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Canadian Journal of Cardiology

Mind the Gap: Current Challenges and Future State of Heart Failure Care

Published:September 04, 2017DOI:https://doi.org/10.1016/j.cjca.2017.08.023

      Abstract

      The past decade has seen many advances in the management of heart failure (HF) that have improved survival and quality of life for patients living with this condition. A number of gaps remain in our understanding of the pathophysiology of HF, and the application of emerging treatment strategies is an exciting but daunting challenge. It is possible that advances in genetic evaluation of cardiomyopathy will provide a more refined approach to characterizing HF syndromes, whereas large-scale clinical trials on the horizon should further clarify the role of novel pharmacologic agents and invasive therapies. Cardiac repair and regeneration hold great promise, but a number of pragmatic issues will limit clinical application in the near term. Replacing cardiac function with ventricular assist devices represents significant progress in the management of advanced disease; however, unacceptable rates of complications and costs need to be addressed before broader use in the general HF population is feasible. The ability to personalize care is limited, and the optimal model of disease management in the Canadian context remains uncertain. The emergence of biomarker-guided management and remote monitoring technologies might facilitate a more personalized approach to care in an effort to maintain health and stability and to prevent worsening HF. Ultimately, a greater understanding of how and when to intervene in the setting of acute HF should translate into improved outcomes for the highest-risk subgroup of patients. This review highlights key challenges in the management of HF and highlights the progress toward an ideal future state.

      Résumé

      Au cours de la dernière décennie, la prise en charge de l’insuffisance cardiaque (IC) a connu de nombreuses avancées qui ont permis d’améliorer la survie et la qualité de vie des patients qui sont atteints de cette affection. Plusieurs lacunes subsistent dans notre compréhension de la physiopathologie de l’IC, et l’application de stratégies thérapeutiques émergentes représente un défi à la fois stimulant et impressionnant. Il est possible que les progrès réalisés en matière d’évaluation génétique de la cardiomyopathie permettent d’approcher de manière plus fine la caractérisation des syndromes d’IC, tandis que les essais cliniques à grande échelle annoncés devraient clarifier le rôle des nouveaux agents pharmacologiques et traitements invasifs. La réparation et la régénération cardiaques sont porteuses d’immenses promesses, mais, à court terme, plusieurs questions pratiques limiteront leur application clinique. Le remplacement de la fonction cardiaque par des dispositifs d’assistance ventriculaire constitue un progrès appréciable dans la prise en charge de la maladie au stade avancé; toutefois, il faut trouver une solution aux taux de complications inacceptables et aux coûts associés à cette technologie avant d’envisager leur utilisation à plus grande échelle dans la population générale des personnes atteintes d’IC. La capacité d’offrir des soins personnalisés est limitée, et le modèle optimal de prise en charge de la maladie dans le contexte canadien demeure incertain. L’émergence de la prise en charge en fonction des biomarqueurs et des technologies de surveillance à distance pourrait faciliter l’avènement d’une approche thérapeutique plus adaptée à chaque patient dans le but de maintenir la santé de ce dernier et la stabilité de son état ainsi que de prévenir l’aggravation de l’IC. En fin de compte, une meilleure compréhension du moment et des modalités appropriées de l’intervention en cas d’IC aiguë devrait se traduire par une amélioration des résultats chez les patients appartenant au sous-groupe le plus à risque. La présente analyse met en lumière les principaux défis de la prise en charge de l’IC et les progrès réalisés sur la voie d’un état optimal.
      Heart failure (HF) has historically portended a poor prognosis, with a substantial burden imposed on patients, caregivers, and the Canadian health care system.
      • Chun S.
      • Tu J.V.
      • Wijeysundera H.C.
      • et al.
      Lifetime analysis of hospitalizations and survival of patients newly admitted with heart failure.
      Recognizing that the disease trajectory for an individual patient can be quite variable and difficult to predict, the onset of HF symptoms often triggers an inexorable decline associated with progressive disability and eventually death. However, the past several years have yielded a number of milestone achievements in our understanding of the disease and provided much cause for optimism. For example, Canadian data suggest that the incidence of new-onset HF may be declining overall; a 32% reduction in HF incidence was observed in Ontario over a 10-year period from 1997-2007,
      • Yeung D.F.
      • Boom N.K.
      • Guo H.
      • et al.
      Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007.
      and age- and sex-standardized HF mortality and hospitalization rates declined in Canada by 23% and 27%, respectively, over a similar period.
      • Tu J.V.
      • Nardi L.
      • Fang J.
      • et al.
      National trends in rates of death and hospital admissions related to acute myocardial infarction, heart failure and stroke, 1994-2004.
      Publication of the comprehensive Canadian Cardiovascular Society's Heart Failure Guidelines in this issue of the Canadian Journal of Cardiology represents the culmination of a 10-year knowledge translation effort and provides an opportunity to reflect on the current state of HF care and its continued evolution.
      A decade ago, HF guidelines focused on the importance of neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers plus β-blockers for patients with a reduced ejection fraction (EF).
      • Arnold J.M.O.
      • Liu P.
      • Demers C.
      • et al.
      Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.
      Mineralocorticoid receptor antagonism was reserved only for patients with severe HF symptoms and disability. Indications for prophylactic implantable cardioverter defibrillators (ICDs) were relatively well established when the Canadian Cardiovascular Society HF guidelines were published in 2006; however, candidate selection for cardiac resynchronization therapy (CRT) has been refined to reflect its indication in minimally symptomatic patients.
      • McKelvie R.S.
      • Moe G.W.
      • Ezekowitz J.A.
      • et al.
      The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure.
      There was also equipoise with respect to coronary bypass surgery for ischemic cardiomyopathy, and long-term mechanical circulatory support (MCS) with continuous-flow left ventricular assist devices (CF LVADs) was in the early stages of investigation. Repair, regeneration, and restoration of heart function with cell- and bioengineering-based therapy was in its infancy, and genetic evaluation of cardiomyopathies was very limited. Disease management clinics had been well established to provide comprehensive HF care, but technology for monitoring patients outside the clinic setting was relatively basic.
      Looking ahead, the future state of HF care should be highly personalized, with great precision around diagnosis, and should take advantage of evidence-based therapies that prevent disease progression, reliably improve heart function, and can be delivered according to the needs of the individual patient. Indeed, much progress has been made in the past 10 years. However, with the growing armamentarium of tools for diagnosing and managing HF, gaps are exposed and new questions arise. The purpose of this review is to highlight some of the ongoing challenges in the diagnosis and treatment of HF and to highlight progress toward an ideal future state (Fig. 1, Table 1).
      Figure thumbnail gr1
      Figure 1Overview of the ideal future state of personalized and patient-centred heart failure (HF) care and the progress required to achieve this goal. LVAD, left ventricular assist device.
      Table 1Key elements of an idealized HF care model and progress needed for implementation
      Key element of optimal HF careProgress required
      Prevention and treatment of acute HFEnhance understanding of pathophysiology of decompensation

      Ongoing evaluation of vasodilator, decongesting, and inotrope therapies
      Remote monitoring applicationsIdentify optimal parameters to maintain clinical stability

      Actionable and cost-effective monitoring strategies
      Biomarker-guided management and risk stratificationIdentify ideal biomarker target

      Identify right treatment in response to changes in biomarker value
      Durable LVAD technology without complicationsClinical trials and registries to inform optimal pump settings, antithrombotic strategies

      Miniaturization of VAD technologies with enhanced hemocompatiblity
      Well-timed implantable device and valve interventionsClinical trials and registries to refine patient selection for ICD, CRT, and percutaneous valve interventions
      Cardiac repair and regenerationEnhanced cell engraftment, survival, and function at site of injury

      Optimal use of biomaterials for scaffolding and function

      Proof of concept studies and well-designed outcome trials of regenerative medicine strategies
      Personalized approach to drug titration and optimizationOutcome studies of novel therapies for HFrEF, HFpEF

      Assessment of combination contemporary therapy

      Assessment of drug efficacy in patients with varying causes, phenotypes, genotypes, and comorbidities
      Genotype-phenotype characterization of cardiomyopathyLeveraging novel gene sequencing techniques

      Determination of gene variant significance

      Identification of genetic risk and phenotypic expression
      CRT, cardiac resynchronization therapy; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; ICD, implantable cardioverter device; LVAD, left VAD; VAD, ventricular assist device.

      Mind the Gap: Current Challenges and Uncertainties

      Defining HF subtypes

      Currently, classification of HF is primarily based on the presenting phenotype; HF with reduced EF (HFrEF; implies EF < 40%) vs HF with preserved EF (HFpEF; implies EF > 45%-50%). Historically, this distinction has been important because it often relates to the underlying cause, pathophysiology, and more importantly, approach to treatment. In the chronic ambulatory HF setting, eg, these distinct groups of patients differ with respect to prognosis and response to pharmacologic treatment, particularly neurohormonal blockade.
      • Solomon S.D.
      • Anavekar N.
      • Skali H.
      • et al.
      Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients.
      The differential neurohormonal activation profiles and response to disease-modifying drug therapy suggests an incomplete understanding of pathophysiology and raises the possibility that HFpEF is a fundamentally different disease process. Alternatively, HFpEF may reflect a more heterogeneous group of patients for whom response to treatment may be more unpredictable. Indeed, the mode of death in HFpEF remains poorly characterized in clinical trials and observational studies, and it is unclear whether this syndrome reflects a high-risk cardiovascular phenotype per se or whether associated comorbidities have the greatest impact on prognosis.
      • Vaduganathan M.
      • Patel R.B.
      • Michel A.
      • et al.
      Mode of death in heart failure with preserved ejection fraction.
      In an attempt to further categorize patients by EF, some authors have proposed a third category known as HF with midrange EF (HFmrEF; EF, 40%-50%).
      • Lam C.S.P.
      • Solomon S.D.
      The middle child in heart failure: heart failure with mid-range ejection fraction (40-50%).
      Recent data confirm an intermediate prognosis for this group of patients and implies a gradient of HF severity according to EF.
      • Nadruz Jr., W.
      • West E.
      • Santos M.
      • et al.
      Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes.
      Better characterization of the causes of HF and a better understanding of the key pathophysiologic derangements across the spectrum of EFs might improve our ability to deliver more disease-specific and personalized HF care. It is anticipated that advances in imaging and genotyping, eg, will help refine prognosis, predict response to therapy, and inform timing of interventions along the disease continuum.

