New Therapies For Heart Failure Research Articles

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Ten year evolution of clinical characteristics and short-term outcome of patients admitted with heart failure

Abstract Background/Introduction Heart failure (HF) continues to be a leading cause of morbidity, decreased quality of life (QoL) and mortality worldwide. Contributing to decreased QoL is the high rehospitalization rate, which is often related to non-cardiac causes, highlighting the important multimorbidity of the HF population. Detailed clinical and outcome data for HF admissions in Belgium over time are only scarcely available. Purpose We aimed to evaluate and compare two groups of patients admitted with HF ten years apart, regarding clinical characteristics, comorbidities, use of HF medication and devices, as well as rehospitalization rate and all-cause mortality three months post-discharge. Methods This is a monocentric retrospective observational cohort study conducted in Belgium. Two groups of patients admitted for acute decompensated HF who were discharged alive were included and compared: 340 patients during 2011-2012 and 319 patients during 2021-2022. Results The two cohorts did not differ significantly regarding age (77.3 vs. 78.4 years), gender (47.4 vs. 44.5% women), number of patients with HF with reduced ejection fraction (47.4 vs. 48.6%) and NT-proBNP on admission (8514 vs. 7398 pg/mL). Similarly, comorbidities including diabetes, chronic obstructive pulmonary disease, peripheral artery disease, stroke and renal failure were comparable in both groups. Concerning medical therapy at discharge, mineralocorticoid receptor antagonists (MRA) were used significantly more frequently in the latest cohort. However, there was no change in administration of beta-blockers or renin angiotensin aldosterone system antagonists. As part of the implementation of new therapies for heart failure with reduced ejection fraction, 29% of patients were prescribed sodium-glucose cotransporter-2 (SGLT-2) inhibitors, while sacubitril/valsartan was given in 13% of the cases. The use of internal defibrillators (ICD) and resynchronization devices (CRT) doubled from 2011-2012 to 2021-2022 (3.9 vs. 9.6%, p = 0.002). In-hospital length of stay decreased significantly over a ten-year period across all ejection fraction subgroups from 7 to 5 days (figure 1). The combined outcome of rehospitalization for HF and all-cause mortality three months post-discharge remained constant at approximately 20% (figure 2). Conclusion Clinical characteristics and comorbidities of patients admitted with acute decompensated HF did not change significantly between 2011 and 2022. Uptake of evidence-based medicine for HF increased, especially for MRA, SGLT-2 inhibitors and sacubitril/valsartan, as did the use of ICD and CRT, but still with considerable potential for improvement. Although in-hospital length of stay decreased significantly over time, rehospitalization rates for HF and all-cause mortality within 90 days post-discharge remained high and did not improve. These sobering results illustrate the need for continuing efforts to improve the care and outcome of HF patients.

Towards precision medicine in heart failure.

The number of therapies for heart failure (HF) with reduced ejection fraction has nearly doubled in the past decade. In addition, new therapies for HF caused by hypertrophic and infiltrative disease are emerging rapidly. Indeed, we are on the verge of a new era in HF in which insights into the biology of myocardial disease can be matched to an understanding of the genetic predisposition in an individual patient to inform precision approaches to therapy. In this Review, we summarize the biology of HF, emphasizing the causal relationships between genetic contributors and traditional structure-based remodelling outcomes, and highlight the mechanisms of action of traditional and novel therapeutics. We discuss the latest advances in our understanding of both the Mendelian genetics of cardiomyopathy and the complex genetics of the clinical syndrome presenting as HF. In the phenotypic domain, we discuss applications of machine learning for the subcategorization of HF in ways that might inform rational prescribing of medications. We aim to bridge the gap between the biology of the failing heart, its diverse clinical presentations and the range of medications that we can now use to treat it. We present a roadmap for the future of precision medicine in HF.

REAL WORLD STUDY OF CHARACTERISTICS AND OUTCOMES OF COMMERCIALLY INSURED PATIENTS WITH STABLE VERSUS WORSENING CHRONIC HEART FAILURE WITH REDUCED EJECTION FRACTION

With the introduction of new therapies for heart failure with reduced ejection fraction (HFrEF) and their clinical and cost implications, an up-to-date understanding of patient characteristics and healthcare resource utilization (HCRU) in patients who develop worsening chronic heart failure (WCHF)

Fibrin Glue-aided, Instant Epicardial Placement Enhances the Efficacy of Mesenchymal Stromal Cell-Based Therapy for Heart Failure

