Effect of the Novel Myotrope Danicamtiv on Cross-Bridge Behavior in Human Myocardium.

Background Omecamtiv mecarbil (OM) and danicamtiv both increase myocardial force output by selectively activating myosin within the cardiac sarcomere. Enhanced force generation is presumably due to an increase in the total number of myosin heads bound to the actin filament; however, detailed comparisons of the molecular mechanisms of OM and danicamtiv are lacking. Methods and Results The effect of OM and danicamtiv on Ca2+ sensitivity of force generation was analyzed by exposing chemically skinned myocardial samples to a series of increasing Ca2+ solutions. The results showed that OM significantly increased Ca2+ sensitivity of force generation, whereas danicamtiv showed similar Ca2+ sensitivity of force generation to untreated preparations. A direct comparison of OM and danicamtiv on dynamic cross-bridge behavior was performed at a concentration that produced a similar force increase when normalized to predrug levels at submaximal force (pCa 6.1). Both OM and danicamtiv-treated groups slowed the rates of cross-bridge detachment from the strongly bound state and cross-bridge recruitment into the force-producing state. Notably, the significant OM-induced prolongation in the time to reach force relaxation and subsequent commencement of force generation following rapid stretch was dramatically reduced in danicamtiv-treated myocardium. Conclusions This is the first study to directly compare the effects of OM and danicamtiv on cross-bridge kinetics. At a similar level of force enhancement, danicamtiv had a less pronounced effect on the slowing of cross-bridge kinetics and, therefore, may provide a similar improvement in systolic function as OM without excessively prolonging systolic ejection time and slowing cardiac relaxation facilitating diastolic filling at the whole-organ level.

Torsional and strain dysfunction precede overt heart failure in a mouse model of dilated cardiomyopathy pathogenesis.

Detailed assessments of whole heart mechanics are crucial for understanding the consequences of sarcomere perturbations that lead to cardiomyopathy in mice. Echocardiography offers an accessible and cost-effective method of obtaining metrics of cardiac function, but the most routine imaging and analysis protocols might not identify subtle mechanical deficiencies. This study aims to use advanced echocardiography imaging and analysis techniques to identify previously unappreciated mechanical deficiencies in a mouse model of dilated cardiomyopathy (DCM) before the onset of overt systolic heart failure (HF). Mice lacking muscle LIM protein expression (MLP-/-) were used to model DCM-linked HF pathogenesis. Left ventricular (LV) function of MLP-/- and wild-type (WT) controls were studied at 3, 6, and 10 wk of age using conventional and four-dimensional (4-D) echocardiography, followed by speckle-tracking analysis to assess torsional and strain mechanics. Mice were also studied with RNA-seq. Although 3-wk-old MLP-/- mice showed normal LV ejection fraction (LVEF), these mice displayed abnormal torsional and strain mechanics alongside reduced ß-adrenergic reserve. Transcriptome analysis showed that these defects preceded most molecular markers of HF. However, these markers became upregulated as MLP-/- mice aged and developed overt systolic dysfunction. These findings indicate that subtle deficiencies in LV mechanics, undetected by LVEF and conventional molecular markers, may act as pathogenic stimuli in DCM-linked HF. Using these analyses in future studies will further help connect in vitro measurements of the sarcomere function to whole heart function.NEW & NOTEWORTHY A detailed study of how perturbations to sarcomere proteins impact whole heart mechanics in mouse models is a major yet challenging step in furthering our understanding of cardiovascular pathophysiology. This study uses advanced echocardiographic imaging and analysis techniques to reveal previously unappreciated subclinical whole heart mechanical defects in a mouse model of cardiomyopathy. In doing so, it offers an accessible set of measurements for future studies to use when connecting sarcomere and whole heart function.

What bothers severe asthma patients most? A paired patient-clinician study across seven European countries.