      Pharmacologic therapy—gaps in evidence-based treatment

      Beyond diagnosis, a personalized approach to HF management will take into account patient-specific factors in designing a treatment strategy. In this regard, there are many outstanding questions surrounding the efficacy of combination therapy with newer drugs, the sequence in which they should be introduced, and whether their benefits can be extrapolated to real-world patients outside of clinical trials.
      For example, although both ivabradine and sacubitril/valsartan have been shown to improve clinically important outcomes in selected HFrEF cohorts,
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Swedberg K.
      • Komajda M.
      • Bohm M.
      • et al.
      Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
      there is a paucity of data from clinical trials on the efficacy and safety of these therapies used in combination. Given that these drugs exert their beneficial effects through different mechanisms (heart rate reduction in the case of ivabradine and neurohormonal modulation in the case of sacubitril/valsartan), there is every reason to believe that their effects may be additive, although no current evidence exists to support this hypothesis. Further, among patients who are candidates for both therapies, there is a lack of clarity as to the sequence in which these drugs should be initiated; patient-specific factors, including heart rate, functional status, ventricular geometry, and EF, may help guide the clinician. Finally, whether these agents will benefit patients who are candidates for implantable devices or valve interventions or those with other HF phenotypes (eg, HFpEF or HFmrEF) remains to be seen. As our understanding of the biological characteristics of HF expands, it may be possible to customize treatment strategies based on specific disease states, and better characterization of pharmacogenetics will further enable a precision approach to HF care.

      Interventional approaches to improve cardiac function: identifying the right intervention at the right time

      Advances in interventional and surgical treatments for HF have occurred in parallel with advances in medical therapy. Well-established invasive therapies such as ICDs and CRT have undergone continuous refinement with respect to patient selection, and the magnitude of benefit of these interventions may change over time as pharmacologic therapy improves. For example, a recent study of primary prevention ICDs in the setting of nonischemic cardiomyopathy showed no overall survival benefit compared with contemporary medical therapy, which has generated more uncertainty about the role of ICDs in this population.
      • Kober L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      Indeed, invasive therapies are generally indicated only if patients have residual risk or disability despite optimal medical therapy. The definition of “optimal medical therapy” is very much a moving target, and it is possible that important patient subgroups may not benefit from devices in the current era of improved pharmacologic management.
      • Kober L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      Novel interventions such as percutaneous mitral valve repair are gaining a foothold in patients with HF and functional mitral regurgitation. Early experience is promising; however, long-term data are limited, and it remains unclear at which stage of disease patients should be considered for this and other invasive therapies.
      • Pighi M.
      • Estevez-Loureiro R.
      • Maisano F.
      • et al.
      Immediate and 12-month outcomes of ischemic versus nonischemic functional mitral regurgitation in patients treated with MitraClip (from the 2011 to 2012 Pilot Sentinel Registry of Percutaneous Edge to Edge Mitral Valve Repair of The European Society of Cardiology).
      Ongoing randomized trials such as the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation Trial (COAPT) should help further define the role of percutaneous mitral valve repair in HF (ClinicalTrials.gov: NCT01626079). Similarly, major improvements in LVAD technology have created a shift in application; once reserved for bridging critically ill patients to cardiac transplantation, LVAD support is increasingly used for destination therapy (DT).
      • Kirklin J.K.
      • Pagani F.D.
      • Kormos R.L.
      • et al.
      Eighth annual INTERMACS report: special focus on framing the impact of adverse events.
      This is particularly germane in the field of advanced HF in which transplantation as definitive cardiac replacement therapy will remain limited by the lack of donor supply for the foreseeable future. Whether LVADs will evolve to the point that they can be reliably used in patients with earlier stages of HF is also uncertain, and a number of current limitations must be overcome.
      • Pagani F.D.
      • Aaronson K.D.
      • Kormos R.
      • et al.
      The NHLBI REVIVE-IT study: Understanding its discontinuation in the context of current left ventricular assist device therapy.
      Beyond device and mechanical therapies, cellular and bioengineering interventions for repairing and restoring heart function hold great potential. Currently, myriad challenges must be addressed for safe and effective translation into the clinical domain. For example, what is the optimal source of cells and tissues? What is the best timing and method of delivery to the heart? What is the mechanism of benefit? How do cell and tissue therapies integrate with the myocardium and contribute to functional improvement? Whether clinical application is realistic within a reasonable time horizon is uncertain.

      Disease management approach to HF—system-wide challenges

      Multidisciplinary disease management programs are associated with improved HF outcomes from both a patient and systems perspective.
      • Wijeysundera H.C.
      • Trubiani G.
      • Wang X.
      • et al.
      A population-based study to evaluate the effectiveness of multidisciplinary heart failure clinics and identify important service components.
      The growing prevalence of HF, coupled with variable and inadequate access to care (particularly in rural communities) and a relative lack of qualified HF care providers, limits the broad applicability of this care model. As such, there is continued interest in identifying disease management strategies that leverage novel technologies to deliver optimal HF care.
      To date, there has not been broad use of remote monitoring (RM) technologies; this may result from limitations in predicting HF decompensation, heterogeneity of populations studied, improvements in HF therapy over time, and care providers' reticence to act on acquired data.
      • Hawkins N.M.
      • Virani S.A.
      • Sperrin M.
      • et al.
      Predicting heart failure decompensation using cardiac implantable electronic devices: a review of practices and challenges.
      Prognostic biomarkers and clinical risk scores may help to identify those patients at highest risk of adverse events and may further provide important target pathophysiological targets that inform management and enable triage to a more comprehensive level of HF care.
      • Felker G.M.
      • Ahmad T.
      • Anstrom K.J.
      • et al.
      Rationale and design of the GUIDE-IT study: guiding evidence based therapy using biomarker intensified treatment in heart failure.
      Whether this approach would result in better outcomes remains unclear. Regardless, the scale of the HF epidemic necessitates a comprehensive health care system that supports patients and their caregivers, manages capacity, and ensures equitable access to optimal HF care.
      Although falling outside the scope of this review, other practical challenges for effective disease management include the difficulty translating clinical advances and knowledge into practice and the care of patients with multiple chronic conditions. Guideline dissemination and related knowledge translation activities are important elements; however, more rigorous, reproducible, and scalable approaches using implementation science protocols are required to optimize the uptake of best practice recommendations for disease management.
      • Proctor E.K.
      • Powell B.J.
      • McMillen J.C.
      Implementation strategies: recommendations for specifying and reporting.
      The issues surrounding real-world management of HF in older patients and those with frailty or multiple comorbidities has been the subject of much discussion, and the reader is referred to a couple of excellent recent reviews that have explored the topic in detail.
      • Kim D.H.
      • Rich M.W.
      Patient-centered care of older adults with cardiovascular disease and multiple chronic conditions.
      • Butous H.
      • Hummel S.L.
      Heart failure in older adults.

      Acute HF—in search of a solution

      Acute HF (AHF) is a harbinger of a poor prognosis,
      • Chun S.
      • Tu J.V.
      • Wijeysundera H.C.
      • et al.
      Lifetime analysis of hospitalizations and survival of patients newly admitted with heart failure.
      and management remains challenging. It is unclear whether short-term interventions aimed at improving symptoms will meaningfully impact longer-term outcomes,
      • Packer M.
      • O'Connor C.
      • McMurray J.J.V.
      • et al.
      The effect of ularitide on cardiovascular mortality in acute heart failure.
      • O'Connor C.M.
      • Starling R.C.
      • Hernandez A.F.
      • et al.
      Effect of nesiritide in patients with acute decompensated heart failure.
      and efforts have primarily focused on treating the hemodynamic perturbations that characterize the AHF state. Congestion, as a hallmark of AHF, is associated with worse outcomes and is often inadequately addressed.
      • Mentz R.J.
      • Kjeldsen K.
      • Rossi G.P.
      • et al.
      Decongestion in acute heart failure.
      Nevertheless, setting defined hemodynamic goals and using invasive measures to direct therapy have not improved outcomes.
      • Binanay C.
      • Califf R.M.
      • Hasselblad V.
      • et al.
      Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.
      Recently published trials of inotropic, ultrafiltration, and novel vasoactive therapies to target congestion and improve loading conditions have also been disappointing, despite inclusion of a broad spectrum of patients with HF.
      • Packer M.
      • O'Connor C.
      • McMurray J.J.V.
      • et al.
      The effect of ularitide on cardiovascular mortality in acute heart failure.
      • O'Connor C.M.
      • Starling R.C.
      • Hernandez A.F.
      • et al.
      Effect of nesiritide in patients with acute decompensated heart failure.
      • Bart B.A.
      • Goldsmith S.R.
      • Lee K.L.
      • et al.
      Ultrafiltration in decompensated heart failure with cardiorenal syndrome.
      • Packer M.
      • Colucci W.
      • Fisher L.
      • et al.
      Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure.
      It is possible that early intervention and effective decongestion will not translate into improved downstream outcomes and that AHF reflects a state of persistent vulnerability despite aggressive symptom control.