Transplantation of mesenchymal stromal cells (MSCs) is a promising new therapy for heart failure. However, the current cell delivery routes result in poor donor cell engraftment. We therefore explored the role of fibrin glue (FG)-aided, instant epicardial placement to enhance the efficacy of MSC-based therapy in a rat ischemic cardiomyopathy model. We identified a feasible and reproducible method to instantly produce a FG-MSC complex directly on the heart surface. This complex exhibited prompt, firm adhesion to the heart, markedly improving initial retention of donor MSCs compared to intramyocardial injection. In addition, maintenance of retained MSCs was enhanced using this method, together contributing the increased donor cell presence. Such increased donor cell quantity using the FG-aided technique led to further improved cardiac function in association with augmented histological myocardial repair, which correlated with upregulation of tissue repair-related genes. We identified that the epicardial layer was eliminated shortly after FG-aided epicardial placement of MSCs, facilitating permeation of the donor MSC’s secretome into the myocardium enabling myocardial repair. These data indicate that FG-aided, on-site, instant epicardial placement enhances MSC engraftment, promoting the efficacy of MSC-based therapy for heart failure. Further development of this accessible, advanced MSC-therapy is justified.

Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored. We will test the hypothesis that elevated mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. Using a unique guinea pig model of nonischemic HF that recapitulates important features of human HF, including prolonged QT interval and high incidence of spontaneous arrhythmic SCD, compartment-specific ROS sensors revealed increased mROS in resting and contracting left ventricular myocytes in failing hearts. Importantly, the mitochondrially targeted antioxidant (MitoTEMPO) normalized global cellular ROS. Further, in vivo MitoTEMPO treatment of HF animals prevented and reversed HF, eliminated SCD by decreasing dispersion of repolarization and ventricular arrhythmias, suppressed chronic HF-induced remodeling of the expression proteome, and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that increased mROS in HF disrupts the normal coupling between cytosolic signals and nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling, and action potential repolarization, suggesting new targets for therapeutic intervention. mROS drive both acute emergent events, such as electrical instability responsible for SCD, and those that mediate chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant, and ion transport protein networks. In vivo reduction of mROS prevents and reverses electrical instability, SCD, and HF. Our findings support the feasibility of targeting the mitochondria as a potential new therapy for HF and SCD while identifying new mROS-sensitive protein modifications.

P63 Silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte-like cells

ObjectiveReprogramming of fibroblasts into induced cardiomyocytes represents a potential new therapy for heart failure. We hypothesized that inactivation of p63, a p53 gene family member, may help overcome human cell resistance to reprogramming. Methodsp63 Knockout (−/−) and knockdown murine embryonic fibroblasts (MEFs), p63−/− adult murine cardiac fibroblasts, and human cardiac fibroblasts were assessed for cardiomyocyte-specific feature changes, with or without treatment by the cardiac transcription factors Hand2–Myocardin (HM). ResultsFlow cytometry revealed that a significantly greater number of p63−/− MEFs expressed the cardiac-specific marker cardiac troponin T (cTnT) in culture compared with wild-type (WT) cells (38% ± 11% vs 0.9% ± 0.9%, P < .05). HM treatment of p63−/− MEFs increased cTnT expression to 74% ± 3% of cells but did not induce cTnT expression in wild-type murine embryonic fibroblasts. shRNA-mediated p63 knockdown likewise yielded a 20-fold increase in cTnT microRNA expression compared with untreated MEFs. Adult murine cardiac fibroblasts demonstrated a 200-fold increase in cTnT gene expression after inducible p63 knockout and expressed sarcomeric α-actinin as well as cTnT. These p63−/− adult cardiac fibroblasts exhibited calcium transients and electrically stimulated contractions when co-cultured with neonatal rat cardiomyocytes and treated with HM. Increased expression of cTnT and other marker genes was also observed in p63 knockdown human cardiac fibroblasts procured from patients undergoing procedures for heart failure. ConclusionsDownregulation of p63 facilitates direct cardiac cellular reprogramming and may help overcome the resistance of human cells to reprogramming.

Effects of catheter-based renal denervation on heart failure with reduced ejection fraction: a systematic review and meta-analysis.

Despite the recent advances in the management of heart failure, the mortality of heart failure patients remains high. It is of urgent need to develop new therapy for heart failure. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Catheter-based renal denervation (RDN) has emerged as an invasive but safe approach that can reduce sympathetic activation. Studies have reported inconsistent results regarding the effect of RDN in heart failure patients due to limited power with small sample sizes. We aimed to conduct a meta-analysis of the effect of RDN on heart failure patients with reduced left ventricular (LV) ejection fraction (EF). An electronic search for studies examining the effect of RDN on LV function in heart failure patients with reduced EF was conducted. Two controlled (80 patients) and 2 uncontrolled studies (21 patients) were included in this meta-analysis. In the pooled analysis, 6months after RDN, there was a greater increase in EF (weighted mean difference [95% CI]=8.63 [6.02, 11.24] %) and a greater decrease in LV end-diastolic diameter (-0.58 [-0.83, -0.34] cm) in RDN group than in control group. No serious adverse events such as acute renal artery stenosis and dissection occurred. Our meta-analysis of feasibility studies suggests that RDN may improve LV function in heart failure patients with reduced EF, providing the rationale to conduct next phase trials to confirm the observed potential benefits of RDN.

