomes) in patients with ischemic HFrEF are research questions being addressed in the ongoing Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) study.85 Because LV dilatation is a marker of poor outcome in patients with CAD and LV dysfunction, surgical ventricular restoration (SVR) of the left ventricle had been recommended as a potentially beneficial way of restoring ventricular shape and function. The STICH trial addressed the role of this intervention in patients with an EF  35% and anterior akinesis that required CABG. STICH found that SVR had no beneficial impact on outcome,86 but that in a subgroup of patients with less severe LV dilatation, SVR may be considered, whereas in patients with greater LV dilatation, SVR should be avoided.87 Improving Mitral Regurgitation An important comorbidity associated with HFrEF is the concurrent existence of significant functional mitral regurgitation (FMR), resulting from annular enlargement or papillary muscle displacement. FMR is frequent, with a prevalence as high as 60% in ischemic cardiomyopathy and in 40% of nonischemic cardiomyopathies.88 Severe MR is an independent predictor of mortality in chronic HF.89 Although angiotensin-converting enzyme inhibitors,90 as well as bblockers,91 have been shown to reduce the severity of MR by increasing forward stroke volume, mortality in patients treated medically remains high. There appears to be a benefit in performing mitral valve surgery in patients with moderate to severe MR undergoing CABG.82 New studies are ongoing to evaluate this impact.92 In patients with severe ischemic MR, mitral valve repair appears safe and at least as effective as mitral valve replacement at 1 year of follow-up.93 The role of mitral valve surgery without performing CABG in patients with HFrEF remains uncertain. The percutaneous treatment of MR using the MitraClip device system (Abbott Vascular, Abbott Park, IL) is another rapidly evolving technique. Although this new technology has been shown to be less effective in reducing MR than mitral valve surgery for MR reduction, it is generally safer and associated with similar clinical outcomes compared with surgery,94 making it an attractive option for high-risk patients with HF and functional MR. Despite these encouraging results, further trials and long-term follow-up of patients with the MitraClip device system are required before fully understanding the place of such devices in the treatment of patients with severe MR. Ongoing clinical trials (NCT01772108 and NCT01626079) will lead to better understanding of the role of MR reduction devices in this population. New technologies are also being developed, such as the permanent percutaneous transvenous mitral annuloplasty system.95 Finally, before considering interventions for the improvement of MR, in persons in whom cardiac resynchronization therapy (CRT) is indicated, it may be worth evaluating the effects of CRT on MR. By providing reverse remodelling to the left ventricle, CRT can dramatically improve MR. One small study in patients with moderate to severe HF and severe MR showed an improvement in MR in close to 50% of patients at 8 months.96

S450

Treating Aortic Stenosis As the number of aging patients increases, so does the number of patients with severe aortic stenosis who are fragile and have other comorbidities rendering surgical aortic valve replacement a high-risk procedure. Fortunately, the development of transcatheter aortic valve replacement (TAVI) has provided a good therapeutic option for such patients. For patients not suitable for surgery (predicted operative mortality >50%), the results of the Placement of Aortic Transcatheter Valves (PARTNER) trial showed a striking 29% absolute reduction in all-cause mortality or repeated hospitalization at 1 year, the coprimary end point (from 50.7% to 30.7%), and 24% reduction in cardiovascular mortality alone. In addition, TAVI was comparable to surgical aortic valve surgery in highrisk but operable patients.97 Refining CRT and Device Therapies CRT is among the very few treatments able to reverse LV remodelling while improving mortality and quality of life in a wide range of patients with HFrEF. However, only a minority of patients qualify for cardiac resynchronization98dthose with NYHA class II or greater HF, a wide QRS with preferably a left bundle branch block (QRS
130 ms if left bundle branch block [LBBB] is present; QRS > 150 ms if LBBB is not present), with LVEF  35%, in sinus rhythm)dand of those patients, about a third do not respond to this therapy. Although many echocardiographic parameters have been studied to predict response to CRT, when applied in multicentre clinical trials none has been proved superior to QRS width on the surface electrocardiogram.99 At this time, ongoing challenges include refining patient selection to both expand the population that could be helped by CRT and reducing use in those in whom it is not helpful, and developing or improving device implantation techniques, or both.100 Numerous studies have shown that implantable cardioverter-defibrillators (ICDs) save lives in secondary as well as primary prevention in ischemic as well as nonischemic cardiomyopathy.101-106 The main drawback of ICDs is the burden of inappropriate shocks, which needs to be further reduced. Although improved programming has been able to decrease their occurrence, inappropriate shocks are a serious side effect of ICDs, leading to increased adverse outcomes, particularly in end-of-life situations.107 Renal Denervation and Vagal Stimulation Chronic HF is associated with sympathetic activationd elevated circulating norepinephrine levels linked to cardiovascular morbidity and mortality.108 Sympathetic activation can be modulated by renal denervation and has been associated with a reduction in LV hypertrophy and improvements in diastolic function.108 A pilot study performed in 7 patients with HFrEF suggested improvements in both symptoms and exercise capacity.109 Unfortunately, renal denervation has not proved effective in the therapy of hypertension, so further investigation in HF is now uncertain. Another potential way of reducing sympathetic stimulation is through carotid (vagal) barostimulation. Although a proofof-concept study in 11 patients showed improvements in