      Potential Solutions and Emerging Strategies

      Innovations in personalized medicine: clinical application of genetics in the diagnosis of cardiomyopathy

      Genetic causes of HF span multiple syndromes, including hypertrophic, arrhythmogenic, and dilated cardiomyopathies. The diagnostic yield of currently available genetic testing varies across these diseases, ranging from 40%-50% for hypertrophic cardiomyopathy to 15%-25% for dilated cardiomyopathy in initial reports.
      • Sturm A.C.
      • Hershberger R.E.
      Genetic testing in cardiovascular medicine: current landscape and future horizons.
      Characterizing the underlying genetic cause of these cases can guide therapy. For example, clarifying that left ventricular (LV) hypertrophy is caused by variants in transthyretin or Fabry disease can allow targeted therapies, including RNA silencing, isoform stabilizers, and enzyme replacement.
      • El Dib R.
      • Gomaa H.
      • Ortiz A.
      • et al.
      Enzyme replacement therapy for Anderson-Fabry disease: a complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies.
      • Niemietz C.J.
      • Sauer V.
      • Stella J.
      • et al.
      Evaluation of therapeutic oligonucleotides for familial amyloid polyneuropathy in patient-derived hepatocyte-like cells.
      Further, genetic diagnosis allows for directed family screening.
      Over the past decade, genetic testing has moved toward the forefront of clinical practice, with applications in cardiovascular (CV) medicine that include long-QT syndrome, familial hypercholesterolemia, and Marfan syndrome as common examples.
      • Parikh V.N.
      • Ashley E.A.
      Next-generation sequencing in cardiovascular disease. Present clinical applications and the horizon of precision medicine.
      Greater application of genetic testing has largely resulted from cost reduction and the increased efficiency made possible by next-generation sequencing (NGS). NGS is capable of sequencing at scale. Mapping and assembly of “short reads” generated by NGS to a reference genome allows the discovery of genetic variants.
      • Parikh V.N.
      • Ashley E.A.
      Next-generation sequencing in cardiovascular disease. Present clinical applications and the horizon of precision medicine.
      Currently, the majority of genetic testing for cardiomyopathies is performed using gene panel testing, although broad sequencing approaches may be helpful in specific cases. Several commercially available disease-specific genetic testing panels exist, and the reported diagnostic yield is variable.
      • Sturm A.C.
      • Hershberger R.E.
      Genetic testing in cardiovascular medicine: current landscape and future horizons.
      Recently, many of these gene variants were reviewed in comparison with large population scale genomic data sets, revealing over-representation in the unaffected population of variation in some genes previously thought to be pathogenic.
      • Walsh R.
      • Thomson K.L.
      • Ware J.S.
      • et al.
      Reassessment of mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.
      Thus the inclusion criteria for genes in panel-based tests may change as our diagnostic precision evolves.
      Although techniques such as NGS have emerged as powerful tools, sequencing does have some technical limitations; moreover, assessment of variant pathogenicity remains an imperfect process. Humans differ at millions of genetic positions, yet only a very small amount of this variation is truly causative of disease. The increasing availability of large genomic databases from unaffected individuals helps narrow the list of rare variants to those that are not prevalent in the general population.
      • Lek M.
      • Karczewski K.J.
      • Minikel E.V.
      • et al.
      Analysis of protein-coding genetic variation in 60,706 humans.
      However, despite these advances, our burgeoning knowledge of the genome remains inadequate to assign pathogenicity to many rare variants (known as variants of uncertain significance [VUS]). VUS in genes known to cause disease creates significant clinical equipoise regarding predictive testing and diagnosis.
      In the field of genetic cardiomyopathies, a number of exciting advances are being made in our ability to evaluate variant pathogenicity. For example, in the genome overall, machine learning techniques have been used to predict variant pathogenicity based on large population-based data sets.
      • Kircher M.
      • Witten D.M.
      • Jain P.
      • et al.
      A general framework for estimating the relative pathogenicity of human genetic variants.
      In dilated cardiomyopathy, analysis of data from diseased and healthy populations demonstrated that variant position predicted pathogenicity in titin and myosin.
      • Helle E.
      • Parikh V.N.
      Wrestling with the giant: new approaches for assessing titin variant pathogenicity.
      Further, genetic variants predicted to shorten gene coding sequences (truncating variants) found in the general population correlate with magnetic resonance imaging evidence of eccentric remodelling and have been associated with peripartum cardiomyopathy.
      • Ware J.S.
      • Li J.
      • Mazaika E.
      • et al.
      Shared genetic predisposition in peripartum and dilated cardiomyopathies.
      Finally, it is worth acknowledging that the results of genetic testing in HF, including the identification of VUS for affected individuals and presymptomatic family members, can create additional concerns with respect to future life planning, employment, or insurability. Recent legislation in Canada, known as the Genetic Non-Discrimination Act (available at www.laws-lois.justice.gc.ca), protects individuals from the disclosure or use of genetic test results outside of medical care. However, it must be emphasized that expert review is crucial to interpretation of genetic testing results, and genetic counsellors are fundamental to the clinical care of families with inherited disease.
      Looking ahead, it is anticipated that the advances in genetic evaluation described in this article will improve the precision of genetic cardiomyopathy diagnostics and expand the current definition of cardiomyopathy to include models of genetic risk beyond more rudimentary classification of HF based on phenotype or EF alone. Greater diagnostic precision for patients with HF will enhance the potential to provide highly personalized pharmacologic and invasive treatment.

      Emerging pharmacologic treatment: clinical trials on the horizon

      Although there are many drugs in development for HF, only those currently in phase III mortality/morbidity trials have the potential to influence guidelines and clinical practice in the immediate future. However, even with this restricted perspective, there are more compounds at an advanced stage of testing in HF than ever before. Table 2 lists key drug trials that may impact HF management in the short term.
      Table 2Anticipated clinical trials of pharmacologic therapy for chronic heart failure
      COMMANDER-HFCardiovascular Outcome Modification, Measurement and Evaluation of Rivaroxaban in Patients With Heart Failure
      VICTORIAVericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction
      GALACTIC-HFGlobal Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure
      DAPA-HFDapagliflozin Heart Failure trial
      EMPEROREmpagliflozin Outcome Trial in Patients with Chronic Heart Failure
      PARAGON-HFProspective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction

      HF with reduced EF

      The largest of the ongoing phase III trials is Cardiovascular Outcome Modification, Measurement and Evaluation of Rivaroxaban in Patients With Heart Failure (COMMANDER-HF) (ClinicalTrials.gov: NCT01877915), which is testing the hypothesis that an anticoagulant (rivaroxaban) might improve the composite outcome of death from any cause, myocardial infarction, or stroke in patients with HF with reduced ejection fraction (HFrEF) of ischemic cause who are in sinus rhythm and have recently been treated for an episode of decompensation.
      • Zannad F.
      • Greenberg B.
      • Cleland J.G.
      • et al.
      Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial.
      Implicit in this hypothesis is the suggestion that some deaths in patients with HFrEF result from coronary thrombosis, cerebral thrombosis (or thromboembolism), and pulmonary venous thromboembolism.
      More recently, Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) has been initiated to test the hypothesis that compared with placebo, the guanylate cyclase stimulator vericiguat will reduce the risk of CV death or HF hospitalization in patients with HFrEF, a recent exacerbation, and elevated natriuretic peptide (NP) levels (ClinicalTrials.gov: NCT02861534). By increasing intracellular cyclic guanosine monophosphate, vericiguat acts through the same second-messenger system as do NPs and has vasodilator as well as other actions.
      • Gheorghiade M.
      • Greene S.J.
      • Butler J.
      • et al.
      Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES-REDUCED randomized trial.
      Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) is testing the hypothesis that the cardiac-specific myosin activator omecamtiv mecarbil will be superior to placebo in reducing the risk of CV death or worsening HF events in patients with HFrEF, recent decompensation, and elevated NP levels (ClinicalTrials.gov: NCT02929329). Omecamtiv mecarbil prolongs LV ejection time, thereby improving systolic function (although it must be dosed carefully so as not to shorten diastole to the point of compromising coronary perfusion).
      • Teerlink J.R.
      • Felker G.M.
      • McMurray J.J.
      • et al.
      Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial.
      Intravenous (but not oral) iron has been shown to improve symptoms, quality of life, and functional capacity in patients with HFrEF in relatively small and short-term trials.
      • Ponikowski P.
      • van Veldhuisen D.J.
      • Comin-Colet J.
      • et al.
      Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.
      Now four larger and longer trials are testing whether this treatment might also reduce the risk of CV death and HF hospitalization (ClinicalTrials.gov: NCT02937454, NCT03037931, NCT03036462, and NCT02642562).
      Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new class of treatment used to lower blood glucose levels in patients with type 2 diabetes mellitus. By blocking proximal tubular reabsorption of filtered glucose, SGLT2 inhibitors cause glycosuria, osmotic diuresis, and natriuresis. In addition to reducing hemoglobin A1c, blood pressure, and body weight, the SGLT2 inhibitor empagliflozin was shown to reduce the risk of CV (and all-cause) death, as well as HF hospitalization in patients with type 2 diabetes and CV disease (but not HF in 90% of cases).
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      Whether this type of treatment might be beneficial in patients with established HF is not known but is being tested in 2 new trials in patients with chronic HFrEF, symptoms, and elevated NP levels. Trials testing dapagliflozin (Dapagliflozin Heart Failure trial [DAPA-HF]) and empagliflozin (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]) are enrolling patients with HFrEF with and without diabetes in part because of the high prevalence not only of diagnosed diabetes in HF but also of prediabetic dysglycemia (ClinicalTrials.gov: NCT03036124 and NCT03057977).
      • Kristensen S.L.
      • Preiss D.
      • Jhund P.S.
      • et al.
      Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial.

      HF with preserved ejection fraction

      Two large trials are under way in patients with HFpEF. The Prospective Comparison of Arni with Arb Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial is comparing sacubitril/valsartan with valsartan (ClinicalTrials.gov: NCT01920711).
      • Solomon S.D.
      • Zile M.
      • Pieske B.
      • et al.
      The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
      The other is a sister trial to EMPEROR-Reduced and is comparing empagliflozin with placebo (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]) (ClinicalTrials.gov: NCT03057951).

