A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

Insights from degradation studies of alpha mangostin from Garcinia mangostana: key findings.

The present study emphasises the necessity of substantiating the stability of plant-derived bioactive compounds for their therapeutic effectiveness in pharmaceutical production. The limelight is on alpha-mangostin (AM), a xanthone from Garcinia mangostana L., renowned for its diverse biological properties. Acid exposure during a forced degradation study on AM resulted in degraded alpha-mangostin (DAM) formation, with structural modifications of the two prenyl groups at C2 and C8 positions as determined by NMR and HRMS analysis. Other conditions (temperature, humidity, photolytic, oxidative, and alkaline) showed a minimal impact on AM. DAM, although showed antibacterial activity at concentration higher than AM (MIC values for AM: 0.39-1.56 µg/mL; DAM: >25 µg/mL), it exhibited potential for binding with Glucosyltransferase-SI from Streptococcus mutans and human Acetylcholinesterase in molecular docking simulations, comparable to AM. This suggests, the importance of prenyl group at C2 and C8 positions for AM's potent antibacterial activity and the decreased activity of DAM is due to lack of the prenyl groups.

Pulmonary sarcoidosis: differences in lung function change over time.

INTRODUCTION: Given the heterogeneity of sarcoidosis, predicting disease course of patients remains a challenge. Our aim was to determine whether the 3-year change in pulmonary function differed between pulmonary function phenotypes and whether there were differential longitudinal changes by race and sex. METHODS: We identified individuals seen between 2005 and 2015 with a confirmed diagnosis of sarcoidosis who had at least two pulmonary function test measurements within 3 years of entry into the cohort. For each individual, spirometry, diffusion capacity, Charlson Comorbidity Index, sarcoidosis organ involvement, diagnosis duration, tobacco use, race, sex, age and medications were recorded. We compared changes in pulmonary function by type of pulmonary function phenotype and for demographic groups. RESULTS: Of 291 individuals, 59% (173) were female and 54% (156) were black. Individuals with restrictive pulmonary function phenotype had significantly greater 3-year rate of decline of FVC% (forced vital capacity) predicted and FEV1% (forced expiratory volume in 1 s) predicted course when compared with normal phenotype. We identified a subset of individuals in the cohort, highest decliners, who had a median 3-year FVC decline of 156 mL. Black individuals had worse pulmonary function at entry into the cohort measured by FVC% predicted, FEV1% predicted and diffusing capacity for carbon monoxide % predicted compared with white individuals. Black individuals' pulmonary function remained stable or declined over time, whereas white individuals' pulmonary function improved over time. There were no sex differences in rate of change in any pulmonary function parameters. SUMMARY: We found significant differences in 3-year change in pulmonary function among pulmonary function phenotypes and races, but no difference between sexes.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

Diagnosis and Management of Cardiac Sarcoidosis: A Scientific Statement From the American Heart Association.

Cardiac sarcoidosis is an infiltrative cardiomyopathy that results from granulomatous inflammation of the myocardium and may present with high-grade conduction disease, ventricular arrhythmias, and right or left ventricular dysfunction. Over the past several decades, the prevalence of cardiac sarcoidosis has increased. Definitive histological confirmation is often not possible, so clinicians frequently face uncertainty about the accuracy of diagnosis. Hence, the likelihood of cardiac sarcoidosis should be thought of as a continuum (definite, highly probable, probable, possible, low probability, unlikely) rather than in a binary fashion. Treatment should be initiated in individuals with clinical manifestations and active inflammation in a tiered approach, with corticosteroids as first-line treatment. The lack of randomized clinical trials in cardiac sarcoidosis has led to treatment decisions based on cohort studies and consensus opinions, with substantial variation observed across centers. This scientific statement is intended to guide clinical practice and to facilitate management conformity by providing a framework for the diagnosis and management of cardiac sarcoidosis.

Chromatography affinity resin with photosynthetically-sourced protein A ligand.