Introduction: Severe asthma is a complex, multidimensional disease. Optimal treatment, adherence and outcomes require shared decision-making, rooted in mutual understanding between patient and clinician. This study used a novel, patient-centred approach to examine the most bothersome aspects of severe asthma to patients, as seen from both perspectives in asthma registries. Methods: Across seven countries, 126 patients with severe asthma completed an open-ended survey regarding most the bothersome aspect(s) of their asthma. Patients' responses were linked with their treating clinician who also completed a free-text survey about each patient's most bothersome aspect(s). Responses were coded using content analysis, and patient and clinician responses were compared. Finally, asthma registries that are part of the SHARP (Severe Heterogeneous Asthma Research collaboration, Patient-centred) Clinical Research Collaboration were examined to see the extent to which they reflected the most bothersome aspects reported by patients. Results: 88 codes and 10 themes were identified. Clinicians were more focused on direct physical symptoms and were less focused on "holistic" aspects such as the effort required to self-manage the disease. Clinicians accurately identified a most bothersome symptom for 29% of patients. Agreement was particularly low with younger patients and those using oral corticosteroids infrequently. In asthma registries, patient aspects were predominantly represented in questionnaires. Conclusions: Results demonstrated different perspectives and priorities between patients and clinicians, with clinicians more focused on physical aspects. These differences must be considered when treating individual patients, and within multidisciplinary treatment teams. The use of questionnaires that include multifaceted aspects of disease may result in improved asthma research.

The contribution of N-terminal truncated cMyBPC to in vivo cardiac function.

Cardiac myosin binding protein C (cMyBPC) is an 11-domain sarcomeric protein (C0-C10) integral to cardiac muscle regulation. In vitro studies have demonstrated potential functional roles for regions beyond the N-terminus. However, the in vivo contributions of these domains are mostly unknown. Therefore, we examined the in vivo consequences of expression of N-terminal truncated cMyBPC (C3C10). Neonatal cMyBPC-/- mice were injected with AAV9-full length (FL), C3C10 cMyBPC, or saline, and echocardiography was performed 6 wk after injection. We then isolated skinned myocardium from virus-treated hearts and performed mechanical experiments. Our results show that expression of C3C10 cMyBPC in cMyBPC-/- mice resulted in a 28% increase in systolic ejection fraction compared to saline-injected cMyBPC-/- mice and a 25% decrease in left ventricle mass-to-body weight ratio. However, unlike expression of FL cMyBPC, there was no prolongation of ejection time compared to saline-injected mice. In vitro mechanical experiments demonstrated that functional improvements in cMyBPC-/- mice expressing C3C10 were primarily due to a 35% reduction in the rate of cross-bridge recruitment at submaximal Ca2+ concentrations when compared to hearts from saline-injected cMyBPC-/- mice. However, unlike the expression of FL cMyBPC, there was no change in the rate of cross-bridge detachment when compared to saline-injected mice. Our data demonstrate that regions of cMyBPC beyond the N-terminus are important for in vivo cardiac function, and have divergent effects on cross-bridge behavior. Elucidating the molecular mechanisms of cMyBPC region-specific function could allow for development of targeted approaches to manipulate specific aspects of cardiac contractile function.

Adverse perception of cough in patients with severe asthma: a discrete choice experiment.

Background: Asthma symptoms adversely impact quality of life in particular in those with poor disease control. Commonly used patient-reported measures for asthma used to assess asthma control often inadequately capture the impact of cough, despite evidence that cough is one of the most bothersome symptoms for patients with asthma. This study aims to improve our understanding of how patients with asthma perceive cough to better understand its clinical impact. Methods: A discrete choice experiment (DCE) was performed in two distinct adult asthma populations; those with severe asthma as defined by Global Initiative for Asthma (GINA) step 4/5 classification and those with moderate asthma (a GINA steps 2 or 3 classification of asthma severity). Results: Choices were highly dominated by the cough attribute in the symptoms complexes; 48.4% of patients with severe asthma and 31.3% with moderate asthma consistently chose the alternative with the lowest level of cough. Furthermore, cough predominance was found to be significantly associated with severity of asthma (p=0.047). Patients with moderate asthma were not willing to accept any additional symptoms to reduce cough from severe to mild. However, these patients were willing to accept mild breathlessness, mild sleep disturbance, severe chest tightness and severe wheezing to remove coughing altogether. Conclusions: Patients with asthma prefer to have less cough and are willing to accept greater levels of other symptoms to achieve this. Additionally, asthma severity may influence an individual's perception of their symptoms; cough is a more important symptom for patients with severe asthma than those with a milder disease.

Planning and Implementation of COVID-19 Isolation and Quarantine Facilities in Hawaii: A Public Health Case Report.