      Innovations in replacing and repairing heart function: evolution of ventricular assist devices to replace native heart function

      In 2001, the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial was published and provided the first randomized trial evidence that MCS in the form of an implantable LVAD could improve both longevity and quality of life.
      • Rose E.
      • Gelijns A.
      • Moskowitz A.
      • et al.
      Long-term use of a left ventricular assist device for end-stage heart failure.
      The REMATCH trial enrolled 68 patients in the treatment arm and evaluated a pulsatile device that was not designed to function for more than 2 years. Shortly thereafter, the era of CF LVADs began, first with the Heartmate II (Thoratec, Pleasanton, CA) and then the HeartWare (Medtronic, Minneapolis, MN) VADs. In stark contrast to REMATCH, the HeartMate II Bridge to Transplant Trial (BTT) recruited 133 patients and reported a 1-year survival of > 70%.
      • Miller L.W.
      • Pagani F.D.
      • Russell S.D.
      • et al.
      Use of a continuous flow device in patients awaiting heart transplant.
      Similarly, the Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) trial recruited 140 patients and reported a remarkable 86% survival at 1 year.
      • Aaronson K.D.
      • Slaughter M.S.
      • Miller L.W.
      • et al.
      Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation.
      Results from this “second-generation” VAD technology were a disruptive force in the surgical management of HF. VAD implantation in North America and Europe began to explode. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry was developed to track clinical outcomes after implantable VAD therapy; VAD volumes grew from 4000 reported implants in 2012 to > 20,000 implants by 2017.
      • Kirklin J.K.
      • Pagani F.D.
      • Kormos R.L.
      • et al.
      Eighth annual INTERMACS report: special focus on framing the impact of adverse events.
      With increasing clinical experience, a variety of adverse events associated with VAD therapy became apparent, and new problems arose.
      Although aortic insufficiency was seen and recognized with pulsatile pumps, de novo aortic insufficiency became evident in almost 20% of patients during the first year of support with a CF-LVAD.
      • Cowger J.
      • Pagani F.D.
      • Haft J.W.
      • et al.
      The development of aortic insufficiency in the left ventricular assist device-supported patients.
      • Cowger J.
      • Rao V.
      • Massey T.
      • et al.
      Comprehensive review and suggested strategies for the detection and management of aortic insufficiency in patients with a continuous flow left ventricular assist device.
      Another unexpected complication associated with CF-LVAD support was the development of gastrointestinal (GI) bleeding, occurring in almost 30% of recipients.
      • Crow S.
      • John R.
      • Boyle A.
      • et al.
      Gastrointestinal bleeding rates in recipients of non-pulsatile and pulsatile left ventricular assist devise.
      • Demirozu Z.T.
      • Radovancevic R.
      • Hochman L.F.
      • et al.
      Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.
      Although many theories exist about the mechanism, there has been very little progress in the prevention of GI bleeding complications, which are associated with major morbidity.
      • DaSilva M.
      • MacIver J.
      • Rodger M.
      • et al.
      Readmissions following implantation of a continuous-flow left ventricular assist device.
      A more recent observation has been an unexpected and abrupt increase in the rate of pump thrombosis with the HeartMate II LVAD.
      • Starling R.C.
      • Moazami N.
      • Silvestry S.C.
      • et al.
      Unexpected abrupt increase in left ventricular assist device thrombosis.
      Although the initial pump thrombus rate reported in the BTT trial was 3%, Starling et al.
      • Starling R.C.
      • Moazami N.
      • Silvestry S.C.
      • et al.
      Unexpected abrupt increase in left ventricular assist device thrombosis.
      reported an 8.4% rate of confirmed thrombus in the real-world setting.
      The HeartMate 3 LVAD was designed to address these concerns by adding intermittent speed reduction to a continuous centrifugal flow design, which provides artificial pulsatility. In addition to the artificial pulse, the HeartMate 3 has novel design features to enhance biocompatibility.
      • Farrar D.J.
      • Bourque K.
      • Dague C.P.
      • Cotter C.J.
      • Poirier V.L.
      Design features, developmental status, and experimental results with the Heartmate III centrifugal left ventricular assist system with a magnetically levitated rotor.
      The recently reported Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) trial evaluated the clinical impact of these design changes.
      • Mehra M.R.
      • Naka Y.
      • Uriel N.
      • et al.
      A fully magnetically levitated circulatory pump for advanced heart failure.
      In this report, 6-month outcomes are presented for patients in the short-term cohort who were assigned to the new centrifugal-flow pump group (n = 152) or to the commercially available axial-flow pump group (n = 142). The trial met its primary end point (composite of survival free of disabling stroke or reoperation to replace or remove the device at 6 months after implantation), and the HeartMate 3 device was found to be superior to the HeartMate II, primarily because of the lack of reoperation for pump thrombus. There were no reported pump thrombus events in any patient who received a HeartMate 3, and there were no significant differences between the 2 pumps in the rates of other major complications, including right HF, stroke, major infection, or bleeding.
      Despite improvements in LVAD technology and biocompatibility, a number of unanswered questions remain with respect to minimizing residual complications. Are there additional design strategies that can mitigate stroke, infection, and bleeding? Will improvements in medical management, including a more focused effort on postoperative blood pressure control, improve device function and prevent complications?
      Clearly, to advance the field of MCS to treat patients with less advanced HF and to see greater uptake of DT LVAD implantation for patients who are not transplant candidates, unacceptable rates of adverse events must be addressed. Indeed, one of the first trials to examine MCS in a less ill population was terminated early. The premature completion of the Randomized Evaluation of VAD Intervention before Inotropic Therapy (REVIVE-IT) trial was a setback for the entire field.
      • Pagani F.D.
      • Aaronson K.D.
      • Kormos R.
      • et al.
      The NHLBI REVIVE-IT study: Understanding its discontinuation in the context of current left ventricular assist device therapy.
      In contrast, the recent Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP) study provided a signal of benefit for LVAD use for more stable ambulatory patients with advanced HF.
      • Estep J.D.
      • Starling R.C.
      • Horstmanshof D.A.
      • et al.
      Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: Results from the ROADMAP study.
      Canadian experience suggests that slightly > 10% of LVADs are implanted as a DT strategy,
      • Ducharme A.
      • Charbonneau E.
      • Cecere R.
      • et al.
      Insights from a Quebec field evaluation of left ventricular assist device therapy compared with the INTERMACS Registry: can small still be beautiful?.
      and this approach has yet to meet usual cost-effectiveness benchmarks for broader applicability.
      • Rogers J.G.
      • Bostic R.R.
      • Tong K.B.
      • et al.
      Cost effectiveness analysis of continuous flow left ventricular assist devices as destination therapy.
      Improved outcomes and a reduction in complications would likely make DT a more feasible long-term cardiac replacement strategy.
      • Nunes A.J.
      • MacArthur R.G.
      • Kim D.
      • et al.
      A systematic review of the cost effectiveness of long term mechanical circulatory support.

      Innovations in replacing and repairing heart function: strategies for regeneration and repair of heart function