Green, photosynthesizing plants can be proficiently used as cost-effective, single-use, fully biodegradable bioreactors for environmentally-friendly production of a variety of valuable recombinant proteins. Being near-infinitely scalable and most energy-efficient in generating biomass, plants represent profoundly valid alternatives to conventionally used stationary fermenters. To validate this, we produced a plastome-engineered tobacco bioreactor line expressing a recombinant variant of the protein A from Staphylococcus aureus, an affinity ligand widely useful in antibody purification processes, reaching accumulation levels up to ~ 250 mg per 1 kg of fresh leaf biomass. Chromatography resin manufactured from photosynthetically-sourced recombinant protein A ligand conjugated to agarose beads demonstrated the innate pH-driven ability to bind and elute IgG-type antibodies and allowed one-step efficient purification of functional monoclonal antibodies from the supernatants of the producing hybridomas. The results of this study emphasize the versatility of plant-based recombinant protein production and illustrate its vast potential in reducing the cost of diverse biotechnological applications, particularly the downstream processing and purification of monoclonal antibodies.

The Association of Unmet Palliative Care Needs and Physical Frailty With Clinical Outcomes: A Prospective Study of Adults With Heart Failure.

BACKGROUND: People with heart failure, particularly those who are physically frail, experience complex needs that can be addressed by palliative care (PC). However, we have a limited understanding of how the intersection of unmet PC needs and physical frailty contributes to health-related quality of life (HRQOL) and risk for hospitalization or mortality. OBJECTIVE: In this study, we sought to examine the association of unmet PC needs and physical frailty with clinical outcomes (baseline HRQOL and hospitalizations or mortality at 6 months). METHODS: We recruited a convenience sample of community-dwelling persons with heart failure from an urban hospital system who were older than 50 years and hospitalized in the last year. We measured physical frailty using the FRAIL scale (nonfrail, 0-2; frail, 3-5), PC needs using the Integrated Palliative Outcome Scale (range, 0-58; higher scores indicating higher needs), and HRQOL using the Kansas City Cardiomyopathy Questionnaire (range, 0-100; higher scores indicate higher HRQOL). We performed multivariable linear regression to test the relationships between physical frailty, PC needs, and HRQOL, and multivariable logistic regression for associations with all-cause 6-month hospitalization or mortality. We also performed an exploratory analysis of 4 PC needs/frailty groups (high PC needs/frail, high PC needs/nonfrail, low PC needs/frail, low PC needs/nonfrail) with outcomes. RESULTS: In our overall sample (n = 298), mean (SD) age was 68 (9.8) years, 37% were women (n = 108), 28% identified as Black/African American (n = 84), and 65% had heart failure with preserved ejection fraction (n = 194). Mean PC needs score was 19.7, and frail participants (n = 130, 44%) had a significantly higher mean PC needs score than nonfrail participants (P < .001). Those with higher PC needs (Integrated Palliative Care Outcome Scale ≥ 20) had significantly worse HRQOL (P < .001) and increased odds of hospitalization or mortality (odds ratio, 2.5; P < .01) compared with those with lower PC needs, adjusting for covariates. Physically frail participants had significantly worse HRQOL (P < .001) and higher odds of hospitalization or mortality at 6 months (odds ratio, 2.6; P < .01) than nonfrail participants, adjusting for covariates. In an exploratory analysis, physically frail participants with high PC needs had the lowest HRQOL score, with an average score of 28.6 points lower (P < .001) and 4.6 times higher odds of hospitalization or mortality (95% confidence interval, 2.03-10.43; P < .001) than low-needs/nonfrail participants. CONCLUSION: Higher unmet PC needs and physical frailty, separately and in combination, were associated with lower HRQOL and higher odds of hospitalization or mortality. Self-reported PC needs and physical frailty assessment in clinical settings may improve identification of patients at the highest risk for poor HRQOL and hospitalization or mortality amenable to PC intervention.

Small dense low-density lipoprotein cholesterol and coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis.