Canadian Journal of Cardiology Volume 30 2014

baroreflex sensitivity, EF, NYHA class, quality of life, and 6-minute hall walking distance,110 the randomized Neo trial (NCT01471860) recently reported no benefit of vagal stimulation in 140 patients with NYHA III HF on LV remodelling (primary end point) but improvement in important secondary end points when compared with optimal HF therapy (Abstract presentation, European Society of Cardiology Congress 2014). Cell Therapy for Cardiac Repair Cell therapy for cardiac repair has been intensively evaluated for more than 15 years since the seminal discovery by Anversa et al.111,112 that the heart had at least a limited capacity to regenerate. Initial studies used a host of unselected cell mixtures from generally poorly fractionated bone-marrowederived mononuclear stem cells and delivered them in varying amounts and by varying techniques. Also, these studies made little effort to program the cells before delivery or to prime the milieu to optimize their development into functioning myocardium. Although these studies did not show consistent benefit, they did demonstrate safety and the potential of such an approach.113 More recent studies have focused on identifying the optimal purified cell populations to be used and how best to prime them and the milieu receiving them for effective cardiac regeneration.113 Although much progress has been made with these more advanced approaches to cell therapy, much remains to be accomplished. For example, determining the optimal number of cells to be delivered has also been a challenge, with studies demonstrating an inverse relationship between the number of cells being delivered and efficacy. Also, the timing of cell delivery in acute diseases, such as myocardial infarction, remains undetermined and how approaches to cardiac regeneration should be adapted to fit the underlying pathologic process as well as acute vs chronic injury at best remains partially unanswered. These limitations notwithstanding, a number of phase II studies, using more comprehensive approaches to cardiac regeneration, have shown some promise, and phase III trials are under way to assess their efficacy. Although much remains to be learned about how best to adapt to the interplay between the diseased heart and regenerative biotherapeutics, progress is being made so that cardiac regeneration remains our best hope for future large-scale improvement in patients with HFrEF and patients with acute cardiac injury. Conclusions Much improvement has been made in the treatment and follow-up of patients with HF. These include a vast array of domains, including advances in drugs, surgical procedures, percutaneous techniques, and implantable devices and monitors. Most of these advances have proved useful only for patients with HFrEF, whereas very few treatments have proved efficacious for patients with HFpEF or ADHF. These advances and other pharmacologic and device therapies in development notwithstanding, to successfully stem the rising tide of HF, it will be necessary to intervene earlier to reduce preventable risk factors for HF and to identify patients with HF earlier in the disease process so that the natural evolution

O’Meara et al. Heart Failure Epidemic

S451

of the disease can be better prevented and sometimes even reversed. Personalization of care through better use of biomarkers and monitoring is also promising, but in the short term, better integration and optimization of our health care systemdfrom patient engagement through primary care to specialized clinicsdperhaps provides the best hope of stemming the rising tide of HF.

15. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987-96.

Disclosures The authors have no conflicts of interest to disclose.

17. Senni M, Paulus WJ, Gavazzi A, et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014.

References

18. Boyde M, Turner C, Thompson DR, Stewart S. Educational interventions for patients with heart failure: a systematic review of randomized controlled trials. J Cardiovasc Nurs 2011;26:E27-35.