      Tissue engineering offers the theoretical promise of a healthy new organ to replace a failing heart, and the field has advanced rapidly.
      • Trommelmans L.
      • Selling J.
      • Dierickx K.
      Is tissue engineering a new paradigm in medicine? Consequences for the ethical evaluation of tissue engineering research.
      Such approaches face significant technical and translational hurdles. More practical and targeted tissue engineering strategies aim to repair, recover, and regenerate host cardiac tissues by leveraging endogenous repair pathways, and this can be accomplished using genes, cells, or biomaterial scaffolds as therapy. When discussing the current advances toward clinical translation for these therapeutic strategies, it is necessary to consider both the promise and the harsh realities of regenerative medicine for CV disease.
      Cardiac gene therapies directly alter heart cell genes in an effort to enhance endogenous cardiac repair and restore function.
      • Matkar P.N.
      • Leong-Poi H.
      • Singh K.K.
      Cardiac gene therapy: are we there yet?.
      Gene therapy for HF has targeted a number of key CV pathways that include calcium-regulating proteins, apoptotic cellular pathways, β-adrenergic systems, G-protein signalling, proangiogenic proteins, and stem cell activators.
      • Kawase Y.
      • Ladage D.
      • Hajjar R.J.
      Rescuing the failing heart by targeted gene transfer.
      A number of randomized clinical trials for gene therapy in patients with HF have been published. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) and AAV1-CMV-Serca2a Gene Therapy Trial in Heart Failure (AGENT-HF) trials (phase II) aimed to rectify cardiomyocyte dysfunction by restoring SERCA2a (calcium-regulating protein) expression and activity through intracoronary adeno-associated viral gene transfer. Although both trials demonstrated favourable safety profiles, they failed to meet key study end points.
      • Greenberg B.
      • Butler J.
      • Felker G.M.
      • et al.
      Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.
      • Hulot J.-S.
      • Salem J.-E.
      • Redheuil A.
      • et al.
      Effect of intracoronary administration of AAV 1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.
      Similarly, Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Heart Failure (STOP-HF) (phase II) sought to bolster endogenous stem cell–mediated repair by transferring a gene encoding a stem cell–activating protein, SDF-1; the primary end point was not met.
      • Chung E.S.
      • Miller L.
      • Patel A.N.
      • et al.
      Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized phase II trial.
      Finally, the adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure trial (phase II) aimed to improve calcium handling by transferring a gene encoding AC6, an adenylate cyclase. The authors concluded that 1-time intracoronary administration of AC6 at the highest tested dose improved LV function more than standard medical therapy in patients with HF; however, the trial had a number of serious limitations.
      • Hammond H.K.
      • Penny W.F.
      • Traverse J.H.
      • et al.
      Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: a randomized clinical trial.
      Clinical gene therapy for HF is probably safe, but a number of translational hurdles and issues must be addressed before further adoption into practice. Important considerations include optimal selection and delivery of DNA vectors to ensure high transfection efficiency with low immunogenicity and the uncertain effects of targeting a single gene in a disease that involves many complex molecular mechanisms and pathways. Combining genetic manipulation with other strategies, such as cell therapy, may circumvent some of the current translational challenges.
      Endogenous stem/progenitor cells can be isolated, expanded, and delivered into tissues with the promise of regeneration. Given that CV tissues are well known to be poorly regenerative compared with other organ systems, there is enthusiasm for cell therapy in HF.
      • Menasché P.
      • Vanneaux V.
      Stem cells for the treatment of heart failure.
      Many wonder why regenerative cell therapy is not currently a conventional treatment for HF; cell therapy is continually challenged with poor cell engraftment and survival in failing myocardium. Mechanisms of benefit remain unclear, and functional benefits of cell therapy may be less regenerative and more restorative through release of prorepair paracrine factors.
      • Menasché P.
      • Vanneaux V.
      Stem cells for the treatment of heart failure.
      To that end, investigators have focused on designing clinical trials that potentiate the paracrine effects of transplanted cells.
      • Miyagawa S.
      • Domae K.
      • Yoshikawa Y.
      • et al.
      Phase I clinical trial of autologous stem cell-sheet transplantation therapy for treating cardiomyopathy.
      Despite numerous translational hurdles, cell therapy has been evaluated in clinical trials (Table 3).
      • Choudry F.
      • Hamshere S.
      • Saunders N.
      • et al.
      A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: The REGENERATE-AMI clinical trial.
      • Perin E.C.
      • Borow K.M.
      • Silva G.V.
      • et al.
      A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure.
      • Noiseux N.
      • Mansour S.
      • Weisel R.D.
      • et al.
      The IMPACT-CABG trial: a multicenter, randomized clinical trial of CD133(+) stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy.
      • Bartunek J.
      • Terzic A.
      • Davison B.A.
      • et al.
      Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.
      • Anker S.D.
      • Coats A.J.S.
      • Cristian G.
      • et al.
      A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial).
      Confirmatory evidence of benefit and safety will be important and may be forthcoming from international multicentre phase III trials such as the Bone Acute Myocardial Infarction (BAMI) trial, A Double-blind, Randomized, Sham-procedure-controlled, Parallel-group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells [CEP-41750] in Patients With Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of Either Ischemic or Nonischemic Etiology (DREAM-HF), and Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-2) (ClinicalTrials.gov: NCT01569178, NCT02032004, and NCT02317458). Such pivotal clinical trial evidence is needed before clinical use in HF; however, cell therapy trials face design challenges to confirm clinical efficacy. For example, assessment of cardiac performance and recovery of function is more complex in patients than in preclinical controlled animal models of human disease. Many trials use EF as a surrogate end point for treatment efficacy, and it may be insensitive and confounded by other clinical and hemodynamic factors. Specific prorepair pathways such as angiogenesis, cell death, and extracellular matrix (ECM) remodelling may mediate functional benefits but are not directly measurable in human patients.
      • Szady A.D.
      • Pepine C.J.
      • Sharma S.V.
      • Cogle C.R.
      A critical analysis of clinical outcomes reported in stem cell trials for acute myocardial infarction: some thoughts for design of future trials.
      Second, selecting appropriate patients for such therapies is difficult. Early after myocardial infarction, some patients may not have significant baseline LV dysfunction despite ischemic injury, and the therapeutic efficacy may therefore be masked.
      • Choudry F.
      • Hamshere S.
      • Saunders N.
      • et al.
      A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: The REGENERATE-AMI clinical trial.
      For studies that apply cell therapy as an adjunct to conventional surgical therapies, such as Implantation of Autologous CD133+ Stem Cells in Patients Undergoing CABG (IMPACT-CABG), it is difficult to discern whether the positive effects are caused by cell therapy or are the result of conventional treatments such as surgical revascularization.
      • Noiseux N.
      • Mansour S.
      • Weisel R.D.
      • et al.
      The IMPACT-CABG trial: a multicenter, randomized clinical trial of CD133(+) stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy.
      Table 3Summary of the strengths, limitations, and key clinical trials pertaining to application of gene, cell, and acellular scaffold therapies
      TypeStrengthsChallengesKey HF trials (< 5 y)Lessons learned
      Gene therapyOffers means of restoring expression and activity of proteins otherwise lost in HF (calcium regulatory proteins)

      May bolster expression and activity of key proteins to enhance effects to greater than baseline (proangiogenic factors, stem cell factors)
      Little consensus on most suitable vector for gene delivery (viral vs nonviral)

      Vector delivery method

      Targets single genes

      Off-target effects
      CUPID 2
      • Greenberg B.
      • Butler J.
      • Felker G.M.
      • et al.
      Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.


      STOP-HF
      • Chung E.S.
      • Miller L.
      • Patel A.N.
      • et al.
      Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized phase II trial.


      Ad5.hAC6
      • Hammond H.K.
      • Penny W.F.
      • Traverse J.H.
      • et al.
      Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: a randomized clinical trial.


      AGENT-HF
      • Hulot J.-S.
      • Salem J.-E.
      • Redheuil A.
      • et al.
      Effect of intracoronary administration of AAV 1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.
      Ad5.hAC6 trial showed significant improvement in LV function at highest doses; phase III trial under way

      AGENT-HF showed no beneficial effect but was prematurely terminated and therefore underpowered
      All 4 trials showed favourable safety profiles compared with placebo controls

      CUPID trials failed to meet their study end points

      STOP-HF showed improvement in EF in patient group with lowest pretreatment EF
      Cell therapyStem/progenitor cells can be isolated from patient's own body

      Isolated stem/progenitor cells can be re-engineered to enhance their therapeutic effects

      Offers potential of cardiogenesis and de novo tissue regeneration
      Little consensus on which cell population offers most therapeutic benefit (eg, pluripotent vs mesenchymal vs bone marrow derived vs cardiac derived)

      Unclear therapeutic window

      Poor cell survivability and engraftment in host tissue

      Clinical trial design issues may be masking potential benefit of cell therapy in humans
      REGENERATE-AMI
      • Choudry F.
      • Hamshere S.
      • Saunders N.
      • et al.
      A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: The REGENERATE-AMI clinical trial.


      Allogeneic MPC
      • Perin E.C.
      • Borow K.M.
      • Silva G.V.
      • et al.
      A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure.


      IMPACT-CABG
      • Noiseux N.
      • Mansour S.
      • Weisel R.D.
      • et al.
      The IMPACT-CABG trial: a multicenter, randomized clinical trial of CD133(+) stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy.


      CHART-1
      • Bartunek J.
      • Terzic A.
      • Davison B.A.
      • et al.
      Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.
      All 4 trials demonstrated favourable safety and feasibility profiles

      REGENERATE-AMI showed small nonsignificant improvement in LVEF; precursor to phase III BAMI trial

      Allogeneic MPC trial suggested therapeutic benefit from high-dose allogeneic MPCs; precursor to phase III DREAM-HF trial
      IMPACT-CABG showed no significant improvement in functional outcome; precursor to IMPACT-CABG II trial

      CHART-1 identified that patients with most severe LV dilatation (baseline LVEDV 200-370 mL) benefit may be greater from cell therapy; precursor to CHART-2 trial
      Acellular bioscaffold therapyReservoir of regenerative growth factors and matricellular proteins

      Can be further enhanced with stem cells or cardioprotective growth factors for enhanced therapeutic effect

      Few translational hurdles relative to gene or cell therapy
      Uncertainty as to which tissue source yields the most therapeutic bioscaffold for the heart

      Uncertain of which delivery method of bioscaffold yields most therapeutic benefit (patch or injectable?)

      Shortage of clinical trials in patients with HF
      AUGMENT-HF
      • Anker S.D.
      • Coats A.J.S.
      • Cristian G.
      • et al.
      A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial).


      VentriGel injectable trial (ongoing)

      CorMatrix-ECM epicardial patch trial (ongoing)
      AUGMENT-HF demonstrated that alginate-hydrogel injection with standard medical therapy improves exercise capacity, symptoms, and clinical status of patients with advanced HF more than standard medical therapy aloneCorMatrix-ECM epicardial patch trial and VentriGel injectable trial are both ongoing phase I trials
      Ad5.hAC6, Adenovirus 5 encoding adenylyl cyclase 6; AGENT-HF, AAV1-CMV-Serca2a Gene Therapy Trial in Heart Failure; Allogeneic MPC, allogeneic mesenchymal precursor cell; AUGMENT-HF, Randomized, Controlled Study to Evaluate Algisyl-LVR as a Method of Left Ventricular Augmentation for Heart Failure; CHART-1, Congestive Heart Failure Cardiopoietic Regenerative Therapy; CUPID 2, Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease; DREAM-HF, A Double-blind, Randomized, Sham-procedure-controlled, Parallel-group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (CEP-41750) in Patients With Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of Either Ischemic or Nonischemic Etiology; ECM, extracellular matrix; EF, ejection fraction; HF, heart failure; IMPACT-CABG, Implantation of Autologous CD133+ Stem Cells in Patients Undergoing CABG; LV, left ventricular; LVEDV, LV end-diastolic volume; MPC, mesenchymal precursor cell; REGENERATE-AMI, Randomised Controlled Clinical Trial of the Use of Autologous Bone Marrow Derived Progenitor Cells to Salvage Myocardium in Patients With Acute Anterior Myocardial Infarction; STOP-HF, Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Heart Failure.
      Finally, tissue engineering using acellular biological scaffolds is gaining momentum, particularly decellularized biological tissue–derived matrices that retain bioactive properties. ECM is a biological structural scaffold with bioactive properties that can be leveraged to stimulate myocardial repair without the underlying safety concerns of an immunogenic response. To date, there is substantial evidence from preclinical studies that outlines the cardioprotective benefits of ECM biomaterials in the failing heart.
      • Mewhort H.E.
      • Turnbull J.D.
      • Meijndert H.C.
      • Ngu J.M.
      • Fedak P.W.
      Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling.
      • Efraim Y.
      • Sarig H.
      • Cohen Anavy N.
      • et al.
      Biohybrid cardiac ECM-based hydrogels improve long term cardiac function post myocardial infarction.
      Given that cell therapy may confer functional benefits through paracrine effects,
      • Fedak P.W.M.
      Paracrine effects of cell transplantation: modifying ventricular remodeling in the failing heart.
      it is conceivable that bioactive acellular matrix scaffolds could have similar paracrine effects without the need for donor cells. An optimal therapy may in fact combine progenitor cells with bioactive scaffolds to enhance engraftment and proreparative effects.
      Although clinical translation is less complicated with acellular biomaterials, additional research is needed. First, the optimal biomaterial for cardiac therapy is not established. Second, biomaterials can be delivered as an injectable or an epicardial patch. Injectable agents are advantageous because they are amenable to less invasive approaches, but delivery is less controlled and the risk of systemic embolization is high.
      • Hasan A.
      • Khattab A.
      • Islam M.A.
      • et al.
      Injectable hydrogels for cardiac tissue repair after myocardial infarction.
      Use of biomaterials as a patch over an injured region is more invasive, but there is no embolization risk and the implant targets the epicardium, which is emerging as a key anatomic regenerative niche.
      • Smart N.
      • Riley P.R.
      The epicardium as a candidate for heart regeneration.
      Finally, more rigorous clinical trials are needed to substantiate the beneficial effects of acellular scaffold therapy previously demonstrated in preclinical studies.