In response to the second surge of COVID-19 cases in Hawaii in the fall of 2020, the Hawaii State Department of Health Behavioral Health Administration led and contracted a coalition of agencies to plan and implement an isolation and quarantine facility placement service that included food, testing, and transportation assistance for a state capitol and major urban center. The goal of the program was to provide safe isolation and quarantine options for individual residents at risk of not being able to comply with isolation and quarantine mandates. Drawing upon historical lived experiences in planning and implementing the system for isolation and quarantine facilities, this qualitative public health case study report applies the plan-do-study-act (PDSA) improvement model and framework to review and summarize the implementation of this system. This case study also offers lessons for a unique opportunity for collaboration led by a public behavioral health leadership that expands upon traditionally narrow infectious disease control, by developing a continuum of care that not only addresses immediate COVID-19 concerns but also longer-term supports and services including housing, access to mental health services, and other social services. This case study highlights the role of a state agency in building a coalition of agencies, including a public university, to respond to the pandemic. The case study also discusses how continuous learning was executed to improve delivery of care.

An observational study to determine the relationship between cough frequency and markers of inflammation in severe asthma.

BACKGROUND: The relationship between objectively measured cough and type 2 (T2) biomarkers and other measures of asthma control and severity is poorly understood. The objective of this study was to assess the relationship between objective and subjective cough measurement tools and clinical biomarkers of asthma. METHODS: Patients with severe asthma and mild-to-moderate asthma completed validated asthma and cough-related measurement tools (including ambulatory cough monitoring) and measurement of spirometry and T2 biomarkers (exhaled nitric oxide fraction (F ENO) and peripheral blood eosinophil count). Patients were classified according to T2 status based on T2-low (F ENO <20 ppb and peripheral blood eosinophils <150 cells·µL-1), T2-intermediate (F ENO ≥20 ppb or peripheral blood eosinophils ≥150 cells·µL-1) or T2-high (F ENO ≥20 ppb and peripheral blood eosinophils ≥150 cells·µL-1). RESULTS: 61 patients completed the study measurements (42 severe asthma and 19 mild-to-moderate asthma). Patients with severe asthma had higher rates of cough than those with mild-to-moderate asthma in terms of total 24-h cough counts (geometric mean±sd 170.3±2.7 versus 60.8±4.1; p=0.002) and cough frequency (geometric mean±sd 7.1±2.7 versus 2.5±4.1 coughs·h-1; p=0.002). T2-low patients with severe asthma had significantly lower 24-h cough frequency compared with T2-intermediate and T2-high patients. CONCLUSIONS: In patients with low biomarkers of T2 inflammation, cough frequency measurements were not elevated, suggesting that the mechanism for cough in asthma is underlying T2 eosinophilic inflammation and the logical first step for treating cough in asthma may be to achieve adequate suppression of T2 inflammation with currently available therapies.

Mitigation Planning and Policies Informed by COVID-19 Modeling: A Framework and Case Study of the State of Hawaii.

In the face of great uncertainty and a global crisis from COVID-19, mathematical and epidemiologic COVID-19 models proliferated during the pandemic. Yet, many models were not created with the explicit audience of policymakers, the intention of informing specific scenarios, or explicit communication of assumptions, limitations, and complexities. This study presents a case study of the roles, uses, and approaches to COVID-19 modeling and forecasting in one state jurisdiction in the United States. Based on an account of the historical real-world events through lived experiences, we first examine the specific modeling considerations used to inform policy decisions. Then, we review the real-world policy use cases and key decisions that were informed by modeling during the pandemic including the role of modeling in informing planning for hospital capacity, isolation and quarantine facilities, and broad public communication. Key lessons are examined through the real-world application of modeling, noting the importance of locally tailored models, the role of a scientific and technical advisory group, and the challenges of communicating technical considerations to a public audience.

Perceptions on Home-Administration of Biologics in the Context of Severe Asthma: An International Qualitative Study.