Exosomes Derived from Embryonic Stem Cells as Potential Treatment for Cardiovascular Diseases.

Cardiovascular diseases resulting from ischemic heart diseases remain to be the main causes of heart failure and death despite significant advances in medical treatment. The development of new therapies for heart failure is thus required to improve the outcome in these patients, and this has led to the development of cell-based therapies. Animal studies showed interesting results using various cell types. Some stem cell based therapies have been tested in clinical trials. Although the results were encouraging, challenges remain. Tumorigenic potential, immune rejection, and low engraftment and survival rate of transplant cells have hindered the widespread application of stem cells in the clinic. Fortunately, exosome based therapy could avoid these problems associated with cell therapy. Future research should focus on how various molecules are sorted into exosomes and this information will help to design better exosomes for treatment of cardiovascular diseases. Recent studies suggest that exosome content can vary depending on how cells are challenged. It would be important to find out exactly what types of cellular stress is needed for producing most useful exosomes. Alternatively, specific molecules can be introduced into exosomes by genetic engineering in order to treat specific conditions and to improve efficacy.

Recombinant Human ACE2 and the Angiotensin 1-7 Axis as Potential New Therapies for Heart Failure

Heart failure (HF) is a common cause of death and disability and a major economic burden in industrialized nations. Heart disease remains the leading cause of death in North America, with ischemic and hypertensive heart disease as the leading cause of HF. Various basic and clinical studies have established the role of an activated renin-angiotensin (Ang) system and Ang II generation in the progression of HF. Inhibition of an activated renin-Ang system using Ang-converting enzyme inhibitors, Ang II type 1 receptor blockers, and mineralocorticoid receptors antagonists have shown clinical benefits in patients with HF, although, largely limited to HF with reduced ejection fraction (HF-rEF). In contrast, there is no approved pharmacotherapy for HF with preserved ejection fraction (HF-pEF). Ang-converting enzyme (ACE) 2 (ACE2) is a homolog of ACE, which, being a monocarboxypeptidase converts Ang II into Ang 1-7 and is downregulated in HF. Various preclinical studies have shown a potent cardioprotective role of ACE2/Ang 1-7 axis in HF, which counter-regulates the ACE/Ang II/Ang II type 1 receptor axis. Importantly, ACE2 and Ang 1-7 show substantial benefit in preclinical models of HF-pEF and HF-rEF. Improvement in endothelial dysfunction, suppression of tissue inflammation and myocardial fibrosis, correction of metabolic dysfunction, and reversal of pathological hypertrophy are the key beneficial effects seen when ACE2 or Ang 1-7 action are enhanced. Clinical benefit of recombinant human ACE2 and Ang 1-7 need to be evaluated in patients with HF-rEF and HF-pEF.

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography

AimsLarge animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. Methods and ResultsMale farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [15O]water and oxygen consumption using [11C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. ConclusionsThe chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.

Guidelines for translational research in heart failure.

Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.

Efficacy of angiotensin-neprilysin inhibition versus enalapril in patient with heart failure with a reduced ejection fraction.

Angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of the treatment for heart failure and a reduced ejection fraction (EF) [1]. The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent and these drugs are recommended primarily for patients who have unacceptable side effects while receiving ACE inhibitors [2]. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin [3] and its inhibitors have been studied as a new therapy for heart failure. Combined inhibition of the renin–angiotensin system and neprilysin was superior to those of either approach alone in experimental studies but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema [4]. LCZ696 consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan and it was expected to minimize the risk of serious angioedema. In a small trial involving patients who had heart failure with a preserved EF, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone [5].

Could vitamin D supplements be a new therapy for heart failure? Possible pathogenic mechanisms from data of intervention studies.

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure (HF), but whether giving patients supplements to raise vitamin D into the normal range improves their survival is not clear. It has been demonstrated that vitamin D deficiency is common in patients with HF, especially the elderly, in obese and in dark skinned people, and that low vitamin D levels are associated with adverse outcome. The epidemiological data have been confirmed by experimental data, which show that knockout mice for the vitamin D receptor developed myocardial hypertrophy and dysfunction. Data from interventional studies are scarce and discordant, and more research is urgently needed to confirm whether add-on supplementation therapy with vitamin D has a role in the management of patients with chronic HF.