      Toward optimal disease management: biomarker-guided HF management

      Although a number of emerging HF biomarkers, such as high-sensitivity troponins, soluble toll-like receptor 2 (myocardial stretch/remodelling), galectin 3 (inflammation), and cystatin C (renal function) have the potential for refining prognosis and providing targets for management, the best-studied biomarkers in HF are the NPs.
      • Ibrahim N.E.
      • Gaggin H.K.
      • Konstam M.A.
      • Januzzi J.L.
      Established and emerging roles of biomarkers in heart failure clinical trials.
      Although NPs have had a well-established role in the evaluation of patients with symptoms of HF, measurement of NPs is now accepted to have additional value in the management of HF. Moreover, serial measures of both B-type natriuretic peptide (BNP) and its amino terminal propeptide cleavage equivalent (N-terminal proBNP [NT-proBNP]) provide incremental improvements in prognostication over a single-point measurement with respect to death or worsening HF.
      Notably, NP measurement may inform the response to a broad range of medical therapies for HF. Most HF drugs, CRT, and exercise training lower concentrations of NPs in parallel with the benefit of such therapies. One notable exception is the effect of neprilysin inhibition (in the form of sacubitril/valsartan). BNP is a substrate of neprilysin, and inhibition with sacubitril/valsartan will raise levels of BNP, whereas NT-proBNP (whose metabolism is independent of neprilysin) levels fall on treatment.
      • Packer M.
      • McMurray J.J.
      • Desai A.S.
      • et al.
      Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.
      To the extent that changes in NPs have prognostic meaning, there has been interest in serial measurement of these peptides not only to longitudinally assess risk but also to serve as a “guide” for HF therapy. The theory underpinning a “guided” approach is that achievement of target HF therapy combined with a reduction in NP concentrations is superior to standard HF care alone without consideration of NP levels. Although this might allow for a more personalized approach to HF care, the rationale for this approach extends beyond the concept of precision care. It is well established that doses of HF therapies achieved in real-world settings are far lower than those used in clinical trials. Reasons for the underachievement of medical therapy are numerous but include the inability to recognize risk and tailor therapy accordingly as well as clinician inertia with respect to adding and titrating medications.
      • Fonarow G.C.
      • Yancy C.W.
      • Albert N.M.
      • et al.
      Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF.
      Thus this NP-guided approach might facilitate better outcomes than a “1 size fits all” approach to HF care.
      Most data regarding the role of NP-guided HF care have been obtained from studies of patients with chronic ambulatory HFrEF. However, some data do suggest the potential utility of using BNP or NT-proBNP as a target for therapy in acute HF. In this setting, concentrations of BNP and NT-proBNP primarily reflect severity of congestion; lack of reduction in NPs after diuresis in hospitalized patients with HF strongly predicts the likelihood of recurrent HF events, including rehospitalization or death. As such, serial measurement of NP levels is now embraced as a strategy to help guide suitability for hospital discharge in acute HF.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      In the setting of chronic HF, trends in NP levels also reveal the severity of myocardial remodelling, valvular regurgitation, and atrial arrhythmias.
      • Troughton R.
      • Michael Felker G.
      • Januzzi Jr., J.L.
      Natriuretic peptide-guided heart failure management.
      Each of these abnormalities have therapeutic interventions. To this end, a number of relatively small underpowered trials with a broad heterogeneity of designs have explored whether BNP- or NT-proBNP–guided medical therapy for chronic HFrEF might reduce the incidence of events. General findings from NP-guided therapy trials suggest that this approach is well tolerated and more often result in greater uptitration of medical therapy compared with usual care.
      • Troughton R.W.
      • Frampton C.M.
      • Brunner-La Rocca H.P.
      • et al.
      Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis.
      Although this strategy may be promising, a recent NT-proBNP–guided trial for HFrEF management was halted for lack of efficacy,
      • Felker G.M.
      • Ahmad T.
      • Anstrom K.J.
      • et al.
      Rationale and design of the GUIDE-IT study: guiding evidence based therapy using biomarker intensified treatment in heart failure.
      although full results are not yet available.
      Understanding the results of NP-guided therapy trials is complex, and biomarker strategy trials may be beset by numerous challenges (Table 4). For example, in earlier studies, BNP or NT-proBNP targets for care were inappropriately high, leading to undertreatment in the guided-therapy arm. In other studies, care in the “usual care” arm was more aggressive than true “standard of care,” leading to overachievement in management compared with what might have been expected outside of a clinical trial.
      Table 4Challenges in natriuretic peptide–guided strategy trials
      ChallengePotential consequence
      High natriuretic peptide targetUndertreatment in guided-therapy arm
      Unblinded designKnowledge of treatment assignment may lead to differences in clinician behaviour in “usual care” arm (including overtreatment relative to true standard of care) vs overtreatment in guided-therapy arm
      Inability to receive natriuretic peptide results in a timely fashion during office encountersTreatment decisions may be made without knowledge of biomarker results
      Lack of response to elevated natriuretic peptide result in the guided-therapy armUndertreatment of higher-risk patients with higher risk for adverse outcomes
      Studies that have triangulated the correct NP target, more aggressive care in the guided-therapy arm, and significant differences in achieved NP levels with guided therapy have typically realized a benefit from this approach. For example, in the ProBNP Outpatient Tailored Chronic HF Therapy (PROTECT) trial,
      • Bohm M.
      • Drexler H.
      • Oswald H.
      • et al.
      OptiLink HFSI
      Fluid status telemedicine alerts for heart failure: a randomized controlled trial.
      NT-proBNP–guided therapy with a target value of 1000 pg/mL was associated with more aggressive medical therapy and more significant NT-proBNP lowering compared with usual care. In PROTECT, NT-proBNP–guided care was associated with a 56% reduction in CV events and greater improvement in patient-reported quality of life.
      • Bhardwaj A.
      • Rehman S.U.
      • Mohammed A.A.
      • et al.
      Quality of life and chronic heart failure therapy guided by natriuretic peptides: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study.

      Toward optimal disease management: an evolving framework for RM in HF

      RM refers to enhanced patient surveillance, either through structured telecommunications support (human to human or human to machine) or telemonitoring using external or internal sensors. Cardiac implantable electronic devices (CIEDs) process electrical signals, with algorithms based on sensing (night heart rate, heart rate variability, atrial and ventricular tachyarrhythmia detection), pacing, and intrathoracic impedance. Most strategies have focused on averting hospitalizations by predicting worsening HF (“crisis detection”) while supporting disease management. Early studies were heterogeneous in methodological quality, sample size, population, intervention, and control group care,
      • Inglis S.C.
      • Clark R.A.
      • McAlister F.A.
      • Stewart S.
      • Cleland J.G.
      Which components of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: Abridged Cochrane Review.
      with meta-analyses suggesting reduced mortality and hospitalizations.
      • Inglis S.C.
      • Clark R.A.
      • McAlister F.A.
      • Stewart S.
      • Cleland J.G.
      Which components of heart failure programmes are effective? A systematic review and meta-analysis of the outcomes of structured telephone support or telemonitoring as the primary component of chronic heart failure management in 8323 patients: Abridged Cochrane Review.
      Numerous subsequent large multicentre randomized controlled trials have demonstrated no benefit (Table 5).
      • Chaudhry S.I.
      • Mattera J.A.
      • Curtis J.P.
      • et al.
      Telemonitoring in patients with heart failure.
      • Ong M.K.
      • Romano P.S.
      • Edgington S.
      • et al.
      Better Effectiveness After Transition-Heart Failure Research Group
      Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the Better Effectiveness After Transition-Heart Failure (BEAT-HF) randomized clinical trial.
      • Koehler F.
      • Winkler S.
      • Schieber M.
      • et al.
      Telemedical Interventional Monitoring in Heart Failure Investigators
      Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.
      • van Veldhuisen D.J.
      • Braunschweig F.
      • Conraads V.
      • et al.
      Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure.
      • Hindricks G.
      • Taborsky M.
      • Glikson M.
      • et al.
      Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial.
      • Bohm M.
      • Drexler H.
      • Oswald H.
      • et al.
      OptiLink HFSI
      Fluid status telemedicine alerts for heart failure: a randomized controlled trial.
      • Abraham W.T.
      • Adamson P.B.
      • Bourge R.C.
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.
      Table 5Landmark randomized clinical trials of remote monitoring in heart failure
      StudyMeasurePopulationFollow-upPrimary end pointSecondary end pointsQuality of life
      TELE-HF