AIMS: Elevated small dense LDL cholesterol (sd-LDL-C) increases atherosclerotic cardiovascular disease (CVD) risk. Although coronary artery calcification (CAC) is widely used for predicting CVD events, few studies have examined the relationship between sd-LDL-C and CAC. METHODS AND RESULTS: This study included 4672 individuals with directly measured baseline sd-LDL-C and CAC from the Multi-Ethnic Study of Atherosclerosis [mean (standard deviation) age: 61.9 (10.4) years; 52.5% women; 47.3% with baseline CAC (mean score >0)]. We used multi-variable general linear models and restricted cubic splines with the goodness of fit testing to evaluate the association of sd-LDL-C with the presence of CAC. Odds ratios [OR (95% confidence interval)] were adjusted for demographics and cardiovascular risk factors, including estimated total LDL-C. Higher quartiles of sd-LDL-C were associated with the presence of CAC, even after accounting for total LDL-C. Compared with the lowest quartile of sd-LDL-C, participants in Quartiles 2, 3, and 4 had higher odds for the presence of baseline CAC [Quartile 2 OR: 1.24 (1.00, 1.53); Quartile 3 OR: 1.51 (1.19, 1.93); and Quartile 4 OR 1.59 (1.17, 2.16)]. Splines suggested a quadratic curvilinear relationship of continuous sd-LDL-C with CAC after adjustment for demographics and CVD risk factors (quadratic vs. first-order sd-LDL-C terms likelihood ratio test: P = 0.015), but not after accounting for total LDL-C (quadratic vs. first-order terms: P = 0.156). CONCLUSION: In a large, multi-ethnic sample without known CVD, higher sd-LDL-C was associated with the presence of CAC, above and beyond total LDL-C. Whether selective direct measurement of sd-LDL-C is indicated to refine cardiovascular risk assessment in primary prevention warrants further investigation.

Higher levels of small dense particles of LDL cholesterol, better known as the 'bad cholesterol', are associated with a greater risk for the presence of coronary artery calcium, a strong marker for heart disease, even when accounting for estimated total (small dense + large body particles) LDL cholesterol.This risk is stronger in older individuals.Peak risk seems to occur between 49 and 71 mg/dL and does not increase further at higher levels.

Diagnostic and management strategies in cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is increasingly recognized in the context of with otherwise unexplained electrical or structural heart disease due to improved diagnostic tools and awareness. Therefore, clinicians require improved understanding of this rare but fatal disease to care for these patients. The cardinal features of CS, include arrhythmias, atrio-ventricular conduction delay and cardiomyopathy. In addition to treatments tailored to these cardiac manifestations, immunosuppression plays a key role in active CS management. However, clinical trial and consensus guidelines are limited to guide the use of immunosuppression in these patients. This review aims to provide a practical overview to the current diagnostic challenges, treatment approach, and future opportunities in the field of CS.

Implementing a Patient-Reported Outcome Dashboard in Oncology Telemedicine Encounters: Clinician and Patient Adoption and Acceptability.

PURPOSE: Telemedicine provides numerous benefits to patients, yet effective communication and symptom assessment remain a concern. The recent uptake of telemedicine provided an opportunity to use a newly developed dashboard with patient-reported outcome (PRO) information to enhance communication and shared decision making (SDM) during telemedicine appointments. The objective of this study was to identify barriers to using the dashboard during telemedicine, develop implementation strategies to address barriers, and pilot test use of this dashboard during telemedicine appointments in two practice settings to evaluate acceptability, adoption, fidelity, and effectiveness. METHODS: Patients and clinicians were interviewed to identify determinants to dashboard use in telemedicine. Implementation strategies were designed and refined through iterative feedback from stakeholders. A pilot study of dashboard use was conducted from March to September 2022. Acceptability, adoption, and fidelity were evaluated using mixed methods. SDM was evaluated using the collaboRATE measure. RESULTS: One hundred two patient encounters were evaluated. Most patients (62; 60%) had completed some PRO data at the time of their telemedicine encounter. Most (82; 80%) encounters had clinician confirmation that PRO data had been reviewed; however, collaborative review of the dashboard was documented in only 27%. Degree of SDM was high (mean collaboRATE score 3.40; SD, 0.11 [95% CI, 3.17 to 3.63] out of a maximum score of 4). Implementation strategies focused on patient engagement, education, and remote PRO completion. Clinician-facing strategies included education, practice facilitation, and small tests of change. CONCLUSION: This study demonstrated that implementation of a PRO-based dashboard into telemedicine appointments was feasible and had acceptable adoption and acceptability by patients and clinicians when several strategies were used to engage end users. Strategies targeting both patients and clinicians are needed to support routine and effective PRO integration in telemedicine.