BACKGROUND: Biologics are an effective therapy for severe asthma. Home administration of biologics by patients is likely to facilitate their accessibility. Yet little is known about patients' and health care providers' (HCPs) perceptions regarding home administration of biologics. OBJECTIVE: The aim of this study is to create more insight into the perceptions and experiences of patients and HCPs regarding home administration of biologics in the context of the treatment of severe asthma. METHODS: A qualitative international study was performed in the Netherlands, United States, Australia, and United Kingdom. In each country, 2 focus groups were held with potential/recent and long-term users of biologics at home. Prior to the focus groups, patients were prompted with themes on online forums. For triangulation purposes, interviews were held with HCPs to discuss salient findings from forums and focus groups. Data were analyzed with qualitative content analysis. RESULTS: In total, 75 patients participated in the forums, of which 40 participated in the focus groups. Furthermore, 12 HCPs were interviewed. The following overarching themes were identified: living with severe asthma; practical aspects of using biologics; the role of HCPs regarding biologics; social support from family, friends, and others; effectiveness of biologics and other treatments; side effects of biologics. CONCLUSIONS: This study showed that, for those using biologics for severe asthma, the benefits of home administration of biologics usually outweigh inconvenience and side effects. Guided practice, accessible support contact, and monitoring including social support should be central in the transition from hospital to home administration of asthma biologics.

Objective and Subjective Measurement of Cough in Asthma: A Systematic Review of the Literature.

BACKGROUND: The extent to which objective and subjective tools has been used to measure the characteristics and burden of cough in patients with asthma has not been reported. OBJECTIVE: To review the large and extensive body of literature in asthma with the specific hypothesis that the characteristics of cough and clinical impact in this disease has only occasionally been studied. METHODS: For this systematic review, we searched EMBASE and MEDLINE databases using a combination of MeSH terms for "cough" and "asthma" for studies published up to and including end of August 2021. Studies included for analysis were confined to those undertaken in adult patients (≥ 18 years) with asthma of any severity where any tool or method to specifically measure cough was employed. RESULTS: Of 12,090 citations identified after our initial search, 112 full-text articles met criteria for inclusion in our analysis. We found that a broad range of objective and subjective measures have been used albeit with a lack of consistency between studies. Clinically important levels of cough associated with impaired health status were identified in patients with asthma. CONCLUSION: Although cough is a common symptom in asthma, the clinical features and accompanying healthcare burden have been studied infrequently. In studies where cough was measured, the methods employed varied considerably. A more consistent use of cough-specific measurement tools is required to better determine the nature and burden of cough in asthma.

Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC.

INTRODUCTION: The central C4 and C5 domains (C4C5) of cardiac myosin binding protein C (cMyBPC) contain a flexible interdomain linker and a cardiac-isoform specific loop. However, their importance in the functional regulation of cMyBPC has not been extensively studied. METHODS AND RESULTS: We expressed recombinant C4C5 proteins with deleted linker and loop regions and performed biophysical experiments to determine each of their structural and dynamic roles. We show that the linker and C5 loop regions modulate the secondary structure and thermal stability of C4C5. Furthermore, we provide evidence through extended molecular dynamics simulations and principle component analyses that C4C5 can adopt a completely bent or latched conformation. The simulation trajectory and interaction network analyses reveal that the completely bent conformation of C4C5 exhibits a specific pattern of residue-level interactions. Therefore, we propose a "hinge-and-latch" mechanism where the linker allows a great degree of flexibility and bending, while the loop aids in achieving a completely bent and latched conformation. Although this may be one of many bent positions that C4C5 can adopt, we illustrate for the first time in molecular detail that this type of large scale conformational change can occur in the central domains of cMyBPC. CONCLUSIONS: Our hinge-and-latch mechanism demonstrates that the linker and loop regions participate in dynamic modulation of cMyBPC's motion and global conformation. These structural and dynamic features may contribute to muscle isoform-specific regulation of actomyosin activity, and have potential implications regarding its ability to propagate or retract cMyBPC's regulatory N-terminal domains.

Utility of fractional exhaled nitric oxide suppression as a prediction tool for progression to biologic therapy.