      2010
      • Chaudhry S.I.
      • Mattera J.A.
      • Curtis J.P.
      • et al.
      Telemonitoring in patients with heart failure.
      Telephone-based interactive voice response systemN = 1653

      Recent HF hospitalization
      180 dDeath and all-cause readmission, 52.3% vs 51.5%; P = 0.75Death, 11.1% vs 11.4%; P = 0.88

      Hospitalization:

      HF, 27.5% vs 27.0%; P = 0.81

      Any, 49.3% vs 47.4%; P = 0.45
      Not assessed
      BEAT-HF

      2016
      • Ong M.K.
      • Romano P.S.
      • Edgington S.
      • et al.
      Better Effectiveness After Transition-Heart Failure Research Group
      Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the Better Effectiveness After Transition-Heart Failure (BEAT-HF) randomized clinical trial.
      BP, heart rate, weight, symptomsN = 1437

      HF hospitalization
      180 dAll-cause readmission, 50.8% vs 49.2%; P = 0.74Death, 14.9% vs 14.0%; P = 0.34MLHFQ 32.6 vs 28.5; P = 0.02
      TIM-HF

      2011
      • Koehler F.
      • Winkler S.
      • Schieber M.
      • et al.
      Telemedical Interventional Monitoring in Heart Failure Investigators
      Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.
      3-lead ECG, BP, weightN = 710

      NYHA II-III

      EF ≤ 35% with HFH

      or EF ≤ 25%
      Median, 26 moDeath, 8.4% vs 8.7% per 100 person-years

      HR, 0.97 (0.67-1.41); P = 0.87
      Hospitalization:

      HF, 0.84 (0.60-1.18); P = 0.32

      CV cause, 1.07 (0.84-1.35); P = 0.58

      Any, 1.12 (0.91-1.37); P = 0.29
      SF-36 physical 54.3 vs 49.9; P = 0.01

      NYHA class, no difference

      PHQ-9, no difference
      DOT-HF

      2011
      • van Veldhuisen D.J.
      • Braunschweig F.
      • Conraads V.
      • et al.
      Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure.
      Impedance audible alertN = 335

      NYHA II-IV, EF ≤ 35%

      CRT-D, ICD
      Median, 14.5 moDeath and HF hospitalization, 29% vs 20%

      HR, 1.52 (0.97-2.37); P = 0.06
      Death, 1.24 (0.63-2.44); P = 0.54

      HFH, 1.79 (1.08-2.95); P = 0.02

      Outpatient visit 250 vs 84; P < 0.0001
      Not assessed
      IN-TIME

      2014
      • Hindricks G.
      • Taborsky M.
      • Glikson M.
      • et al.
      Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial.
      MultiparametricN = 664

      NYHA II-III, EF ≤ 35%

      CRT-D, ICD
      1 yComposite clinical score, 18.9% vs 27.2% Worsened score, OR, 0.63 (0.43-0.90)Death, 3.0% vs 8.2%; P = 0.004

      HFH, 13.2% vs 14.2%; P = 0.38
      NYHA class, no difference

      Patient global assessment, no difference
      OptiLink-HF

      2016
      • Bohm M.
      • Drexler H.
      • Oswald H.
      • et al.
      OptiLink HFSI
      Fluid status telemedicine alerts for heart failure: a randomized controlled trial.
      ImpedanceN = 1002

      NYHA II-III, EF ≤ 35%

      HFH < 12 mo
      1.9 yDeath or CV hospitalization, 45.0% vs 48.1%

      HR, 0.87 (0.72-1.04); P = 0.13
      Death, 0.89 (0.62-1.28); P = 0.52

      Hospitalization:

      HF, 0.87 (0.67-1.12); P = 0.28

      CV, 0.89 (0.73-1.08); P = 0.22
      Not assessed
      CHAMPION

      2011
      • Abraham W.T.
      • Adamson P.B.
      • Bourge R.C.
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.
      CardioMEMS pulmonary artery pressureN = 550

      NYHA III, any EF

      Previous HFH
      6 moHF hospitalization, 0.32 vs 0.44

      HR, 0.72 (0.60-0.85); P = 0.0002
      DAOH, 174.4 vs 172.1; P = 0.02MLHFQ, 45 vs 51; P = 0.02
      REM-HF

      ESC 2016
      MultiparametricN = 1650

      NYHA II-IV

      CRT-D, ICD, CRT-P
      Mean, 2.8 yDeath or CV hospitalization, 42.4% vs 40.8%

      HR, 1.01 (0.87-1.18); P = 0.87
      Not yet reportedNot yet reported
      BEAT-HF, Better Effectiveness After Transition-Heart Failure; BP, blood pressure; CHAMPION, CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients; CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; CV, cardiovascular; DAOH, days alive out of hospital; DOT-HF, Diagnostic Outcome Trial in Heart Failure; ECG, electrocardiogram; EF, ejection fraction; ESC, European Society of Cardiology; HF, heart failure; HFH, HF hospitalization; HR, hazard ratio; ICD, implantable cardioverter device; IN-TIME, Implant-Based Multiparameter Telemonitoring of Patients With Heart Failure; MLHFQ, Minnesota Living With Heart Failure Questionnaire; NYHA, New York Heart Association; OR, odds ratio; PHQ-9, Patient Health Questionnaire 9; REM-HF, Remote Management of Heart Failure Using Implantable Electronic Devices; SF-36, 36-item Short Form; TELE-HF, Telemonitoring to Improve Heart Failure Outcomes; TIM-HF, Telemedical Interventional Monitoring in Heart Failure.
      Failings to date are unsurprising given the heterogeneity of HF and manifestations of acute decompensation. For example, only a minority of patients have substantial weight gain before decompensation, and monitoring based on weight alone is ineffective.
      • Zhang J.
      • Goode K.M.
      • Cuddihy P.E.
      • et al.
      Predicting hospitalization due to worsening heart failure using daily weight measurement: analysis of the Trans-European Network-Home-Care Management System (TEN-HMS) study.
      Weight gain is typically preceded by several weeks of reducing intrathoracic impedance and increasing pulmonary artery diastolic and right ventricular pressure, potentially offering a more precise monitoring signal.
      • Zile M.R.
      • Bennett T.D.
      • St John Sutton M.
      • et al.
      Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures.
      However, impedance-based monitoring alone has failed to improve outcomes in multiple clinical trials (Table 5).
      • van Veldhuisen D.J.
      • Braunschweig F.
      • Conraads V.
      • et al.
      Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure.
      • Bohm M.
      • Drexler H.
      • Oswald H.
      • et al.
      OptiLink HFSI
      Fluid status telemedicine alerts for heart failure: a randomized controlled trial.
      CIED algorithms have combined impedance, sensing, and pacing variables into composite HF risk scores with little improvement.
      • Whellan D.J.
      • Sarkar S.
      • Koehler J.
      • et al.
      Development of a method to risk stratify patients with heart failure for 30-day readmission using implantable device diagnostics.
      Such approaches are inherently limited by reliance on electrical signals that characterize only a proportion of the disease pathway.
      Crisis detection strategies effectively “test” patients repeatedly for impending decompensation. However, using single thresholds in fluctuant biological measures limits accuracy. Combining this with complex substrate, limited test performance, and long test to decompensation times inevitably generates low positive predictive values and numerous false-positive alerts. Moreover, the entire paradigm of physiological monitoring requires actionable effective therapies to either avert decompensation or maintain clinical stability. A huge challenge for all “crisis detection” strategies is the lack of effective therapies for AHF.
      Clinical trials in HF have focused on harder morbidity and mortality end points (Table 5). RM did significantly improve quality of life in CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION),
      • Abraham W.T.
      • Adamson P.B.
      • Bourge R.C.
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.
      Better Effectiveness After Transition-Heart Failure (BEAT-HF),
      • Ong M.K.
      • Romano P.S.
      • Edgington S.
      • et al.
      Better Effectiveness After Transition-Heart Failure Research Group
      Effectiveness of remote patient monitoring after discharge of hospitalized patients with heart failure: the Better Effectiveness After Transition-Heart Failure (BEAT-HF) randomized clinical trial.
      and Telemedical Interventional Monitoring in Heart Failure (TIM-HF),
      • Koehler F.
      • Winkler S.
      • Schieber M.
      • et al.
      Telemedical Interventional Monitoring in Heart Failure Investigators
      Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.
      although the magnitude of improvement was modest. Although there is a need to integrate both quantity and quality of health in outcome assessment, the patient experience must also be valued in relation to opportunity costs. It is essential that incremental benefit be demonstrated using accepted metrics such as quality-adjusted life-years. This will most likely be driven by a combination of reduced hospitalizations and improved quality of life, emphasizing the need for novel end points. Economic analyses of RM have suffered from limited methodological quality, heterogeneity in populations and interventions, and poorly described costs.
      • Grustam A.S.
      • Severens J.L.
      • van Nijnatten J.
      • et al.
      Cost-effectiveness of telehealth interventions for chronic heart failure patients: a literature review.
      For affordable implementation of RM strategies, careful consideration must be given to the resources required: Who bears responsibility for monitoring and acting on the data? What is the acceptable time frame in which to act? What are the medicolegal implications of RM?
      Monitoring requires either single or multiple signals strongly associated with the underlying disease process. Direct cardiac pressure monitoring is the most promising of the former. Over 6 months, continuous pulmonary artery pressure monitoring was associated with fewer HF-related hospitalizations and improved quality of life in the CHAMPION trial.
      • Abraham W.T.
      • Adamson P.B.
      • Bourge R.C.
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial.
      Monitored patients received 0.88 additional medication changes monthly, largely diuretics or vasodilators. Although changes dropped sharply after the initial study phase, the intervention was found to be cost-effective,
      • Martinson M.
      • Bharmi R.
      • Dalal N.
      • Abraham W.T.
      • Adamson P.B.
      Pulmonary artery pressure-guided heart failure management: US cost-effectiveness analyses using the results of the CHAMPION clinical trial.
      and preliminary real-world experience suggests that this approach to ambulatory hemodynamic monitoring reduces HF hospitalization and related costs.
      • Desai A.S.
      • Bhimaraj A.
      • Bharmi R.
      • et al.
      Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in “real-world” clinical practice.
      Dynamic interaction between multiple signals may further refine the patient trajectory. Multidimensional strategies should integrate many biological variables with more sophisticated scales, rate of change measures, and individualized thresholds. These should be coupled with advanced analytics, machine learning and “N-of-1” meta-analytic and multilevel modelling approaches to characterize patient phenotypes.
      RM is a complex intervention, involving complex interactions between system components and those delivering or receiving care, targeting diverse outcomes, and requiring flexibility and tailoring of the intervention. As such, effectiveness, cost-effectiveness, and implementation all require equally rigorous evaluation before routine integration into clinical practice.