Role of genetics in inflammatory cardiomyopathy.

Traditional cardiomyopathy paradigms segregate inflammatory etiologies from those caused by genetic variants. An identified or presumed trigger is implicated in acute myocarditis or chronic inflammatory cardiomyopathy but growing evidence suggests a significant proportion of patients have an underlying cardiomyopathy-associated genetic variant often even when a clear inflammatory trigger is identified. Recognizing a possible genetic contribution to inflammatory cardiomyopathy may have major downstream implications for both the patient and family. The presenting features of myocarditis (i.e. chest pain, arrhythmia, and/or heart failure) may provide insight into diagnostic considerations. One example is isolated cardiac sarcoidosis, a distinct inflammatory cardiomyopathy that carries diagnostic challenges and clinical overlap; genetic testing has increasingly reclassified cases of isolated cardiac sarcoidosis as genetic cardiomyopathy, notably altering management. On the other side, inflammatory presentations of genetic cardiomyopathies are likewise underappreciated and a growing area of investigation. Inflammation plays an important role in the pathogenesis of several familial cardiomyopathies, especially arrhythmogenic phenotypes. Given these clinical scenarios, and the implications on clinical decision making such as initiation of immunosuppression, sudden cardiac death prevention, and family screening, it is important to recognize when genetics may be playing a role.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

BACKGROUND: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS: Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION: Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.

Occult right ventricular dysfunction and right ventricular-vascular uncoupling in left ventricular assist device recipients.

BACKGROUND: Detecting right heart failure post left ventricular assist device (LVAD) is challenging. Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction. METHODS: Thirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial coupling (ratio of Ees/Ea). RESULTS: LVAD patients had lower RV Ees (0.20 ± 0.08 vs 0.30 ± 0.15 mm Hg/ml, p = 0.01) and lower RV Ees/Ea (0.37 ± 0.14 vs 1.20 ± 0.54, p < 0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r = 0.68, p = 0.004) as well as the LVAD cohort itself (r = 0.78, p = 0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p = 0.048), driven by an inability to augment RV Ees (0.22 ± 0.11 vs 0.19 ± 0.02 mm Hg/ml, p = 0.95) to accommodate higher RV Ea (0.82 ± 0.38 vs 0.39 ± 0.08 mm Hg/ml, p = 0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients ((area under the curve) AUC = 0.80); during the ramp study, change in PAPi also correlated with change in RV Ees/Ea (r = 0.58, p = 0.04). CONCLUSIONS: LVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD left ventricular unloading, which reduces septal contractility.

Management Strategies in Arrhythmogenic Cardiomyopathy across the Spectrum of Ventricular Involvement.

Improved disease recognition through family screening and increased life expectancy with appropriate sudden cardiac death prevention has increased the burden of heart failure in arrhythmogenic cardiomyopathy (ACM). Heart failure management guidelines are well established but primarily focus on left ventricle function. A significant proportion of patients with ACM have predominant or isolated right ventricle (RV) dysfunction. Management of RV dysfunction in ACM lacks evidence but requires special considerations across the spectrum of heart failure regarding the initial diagnosis, subsequent management, monitoring for progression, and end-stage disease management. In this review, we discuss the unique aspects of heart failure management in ACM with a special focus on RV dysfunction.

Toxicity prediction and analysis of flavonoid apigenin as a histone deacetylase inhibitor: an in-silico approach.