1. Chow CM, Donovan L, Manuel D, Johansen H, Tu JV. Regional variation in self-reported heart disease prevalence in Canada. Can J Cardiol 2005;21:1265-71. 2. Johansen H, Strauss B, Arnold JM, Moe G, Liu P. On the rise: the current and projected future burden of congestive heart failure hospitalization in Canada. Can J Cardiol 2003;19:430-5. 3. Darwin F, Yeung MD, Nicole K. Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007. CMAJ 2012;184: E765-73. 4. Brouwers FP, de Boer RA, van der Harst P, et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J 2013;34:1424-31. 5. Blair JE, Huffman M, Shah SJ. Heart failure in North America. Curr Cardiol Rev 2013;9:128-46. 6. Hellermann JP, Jacobsen SJ, Redfield MM, et al. Heart failure after myocardial infarction: clinical presentation and survival. Eur J Heart Fail 2005;7:119-25. 7. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 2002;106:3068-72. 8. Arnlov J, Lind L, Sundstrom J, et al. Insulin resistance, dietary fat intake and blood pressure predict left ventricular diastolic function 20 years later. Nutr Metab Cardiovasc Dis 2005;15:242-9. 9. Arnlov J, Lind L, Zethelius B, et al. Several factors associated with the insulin resistance syndrome are predictors of left ventricular systolic dysfunction in a male population after 20 years of follow-up. Am Heart J 2001;142:720-4. 10. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347:305-13. 11. Bleumink GS, Knetsch AM, Sturkenboom MC, et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 2004;25: 1614-9. 12. He J, Ogden LG, Bazzano LA, et al. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996-1002.

16. Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-50.

19. Cowie MR. Person-centred care: more than just improving patient satisfaction? Eur Heart J 2012;33:1037-9. 20. Ekman I, Wolf A, Olsson LE, et al. Effects of person-centred care in patients with chronic heart failure: the PCC-HF study. Eur Heart J 2012;33:1112-9. 21. Thomas R, Huntley A, Mann M, et al. Specialist clinics for reducing emergency admissions in patients with heart failure: a systematic review and meta-analysis of randomised controlled trials. Heart 2013;99:233-9. 22. Ducharme A, Doyon O, White M, Rouleau JL, Brophy JM. Impact of care at a multidisciplinary congestive heart failure clinic: a randomized trial. CMAJ 2005;173:40-5. 23. Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol 2008;51:1073-9. 24. Abraham WT. Disease management: remote monitoring in heart failure patients with implantable defibrillators, resynchronization devices, and haemodynamic monitors. Europace 2013;15(suppl 1):i40-6. 25. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658-66. 26. Woodlend AK, Sherrard H, Fraser M, et al. Telehome monitoring in patients with cardiac disease who are at high risk of readmission. Heart Lung 2008;37:36-45. 27. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptorepositive breast cancer. J Clin Oncol 2010;28:3784-96. 28. de Denus S, Labbe C, Philipps MS, Tardif JC, Rioux JD. Pharmacogenomics. In: Theroux P, ed. Acute Coronary Syndromes: A companion to Braunwald’s Heart Disease. 2nd ed. Saunder, 2011:81-93. 29. de Denus S, Letarte N, Hurlimann T, et al. An evaluation of pharmacists’ expectations towards pharmacogenomics. Pharmacogenomics 2013;14:165-75.

13. Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. JAMA 2009;302:394-400.

30. Bonter K, Desjardins C, Currier N, Pun J, Ashbury FD. Personalised medicine in Canada: a survey of adoption and practice in oncology, cardiology and family medicine. BMJ Open 2011;1:e000110.

14. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66-74.

31. Tenori L, Hu X, Pantaleo P, et al. Metabolomic fingerprint of heart failure in humans: a nuclear magnetic resonance spectroscopy analysis. Int J Cardiol 2013;168:e113-5.

S452

Canadian Journal of Cardiology Volume 30 2014

32. Kang SM, Park JC, Shin MJ, et al. 1H nuclear magnetic resonance based metabolic urinary profiling of patients with ischemic heart failure. Clin Biochem 2011;44:293-9.

49. Konstam MA, Pang PS, Gheorghiade M. Seeking new heights in acute heart failure syndromes: lessons from ASCEND and EVEREST. Eur Heart J 2013;34:1345-9.

33. Palmieri V, Roman MJ, Bella JN, et al. Prognostic implications of relations of left ventricular systolic dysfunction with body composition and myocardial energy expenditure: the Strong Heart Study. J Am Soc Echocardiogr 2008;21:66-71.

