Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions.

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) ß-adrenergic (ß-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that ß-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

Mavacamten, a precision medicine for hypertrophic cardiomyopathy: From a motor protein to patients.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of the heart. These functional derangements arise directly from altered sarcomeric function due to either mutations in genes encoding sarcomere proteins, or other defects such as abnormal energetics. Current treatment options do not directly address this causal biology but focus on surgical and extra-sarcomeric (sarcolemmal) pharmacological symptomatic relief. Mavacamten (formerly known as MYK-461), is a small molecule designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin, the fundamental motor of the sarcomere. This review summarizes the mechanism and translational progress of mavacamten from proteins to patients, describing how the mechanism of action and pharmacological characteristics, involving both systolic and diastolic effects, can directly target pathophysiological derangements within the cardiac sarcomere to improve cardiac structure and function in HCM. Mavacamten was approved by the Food and Drug Administration in April 2022 for the treatment of obstructive HCM and now goes by the commercial name of Camzyos. Full information about the risks, limitations, and side effects can be found at www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.

Multilevel Stigma and Its Associations with Medical Care Ratings Among Men Who Have Sex With Men in HPTN 078.

INTRODUCTION: Our research assessed associations between stigma-related variables and medical care ratings among clients with HIV in HIV Prevention Trials Network (HPTN) 078 who were men who have sex with men (MSM). METHODS: Logistic regression explored care ratings, stigma, socio-demographics (N = 637). Qualitative thematic coding and themes explored stigmatizing experiences in different settings (N = 111). RESULTS: Whites were twice as likely as African-Americans to report high care ratings (P < .05). Clients who reported familial exclusion due to having sex with men were 40% less likely to report high medical care ratings (P < .05). Clients who agreed healthcare providers think people with HIV "sleep around" were half as likely to report high care ratings (P < .08). Stigmatization included "treating me like they'll catch HIV from my hand," and care avoidance so others didn't "know I was having sex with men". CONCLUSIONS: Providers can promote African American MSM client retention with more affirming healthcare provision, namely minimizing assumptions and addressing identities and client needs beyond just HIV care.

The Testing Imperative: Why the US Ending the Human Immunodeficiency Virus (HIV) Epidemic Program Needs to Renew Efforts to Expand HIV Testing in Clinical and Community-Based Settings.

Data from several modeling studies demonstrate that large-scale increases in human immunodeficiency virus (HIV) testing across settings with a high burden of HIV may produce the largest incidence reductions to support the US Ending the HIV Epidemic (EHE) initiative's goal of reducing new HIV infections 90% by 2030. Despite US Centers for Disease Control and Prevention's recommendations for routine HIV screening within clinical settings and at least yearly screening for individuals most at risk of acquiring HIV, fewer than half of US adults report ever receiving an HIV test. Furthermore, total domestic funding for HIV prevention has remained unchanged between 2013 and 2019. The authors describe the evidence supporting the value of expanded HIV testing, identify challenges in implementation, and present recommendations to address these barriers through approaches at local and federal levels to reach EHE targets.

Human Immunodeficiency Virus (HIV) Care Continuum Outcomes After Transition to Adult Care Among a Prospective Cohort of Youth With HIV in Atlanta, Georgia.

BACKGROUND: Healthcare transition from pediatric to adult-oriented clinical settings is often viewed as a high-risk time for care disengagement. However, there is a paucity of prospective, longitudinal research documenting human immunodeficiency virus (HIV) care outcomes after healthcare transition. METHODS: We conducted a prospective, observational cohort study of healthcare transition among youth enrolled at an HIV care center in Atlanta, Georgia. Pediatric clinic patients (average age, 24 years) were enrolled up to 3 months before the expected transition and were followed up to determine linkage, retention, and viral suppression in adult care through electronic medical record abstractions at the baseline and at 6, 12, 18, and 24 months. RESULTS: The majority of our cohort (n = 70) was male (88.6%) and black (92.9%) and acquired HIV horizontally (80%). Most of our cohort was linked to adult care by 12 months (84%) after enrollment. Of those who linked to adult care by 12 months, retention rates were 86% (95% confidence interval, 78%-94%) at 6 months, 76% (66%-86%) at 12 months, and 66% (55%-78%) at 18 and 24 months. Once in adult care, the proportion with viral suppression was stable (73% at baseline and 74%, 77%, 67%, and 78% at 6, 12, 18, and 24 months, respectively). CONCLUSIONS: Although most youth successfully linked to adult care, retention rates decreased over the 24-month follow-up period. Rates of viral suppression were stable for those who remained in care. Strategies to support retention in adult care will be critical to optimizing this transition for youth with HIV.

Stakeholder-led design of a mobile HIV clinic model to enhance engagement and retention in HIV care in the Southern United States.