Occurrence of cancer is driving up on a global scale that exerts greater implications on the physical, psychological and economic stability of the human population. In the present context, numerous research studies are being conducted to explore and discover the drug molecule as an anticancer agent. Diverse scales of flavonoids entail the human diet, and they displayed prospective curative effects against an array of ailments. Among different categories of flavonoids, apigenin a trihydroxy flavone has been proven to have various pharmacological effects. Molecular docking is a key tool in structural molecular biology and computer assisted drug design. In this study, HDAC inhibitory action of apigenin and its probable toxicity was assessed by docking study using Auto dock platform. Molecular dynamics simulation was done by using iMODS server for elucidating the stability of the receptor-ligand complex. Toxicity predictions were evaluated by using tools such as CarcinoPred for carcinogenicity study, pkCSM for ADMET analysis, ProTox-II for rodent oral toxicity, lazar for estimating mutagenicity, BOILED Egg plot analysis for examining the gastrointestinal absorption and blood brain permeability, PASS prediction to identify the various biological functions and DruLiTo program to compute the drug likeness property.

Noninvasive Point of Care Device for Assessing Cardiac Response to Acute Volume Changes.

Purpose: The change in the amplitude of a peripheral pulse in response to a Valsalva maneuver has diagnostic utility for assessing volume status at the bedside. We have developed a device to automatically quantify the Valsalva pulse response (VPR) to a standardized Valsalva maneuver that the device guides a user to perform. In this study, we sought to determine whether VPR by the device, Indicor, is sensitive enough to detect the acute increase in central pressure and volume load that occurs with a passive leg raise (PLR) in healthy volunteers. Methods: Healthy volunteers were tested semirecumbently at 45 degrees, then again after being leaned back on a pivoted wedge with legs raised at 45 degrees and torso and head flat, and then again in the semirecumbent position. The device recorded a finger photoplethysmography (PPG) signal during a 10-second expiratory effort of 20 mmHg as guided by the device. VPR was automatically calculated as the ratio of the end-Valsalva pulse amplitude to the baseline pulse amplitude. Results: In the 30 participants who completed testing, VPR increased from baseline to PLR in every participant, from 0.34 ± 0.13 to 0.60 ± 0.14 (p < 0.0001). Back upright, VPR decreased back to 0.33 ± 0.10 (p < 0.0001 versus PLR; NS versus baseline position). Conclusion: In this proof-of-concept study of healthy participants, the Indicor device, a noninvasive, convenient device that automatically calculates VPR from a finger photoplethysmography signal during a standardized Valsalva maneuver, was sensitive enough to detect the increase in VPR that occurred with an acute central volume load from a PLR. Future studies should examine whether VPR responds differently to a PLR in heart failure patients with abnormal cardiac performance and/or congestion.

Use of Human-Centered Design Methodology to Develop a Digital Toolkit to Optimize Heart Failure Guideline-Directed Medical Therapy.

BACKGROUND: Guideline-directed medical therapies (GDMTs) improve quality of life and health outcomes for patients with heart failure (HF). However, GDMT utilization is suboptimal among patients with HF. OBJECTIVE: The aims of this study were to engage key stakeholders in semistructured, virtual human-centered design sessions to identify challenges in GDMT optimization posthospitalization and inform the development of a digital toolkit aimed at optimizing HF GDMTs. METHODS: For the human-centered design sessions, we recruited (a) clinicians who care for patients with HF across 3 hospital systems, (b) patients with HF with reduced ejection fraction (ejection fraction ≤ 40%) discharged from the hospital within 30 days of enrollment, and (c) caregivers. All participants were 18 years or older, English speaking, with Internet access. RESULTS: A total of 10 clinicians (median age, 37 years [interquartile range, 35-41], 12 years [interquartile range, 10-14] of experience caring for patients with HF, 80% women, 50% White, 50% nurse practitioners) and three patients and one caregiver (median age 57 years [IQR: 53-60], 75% men, 50% Black, 75% married) were included. Five themes emerged from the clinician sessions on challenges to GDMT optimization (eg, barriers to patient buy-in). Six themes on challenges (eg, managing medications), 4 themes on motivators (eg, regaining independence), and 3 themes on facilitators (eg, social support) to HF management arose from the patient and caregiver sessions. CONCLUSIONS: The clinician, patient, and caregiver insights identified through human-centered design will inform a digital toolkit aimed at optimizing HF GDMTs, including a patient-facing smartphone application and clinician dashboard. This digital toolkit will be evaluated in a multicenter, clinical trial.