50. MacDonald MR, Petrie MC, Hawkins NM, et al. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J 2008;29:1224-40.

34. Shah SH, Kraus WE, Newgard CB. Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. Circulation 2012;126: 1110-20. 35. Rhee EP, Gerszten RE. Metabolomics and cardiovascular biomarker discovery. Clin Chem 2012;58:139-47. 36. Du Z, Shen A, Huang Y, et al. 1H-NMR-based metabolic analysis of human serum reveals novel markers of myocardial energy expenditure in heart failure patients. PLoS One 2014;9:e88102. 37. Felker GM, Hasselblad V, Hernandez AF, O’Connor CM. Biomarkerguided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J 2009;158:422-30. 38. Porapakkham P, Porapakkham P, Zimmet H, Billah B, Krum H. Btype natriuretic peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med 2010;170:507-14. 39. Masson S, Anand I, Favero C, et al. Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure: data from 2 large randomized clinical trials. Circulation 2012;125:280-8. 40. Gravning J, Askevold ET, Nymo SH, et al. Prognostic effect of highsensitive troponin T assessment in elderly patients with chronic heart failure: results from the CORONA trial. Circ Heart Fail 2014;7: 96-103. 41. Ahmad T, Fiuzat M, Pencina MJ, et al. Charting a roadmap for heart failure biomarker studies [e-pub ahead of print]. JACC Heart Fail http://dx.doi.org/10.1016/j.jchf.2014.02.005.2014. Accessed: September 17, 2014. 42. Cheng A, Dalal D, Butcher B, et al. Prospective observational study of implantable cardioverter-defibrillators in primary prevention of sudden cardiac death: study design and cohort description. J Am Heart Assoc 2013;2:e000083.

51. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010;12:1076-84. 52. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803-69. 53. Barfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 2012;7:1385-403. 54. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J 2013;34:2453-63. 55. McMurray JJV, Packer M, Desai AS, et al. Angiotensineneprilysin inhibition versus Enalapril in heart failure. N Engl J Med 2014;371: 993-1004. 56. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263-71. 57. Pons J, Leblanc MH, Bernier M, et al. Effects of chronic sildenafil use on pulmonary hemodynamics and clinical outcomes in heart transplantation. J Heart Lung Transplant 2012;31:1281-7. 58. Potter BJ, White M, Carrier M, et al. Hemodynamic and clinical benefits associated with chronic sildenafil therapy in advanced heart failure: experience of the Montreal Heart Institute. Can J Cardiol 2012;28:69-73. 59. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268-77.

43. Mordi I, Jhund PS, Gardner RS, et al. LGE and NT-proBNP identify low risk of death or arrhythmic events in patients with primary prevention ICDs. JACC Cardiovasc Imaging 2014;7:561-9.

60. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol 2003;41:997-1003.

44. Karantalis V, Schulman IH, Hare JM. Nitroso-redox imbalance affects cardiac structure and function. J Am Coll Cardiol 2013;61:933-5.

61. Koniari K, Parissis J, Paraskevaidis I, Anastasiou-Nana M. Treating volume overload in acutely decompensated heart failure: established and novel therapeutic approaches. European heart journal. Acute Cardiovascular Care 2012;1:256-68.

45. Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 2008;51:2301-9. 46. De Marco T, Chatterjee K, Rouleau JL, Parmley WW. Abnormal coronary hemodynamics and myocardial energetics in patients with chronic heart failure caused by ischemic heart disease and dilated cardiomyopathy. Am Heart J 1988;115:809-15. 47. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diabetes Vasc Dis Res 2012;9:95-108. 48. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-92.

62. Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 2011;331:1439-43. 63. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378:676-83. 64. Toischer K, Lehnart SE, Tenderich G, et al. K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2þ leak from the sarcoplasmic reticulum. Basic Res Cardiol 2010;105:279-87.

O’Meara et al. Heart Failure Epidemic 65. Kranias EG, Hajjar RJ. Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome. Circ Res 2012;110:1646-60. 66. Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statisticse2012 update: a report from the American Heart Association. Circulation 2012;125:188-97. 67. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482-7. 68. Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363: 1419-28. 69. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43. 70. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or lowdose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533-43. 71. Mitrovic V, Seferovic PM, Simeunovic D, et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J 2006;27:2823-32. 72. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7:75-82. 73. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29-39.

S453

84. Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011;364: 1617-25. 85. O’Meara E, Mielniczuk LM, Wells GA, et al. Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project IA: study protocol for a randomized controlled trial. Trials 2013;14:218. 86. Jones RH, Velazquez EJ, Michler RE, et al. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med 2009;360:1705-17. 87. Michler RE, Rouleau JL, Al-Khalidi HR, et al. Insights from the STICH trial: change in left ventricular size after coronary artery bypass grafting with and without surgical ventricular reconstruction. J Thorac Cardiovasc Surg 2013;146:1139-1145.e6. 88. Ducas RA, White CW, Wassef AW, et al. Functional mitral regurgitation: current understanding and approach to management. Can J Cardiol 2014;30:173-80. 89. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524-9. 90. Seneviratne B, Moore GA, West PD. Effect of captopril on functional mitral regurgitation in dilated heart failure: a randomised double blind placebo controlled trial. Br Heart J 1994;72:63-8. 91. Capomolla S, Febo O, Gnemmi M, et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. Am Heart J 2000;139:596-608.