Temporal Trends in Treatment and Outcomes for Advanced Heart Failure With Reduced Ejection Fraction From 1993–2010

Background— Randomized trials have demonstrated the efficacy of several new therapies for heart failure (HF) with reduced ejection fraction over the preceding 2 decades. This study investigates whether these therapeutic advances have translated into improvement in outcomes for patients with advanced HF referred to a heart transplant center. Methods and Results— Patients with HF (n=2507) referred to a single university center were analyzed in three 6-year eras during which medical and device therapies were evolving: 1993 to 1998 (era 1), 1999 to 2004 (era 2), and 2005 to 2010 (era 3). Impaired hemodynamics and comorbidities were more frequent at time of referral in later eras, whereas other HF severity parameters where similar or improved. Successive eras had greater usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, aldosterone antagonists, implantable cardioverter defibrillators, and cardiac resynchronization therapy, consistent with evolving evidence and guideline recommendations over the study period. All-cause mortality and sudden death were significantly lower in era 2 and 3 compared with era 1. After multivariable risk adjustment, era 3 had significantly decreased 2- and 3-year all-cause mortality risk and significantly decreased 1- and 3-year sudden death risk compared with era 1. However, progressive HF death and the combined outcome of mortality/urgent transplant/ventricular assist device were modestly increased in the latter eras. Conclusions— Over the past 2 decades, patients with advanced HF referred to and managed at a tertiary university referral center have benefited from advances in HF medications and devices, as evidenced by improvements in overall survival and sudden death risk.

Critical reappraisal of pulmonary artery catheterization and invasive hemodynamic assessment in acute heart failure

Use of the pulmonary artery catheter (PAC) in the management of heart failure has declined precipitously despite guideline-supported indications, especially among patients hospitalized with acute heart failure (HF) syndromes. Here, the authors critically review the current role of the PAC and the management of patients with HF, and discuss the role of the PAC in the development of new therapies for HF. Pulmonary artery catheterization is a safe procedure when performed by experienced operators, and invasive hemodynamic evaluation with the PAC is recommended in select clinical settings. The PAC may have a unique role in identifying high-risk HF patients with persistent hemodynamic abnormalities during hospitalization. Early-phase trials of novel therapies to improve outcomes in patients with acute HF should include an assessment of hemodynamic effects utilizing the PAC. Once therapies that are effective in improving outcomes are available, the PAC might be a useful or necessary tool in the initiation and titration of such treatments and improved outcomes from PAC guided therapy may be demonstrated. Adequate training and experience are required to successfully use the PAC to minimize complications, ensure proper data collection and appropriate decision-making. Improved education and guidelines are required to ensure continued safe and appropriate contemporary use of the PAC.

Rethinking Phase II Clinical Trial Design in Heart Failure.

The incidence and economic burden of heart failure continue to rise worldwide, despite implementation of a number of effective heart failure therapies. Although there have been a number phase I-II studies of potential novel heart failure therapies over the past decade, none of these new compounds have been successful in phase III clinical trials. While there are likely a number of reasons for this failure, one of the problems that has become increasingly apparent is the inability of phase II trials to correctly identify novel therapies that will be successful in phase III clinical trials. In the following review, we will discuss the some of the problems inherent with current phase II heart failure clinical trials, as well as discuss possible ways to rethink phase II development of new therapies for heart failure.

The uroguanylin system and human disease

The uroguanylin system is a newly discovered endocrine/paracrine system that may have a role in the regulation of salt balance, appetite and gut health. The precursor pro-uroguanylin is predominantly synthesized in the gut, although there may be other sites of synthesis, including the kidney tubules. Products from pro-uroguanylin may mediate natriuresis following oral consumption of a salt load through both GC-C (guanylate cyclase C)-dependent and -independent mechanisms, and recent evidence suggests a role in appetite regulation. Local paracrine effects in the gut through GC-C stimulation may have tumour-suppressing actions through the regulation of cell proliferation and metabolism. Although most information on this system has been derived from knockout models, recent human studies have indicated possible roles in heart failure and renal failure. An improved understanding of the nature of its natriuretic, appetite and tumour-suppressing actions may facilitate the discovery of new therapies for heart failure, obesity and cancer prophylaxis.

Targeting myocardial substrate metabolism in heart failure: potential for new therapies

The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.

Biomarkers as Surrogate End Points in Heart Failure Trials

Despite the continued growth of heart failure as a major public health problem, the development of new therapies for heart failure has slowed and recent studies have been neutral, suggesting the need for a reappraisal of the clinical research enterprise. Surrogate end points, defined as measurements that are used as substitutes for the more clinically meaningful end points, can play a valuable role in clinical trials by accelerating the timeline for determining appropriate dosages, efficacy, and safety. Biomarkers, such as the natriuretic peptides, have many of the characteristics of valid surrogates but have not been sufficiently validated for widespread use. Ongoing research into the role of biomarkers as surrogates may lead to better clinical trial design and more efficient development of new therapies for heart failure.