RATIONALE: The utility of fractional exhaled nitric oxide (F ENO) suppression (FeNOSuppT) to identify non-adherence to inhaled corticosteroid (ICS) treatment has previously been reported, but whether it can predict clinical outcome remains unclear. OBJECTIVES: We examined the utility of FeNOSuppT in prediction of progression to biologic agents or discharge from specialist care. METHODS: FeNOSuppT was measured at home using remote monitoring technology of inhaler use alongside daily F ENO measurement over 7 days. Long-term clinical outcomes in terms of progression to biologic agent or discharge from specialist care were compared for non-suppressors and suppressors. MEASUREMENTS AND MAIN RESULTS: Of the 162 subjects, 135 successfully completed the test with 81 (60%) positive F ENO suppression tests. Subjects with a negative FeNOSuppT were more likely to proceed to biologic therapy (39 of 54 patients, 72%) compared to those with a positive FeNOSuppT (35 of 81 patients, 43%, p=0.001). In subjects with a positive FeNOSuppT, predictors of progression to biologic therapy included higher dose of maintenance steroid at initial assessment and prior intensive care unit admission. These subjects had a significant rise in F ENO between post-suppression test and follow-up (median, 33 (IQR 25-55) versus 71 (IQR 24-114); p=0.009), which was not explained by altered corticosteroid dose. CONCLUSIONS: A negative FeNOSuppT correlates with progression to biologic therapy. A positive FeNOSuppT, with subsequent maintenance of "optimised" F ENO, predicts a subgroup of patients in whom asthma control is preserved with adherence to high-dose ICS/long-acting ß2 agonist and who can be discharged from specialist care.

Measuring adherence to therapy in airways disease.

Non-adherence to medication is one of the most significant issues in all airways disease and can have a major impact on disease control as well as on unscheduled healthcare utilisation. It is vital that clinicians can accurately determine a patient's level of adherence in order to ensure they are gaining the maximal benefit from their therapy and also to avoid any potential for unnecessary increases in therapy. It is essential that measurements of adherence are interpreted alongside biomarkers of mechanistic pathways to identify if improvements in medication adherence can influence disease control. In this review, the most common methods of measuring adherence are discussed. These include patient self-report, prescription record checks, canister weighing, dose counting, monitoring drug levels and electronic monitoring. We describe the uses and benefits of each method as well as potential shortcomings. The practical use of adherence measures with measurable markers of disease control is also discussed. EDUCATIONAL AIMS: To understand the various methods available to measure adherence in airways disease.To learn how to apply these adherence measures in conjunction with clinical biomarkers in routine clinical care.

cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation.

Omecamtiv mecarbil (OM), a direct myosin motor activator, is currently being tested as a therapeutic replacement for conventional inotropes in heart failure (HF) patients. It is known that HF patients exhibit dysregulated ß-adrenergic signaling and decreased cardiac myosin-binding protein C (cMyBPC) phosphorylation, a critical modulator of myocardial force generation. However, the functional effects of OM in conditions of altered cMyBPC phosphorylation have not been established. Here, we tested the effects of OM on force generation and cross-bridge (XB) kinetics using murine myocardial preparations isolated from wild-type (WT) hearts and from hearts expressing S273A, S282A, and S302A substitutions (SA) in the M domain, between the C1 and C2 domains of cMyBPC, which cannot be phosphorylated. At submaximal Ca2+ activations, OM-mediated force enhancements were less pronounced in SA than in WT myocardial preparations. Additionally, SA myocardial preparations lacked the dose-dependent increases in force that were observed in WT myocardial preparations. Following OM incubation, the basal differences in the rate of XB detachment (krel) between WT and SA myocardial preparations were abolished, suggesting that OM differentially affects the XB behavior when cMyBPC phosphorylation is reduced. Similarly, in myocardial preparations pretreated with protein kinase A to phosphorylate cMyBPC, incubation with OM significantly slowed krel in both the WT and SA myocardial preparations. Collectively, our data suggest there is a strong interplay between the effects of OM and XB behavior, such that it effectively uncouples the sarcomere from cMyBPC phosphorylation levels. Our findings imply that OM may significantly alter the in vivo cardiac response to ß-adrenergic stimulation.

The impact of the first COVID-19 surge on severe asthma patients in the UK. Which is worse: the virus or the lockdown?

Asthma therapy, including monoclonal antibodies, was not associated with #COVID19 infection or hospitalisation in a UK severe asthma population. Shielding led to a reported worsening of mental health in nearly half of patients contacted (47%). https://bit.ly/3jImUsG.

Injury during adolescence leads to sex-specific executive function deficits in adulthood in a pre-clinical model of mild traumatic brain injury.