74. Mentz RJ, Kjeldsen K, Rossi GP, et al. Decongestion in acute heart failure. Eur J Heart Fail 2014;16:471-82.

92. Smith PK, Michler RE, Woo YJ, et al. Design, rationale, and initiation of the Surgical Interventions for Moderate Ischemic Mitral Regurgitation Trial: a report from the Cardiothoracic Surgical Trials Network. J Thorac Cardiovasc Surg 2012;143:111-7. 117.e1.

75. McKelvie RS, Moe GW, Ezekowitz JA, et al. The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Can J Cardiol 2013;29:168-81.

93. Acker MA, Parides MK, Perrault LP, et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 2014;370:23-32.

76. DiNicolantonio JJ. Should torsemide be the loop diuretic of choice in systolic heart failure? Future Cardiol 2012;8:707-28.

94. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395-406.

77. Bikdeli B, Strait KM, Dharmarajan K, et al. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives? J Am Coll Cardiol 2013;61:1549-50. 78. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797-805. 79. Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol 2012;59:2145-53. 80. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332-43. 81. Gandhi S, Mosleh W, Myers RB. Hypertonic saline with furosemide for the treatment of acute congestive heart failure: a systematic review and meta-analysis. Int J Cardiol 2014;173:139-45. 82. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364: 1607-16. 83. Panza JA, Velazquez EJ, She L, et al. Extent of coronary and myocardial disease and benefit from surgical revascularization in LV dysfunction. J Am Coll Cardiol 2014;64:553-61.

95. Machaalany J, Bilodeau L, Hoffmann R, et al. Treatment of functional mitral valve regurgitation with the permanent percutaneous transvenous mitral annuloplasty system: results of the multicenter international Percutaneous Transvenous Mitral Annuloplasty System to Reduce Mitral Valve Regurgitation in Patients with Heart Failure trial. Am Heart J 2013;165:761-9. 96. van Bommel RJ, Marsan NA, Delgado V, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation 2011;124:912-9. 97. Elmariah S, Palacios IF, McAndrew T, et al. Outcomes of transcatheter and surgical aortic valve replacement in high-risk patients with aortic stenosis and left ventricular dysfunction: results from the Placement of Aortic Transcatheter Valves (PARTNER) trial (cohort A). Circ Cardiovasc Interv 2013;6:604-14. 98. Parkash R, Philippon F, Shanks M, et al. Canadian Cardiovascular Society guidelines on the use of cardiac resynchronization therapy: implementation. Can J Cardiol 2013;29:1346-60. 99. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608-16. 100. Yu CM, Hayes DL. Cardiac resynchronization therapy: state of the art 2013. Eur Heart J 2013;34:1396-403.

S454

101. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997;337:1576-83. 102. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101: 1297-302. 103. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102:748-54. 104. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83. 105. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933-40. 106. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882-90.

Canadian Journal of Cardiology Volume 30 2014 107. Kinch Westerdahl A, Sjoblom J, Mattiasson AC, Rosenqvist M, Frykman V. Implantable cardioverter-defibrillator therapy before death: high risk for painful shocks at end of life. Circulation 2014;129:422-9. 108. Bohm M, Ewen S, Linz D, et al. Therapeutic potential of renal sympathetic denervation in patients with chronic heart failure. EuroIntervention 2013;9(suppl R):R122-6. 109. Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013;162:189-92. 110. Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail 2014;16:977-83. 111. Anversa P, Capasso JM, Sonnenblick EH, Olivetti G. Mechanisms of myocyte and capillary growth in the infarcted heart. Eur Heart J 1990;11(suppl B):123-32. 112. Anversa P, Sonnenblick EH. Ischemic cardiomyopathy: pathophysiologic mechanisms. Prog Cardiovasc Dis 1990;33:49-70. 113. Behfar A, Crespo-Diaz R, Terzic A, Gersh BJ. Cell therapy for cardiac repairelessons from clinical trials. Nat Rev Cardiol 2014;11:232-46.