      Promising interventions for acute HF

      The past few years have witnessed the assessment of multiple interventions for the treatment of AHF. Although promising AHF therapies have recently been characterized by disappointing results in large-scale outcome trials, it is worth highlighting the novel strategies under evaluation. Although there is overlap, these therapeutic approaches have targeted volume removal and renal function, vasodilation, or cardiac performance.
      Mechanical ultrafiltration (UF) is the most direct method for volume removal, with many theoretical advantages over the more commonly used diuretics, including the removal of isotonic fluid compared with hypotonic fluid with diuretic agents. This excess removal of sodium, possibly associated with less neurohormonal activation, has provided biological plausibility for the improved outcomes observed in some early UF studies.
      • Costanzo M.R.
      • Guglin M.E.
      • Saltzberg M.T.
      • et al.
      Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure.
      A report from the prematurely terminated Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial suggested that patients hospitalized for HF treated with adjustable UF had a trend toward a longer time to a first HF event and fewer HF events overall
      • Costanzo M.R.
      • Negoianu D.
      • Jaski B.E.
      • et al.
      Aquapheresis versus intravenous diuretics and hospitalizations for heart failure.
      ; however, other randomized trials have failed to show any advantage of UF.
      • Bart B.A.
      • Goldsmith S.R.
      • Lee K.L.
      • et al.
      Ultrafiltration in decompensated heart failure with cardiorenal syndrome.
      Other ongoing trials will test this concept more fully (ClinicalTrials.gov: NCT02846337 and NCT02769351).
      A number of novel approaches to vasodilation therapy have been developed for AHF. TRV027, a “biased” ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizes the negative effects of angiotensin II while preserving the potential procontractility effects of AT1R stimulation. In the phase II Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure (BLAST-AHF) study,
      • Pang P.S.
      • Butler J.
      • Collins S.P.
      • et al.
      Biased ligand of the angiotensin II type 1 receptor in patients with acute heart failure: a randomized, double-blind, placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF).
      621 patients hospitalized for AHF were randomized to different doses of TRV027. It did not confer any benefit over placebo at any dose regarding the primary composite end point or any of the individual components. However, the approach of using biased ligands is intriguing and may provide future directions for AHF therapies.
      Ularitide is the synthetic form of urodilatin, a human NP that is generated by differential processing of pro–atrial NP in distal renal tubule cells and appears to be involved in sodium homeostasis. Ularitide exerts vasodilatory, diuretic, and natriuretic actions through the same pathways as the other NPs, nesiritide (B-type NP) and cenderitide (an A-type NP).
      • Anker S.D.
      • Ponikowski P.
      • Mitrovic V.
      • Peacock W.F.
      • Filippatos G.
      Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies.
      Small hemodynamic studies demonstrated beneficial effects of ularitide in reducing pulmonary capillary wedge pressure and systemic vascular resistance, with commensurate increases in cardiac index and decreases in blood pressure, consistent with its mechanism as a vasodilator.
      • Mitrovic V.
      • Seferovic P.M.
      • Simeunovic D.
      • et al.
      Haemodynamic and clinical effects of ularitide in decompensated heart failure.
      The Trial of Ularitide's Efficacy and Safety in Patients With Acute Heart Failure (TRUE-AHF) trial evaluated the effect of a 48-hour infusion of ularitide compared with placebo in 2157 patients with AHF.
      • Packer M.
      • O'Connor C.
      • McMurray J.J.V.
      • et al.
      The effect of ularitide on cardiovascular mortality in acute heart failure.
      Neither of the 2 primary end points (CV death or the clinical composite over the initial 48 hours) was improved.
      Serelaxin is a recombinant form of human relaxin-2, a hormone that is believed to play a central role in maternal adaptations to pregnancy, improving vascular compliance and renal function while providing end organ protection.
      • Ponikowski P.
      • Mitrovic V.
      • Ruda M.
      • et al.
      A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure.
      Mechanistic studies confirmed its beneficial hemodynamic effects of reducing wedge pressure and systemic and pulmonary vascular resistance.
      • Ponikowski P.
      • Mitrovic V.
      • Ruda M.
      • et al.
      A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure.
      The first phase III trial of serelaxin, Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF),
      • Teerlink J.R.
      • Cotter G.
      • Davison B.A.
      • et al.
      Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.
      met its primary end point of demonstrating significant improvement in dyspnea during the first 5 days in patients admitted with AHF, dyspnea, mild to moderate renal dysfunction, and normal to elevated systolic blood pressures treated with a 48-hour infusion of serelaxin compared with placebo, as well as a reduction in all-cause mortality at 180 days. The second phase III trial, serelaxin, RELAX-AHF-2, randomized 6545 patients with AHF to either 48-hour infusions of serelaxin or placebo. As recently reported,

      Teerlink JR, Metra M. RELAX-AHF-2: a multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy, safety and tolerability of serelaxin when added to standard therapy in acute heart failure patients. Paper presented at: European Society of Cardiology Heart Failure 2017. April 29-May 2, 2017; Paris, France.

      serelaxin-treated patients had no improvement in either primary end point (180-day CV mortality or worsening HF through day 5) or in in any secondary end point.
      For decades, investigators have attempted to develop therapies that improve cardiac performance without the deleterious effects of current inotropic agents. One of these approaches has been the development of nitroxyl donors. In preclinical models, these agents have positive inotropic, lusitropic, and vasodilator effects that are cyclic adenosine monophosphate independent.
      • Sabbah H.N.
      • Tocchetti C.G.
      • Wang M.
      • et al.
      Nitroxyl (HNO): a novel approach for the acute treatment of heart failure.
      Early dose finding studies have supported the vasodilating effects of these agents, although demonstrating direct myocardial effects has been confounded by this vasodilation. This approach is currently under investigation with the nitroxyl donor BMS-986231 in the Evaluate the Safety and Efficacy of 48-hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients with Heart Failure (STANDUP AHF) study (ClinicalTrials.gov: NCT03016325), enrolling patients admitted for AHF.
      Another recent approach to improve cardiac performance is the development of cardiac myosin activators. Omecamtiv mecarbil is a selective cardiac myosin activator that enhances myocardial performance with no increase in intracellular calcium transients and myocardial oxygen demand.
      • Malik F.I.
      • Hartman J.J.
      • Elias K.A.
      • et al.
      Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.
      As discussed earlier, this agent is being evaluated in the setting of chronic HF in the GALACTIC-HF trial. In the setting of AHF, the Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) was a phase II dose-finding study in patients admitted with AHF, dyspnea, and reduced EF who were randomized to a 48-hour infusion of 1 of multiple omecamtiv mecarbil doses or placebo.
      • Teerlink J.R.
      • Felker G.M.
      • McMurray J.J.
      • et al.
      Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure: the ATOMIC-AHF study.
      The primary end point of dyspnea relief from an individual omecamtiv mecarbil dose compared with placebo was not achieved, but there was significant improvement in dyspnea in the high-dose group compared with its paired placebo group.
      Despite disappointing results in the recent major outcomes trials in patients with AHF, there have been many interesting and compelling approaches in development for the treatment of these patients. To date, it is unclear whether the failure of some potential AHF therapies relates to the heterogeneous populations studied, the choice of clinical end points, or the time horizon over which the intervention is made and outcomes are assessed. Although AHF may represent a severe manifestation of a chronic and deteriorating physiological state, it is possible that the use of biomarkers and RM strategies to intervene earlier, before the onset of overt signs or symptoms, may yield more meaningful clinical benefits.

      Conclusions

      Comprehensive and highly personalized HF care will leverage advances in precision diagnosis, drug development, device technology, and, possibly, regenerative medicine. Further, developments in disease-monitoring strategies and identification of appropriate interventions in response to changes in clinical course will afford new opportunities to change the trajectory of illness and improve prognosis. Despite the gaps in knowledge and challenges in application of emerging therapies, the future of HF care is exciting and full of promise.

      Acknowledgements

      The authors wish to thank Justin Ezekowitz, Eileen O'Meara, and Christianna Brooks for their assistance and guidance in preparing the manuscript.

      Disclosures

      M.A.M. has received honoraria from Novartis and Servier. E.A.A. owns Personalis Inc. V.R. has received honoraria from Abbot, Medtronic, and CorMatrix Cardiovascular. J.J. has received research support from Roche Diagnostics, Siemens, Singulex, Prevencio, Abbott, Cleveland Heart Labs, Novartis, Amgen, Boehringer-Ingelheim, Janssen, Abbie, Pfizer, and General Electric; and consulting from Roche Diagnostics, Singulex, Novartis, and Abbott. P.F. has received research support from Heart and Stroke Foundation. S.V. has received honoraria from Novartis, Servier, Bayer, Lilly, BI, Medtronic, and Otsuka; and research support was received from Novartis, Servier, Bayer, BI, Medtronic, Otsuka, Pfizer, and Merck. The other authors have no conflicts of interest to disclose.

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