Adolescents are more likely than adults to develop chronic symptoms, such as impulsivity and difficulty concentrating, following a mild traumatic brain injury (mTBI) which may relate to disruption of pre-frontal cortex (PFC development). During adolescence the PFC is undergoing extensive remodelling, driving maturation of executive functions incorporating attention, motivation and impulse control. In part maturation of the PFC is driven by outgrowth of dopaminergic neurons to the PFC under the guidance of specific axonal targeting cues, including netrin-1. How a mTBI in adolescence may alter the expression of these axonal targeting cues, and the influence on PFC development is not yet known. As such the effects of mTBI in mid-adolescence on executive functioning in adulthood (12 weeks) were examined via the 5-choice serial reaction task in both male and female Sprague Dawley rats. Animals at p35 (n = 12-16 per group) were injured via weight drop (100 g from 0.75 m) and injury confirmed by a significant increase in righting reflex. Interestingly, while a mid-adolescence mTBI in females led to significantly higher omissions and decreased accuracy when task difficulty was high (stimulus duration 1 s), males had significantly increased premature response rate when the intertrial interval was varied. Examination of levels of TH, as a reflection of dopaminergic innervation, found no difference in either gender post-TBI in the PFC, but a significant increase in the limbic system (nucleus accumbens) in males, but not females, chronically post-TBI, suggesting an imbalance between the regions. The increase in TH was accompanied by a chronic reduction in netrin-1 within the nucleus accumbens in males only. Taken together, these results indicate that mTBI in adolescence leads to sex specific effects in different domains of PFC function in adulthood, which may relate to subtle alterations in the developmental trajectory of the mesocortical limbic pathway in males only.

AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice.

Decreased cardiac myosin-binding protein C (cMyBPC) expression due to inheritable mutations is thought to contribute to the hypertrophic cardiomyopathy (HCM) phenotype, suggesting that increasing cMyBPC content is of therapeutic benefit. In vitro assays show that cMyBPC N-terminal domains (NTDs) contain structural elements necessary and sufficient to modulate actomyosin interactions, but it is unknown if they can regulate in vivo myocardial function. To test whether NTDs can recapitulate the effects of full-length (FL) cMyBPC in rescuing cardiac function in a cMyBPC-null mouse model of HCM, we assessed the efficacy of AAV9 gene transfer of a cMyBPC NTD that contained domains C0C2 and compared its therapeutic potential with AAV9-FL gene replacement. AAV9 vectors were administered systemically at neonatal day 1, when early-onset disease phenotypes begin to manifest. A comprehensive analysis of in vivo and in vitro function was performed following cMyBPC gene transfer. Our results show that a systemic injection of AAV9-C0C2 significantly improved cardiac function (e.g., 52.24 ± 1.69 ejection fraction in the C0C2-treated group compared with 40.07 ± 1.97 in the control cMyBPC-/- group, P < 0.05) and reduced the histopathologic signs of cardiomyopathy. Furthermore, C0C2 significantly slowed and normalized the accelerated cross-bridge kinetics found in cMyBPC-/- control myocardium, as evidenced by a 32.41% decrease in the rate of cross-bridge detachment (krel). Results indicate that C0C2 can rescue biomechanical defects of cMyBPC deficiency and that the NTD may be a target region for therapeutic myofilament kinetic manipulation.

Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery.

Introduction: Heart failure remains one of the largest clinical challenges in the United States. Researchers have continually searched for more effective heart failure treatments that target the cardiac sarcomere but have found few successes despite numerous expensive cardiovascular clinical trials. Among many reasons, the high failure rate of cardiovascular clinical trials may be partly due to incomplete characterization of a drug candidate's complex interaction with cardiac physiology.Areas covered: In this review, the authors address the issue of preclinical cardiovascular studies of sarcomere-targeting heart failure therapies. The authors consider inherent tradeoffs made between mechanistic transparency and physiological fidelity for several relevant preclinical techniques at the atomic, molecular, heart muscle fiber, whole heart, and whole-organism levels. Thus, the authors suggest a comprehensive, bottom-up approach to preclinical cardiovascular studies that fosters scientific rigor and hypothesis-driven drug discovery.Expert opinion: In the authors' opinion, the implementation of hypothesis-driven drug discovery practices, such as the bottom-up approach to preclinical cardiovascular studies, will be imperative for the successful development of novel heart failure treatments. However, additional changes to clinical definitions of heart failure and current drug discovery culture must accompany the bottom-up approach to maximize the effectiveness of hypothesis-driven drug discovery.