To foster retention of people living with HIV (PLWH) in HIV care in the Southern United States, we aimed to develop a stakeholder-driven mobile HIV clinic (MHC) model. From June 2019 to May 2021 we conducted a mixed-methods study: 50 surveys with out-of-care PLWH and 41 in-depth interviews with PLWH, HIV clinic staff, city officials, AIDS service organizations, and mobile clinics to examine preferences for MHC implementation. Survey data was analyzed descriptively, and interview transcripts were coded thematically. Participants recommended the MHC: (1) have nondescript exterior and HIV services nested in non-HIV care to foster confidentiality, (2) be located along public transportation and have extended hours to promote accessibility, (3) have established protocols addressing security, biosafety, and data safety; (4) provide comprehensive clinical and support services to address retention barriers; and (5) be integrated within the health system, use low-cost, diverse staffing, and establish appointment notification systems. By informing MHC design, these findings add to the toolbox of strategies that can render HIV care more accessible.

Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus.

BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.

Human Immunodeficiency Virus transmission by HIV Risk Group and Along the HIV Care Continuum: A Contrast of 6 US Cities.

BACKGROUND: Understanding the sources of HIV transmission provides a basis for prioritizing HIV prevention resources in specific geographic regions and populations. This study estimated the number, proportion, and rate of HIV transmissions attributable to individuals along the HIV care continuum within different HIV transmission risk groups in 6 US cities. METHODS: We used a dynamic, compartmental HIV transmission model that draws on racial behavior-specific or ethnic behavior-specific and risk behavior-specific linkage to HIV care and use of HIV prevention services from local, state, and national surveillance sources. We estimated the rate and number of HIV transmissions attributable to individuals in the stage of acute undiagnosed HIV, nonacute undiagnosed HIV, HIV diagnosed but antiretroviral therapy (ART) naïve, off ART, and on ART, stratified by HIV transmission group for the 2019 calendar year. RESULTS: Individuals with undiagnosed nonacute HIV infection accounted for the highest proportion of total transmissions in every city, ranging from 36.8% (26.7%-44.9%) in New York City to 64.9% (47.0%-71.6%) in Baltimore. Individuals who had discontinued ART contributed to the second highest percentage of total infections in 4 of 6 cities. Individuals with acute HIV had the highest transmission rate per 100 person-years, ranging from 76.4 (58.9-135.9) in Miami to 160.2 (85.7-302.8) in Baltimore. CONCLUSION: These findings underline the importance of both early diagnosis and improved ART retention for ending the HIV epidemic in the United States. Differences in the sources of transmission across cities indicate that localized priority setting to effectively address diverse microepidemics at different stages of epidemic control is necessary.

The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium.

[Figure: see text].

HIV Prevention Trials Network 078: High Prevalence of Hepatitis C Virus Antibodies Among Urban US Men Who Have Sex With Men, Independent of Human Immunodeficiency Virus Status.

BACKGROUND: Sexual transmission of hepatitis C virus (HCV) is uncommon, yet documented among men who have sex with men (MSM), primarily among those with human immunodeficiency virus (HIV). METHODS: In the HIV Prevention Trials Network 078 study (HPTN 078), which assessed an integrated strategy to achieve HIV viral suppression, 1305 MSM were screened across 4 geographically diverse US cities. At screening, demographic/behavioral/psychosocial questionnaires were completed, along with HIV and HCV testing. Multivariable logistic regression was used to evaluate associations with HCV antibody positivity. RESULTS: Among the 1287 (99%) of the MSM with HCV antibody results, the median age was 41, 69% were black, 85% had a high school education or more, 35% were employed, 70% had HIV, and 21% had undergone substance use counseling. The median lifetime number of male sexual partners was 17 (interquartile range, 6-50), and 246 (19%) were HCV antibody positive. HCV antibody positivity was high in MSM with HIV (20%) and MSM without HIV (17%) (P = .12) and was higher in those receiving substance use counseling (36%) than in those who had not (15%) (P ≤ .01). Substance use counseling (odds ratio, 2.51; 95% confidence interval, 1.80-3.51) and unstable housing (2.16; 1.40-3.33) were associated with HCV antibody positivity. CONCLUSIONS: Nearly 1 in 5 MSM screened for HPTN 078 have been infected with HCV. The prevalence is high regardless of HIV status and is high even in those who did not undergo substance use counseling. In HIV burden networks, high HCV infection prevalence may occur in MSM without HIV. As implementation of preexposure prophylaxis expands and condom use declines, routine HCV counseling and screening among MSM are important.

Maternal smoking during pregnancy and physiological anxiety in children with attention deficit hyperactivity disorder.

Our objective was to explore the relationship between mother smoking during pregnancy and physiological anxiety of children with Attention deficit-hyperactivity disorder. Cognitive profile was evaluated by Wechsler Intelligence Scale for Children, physiological anxiety by Children's Manifest Anxiety Scale. Mother's smoking was evaluated by the Fagerström test for nicotine dependence. Ninety-seven children with Attention Deficit-Hyperactivity Disorder combined type, 70 inattentive, and 48 hyperactive-impulsive, and 130 controls were studied. We found a higher frequency of high smoking dependence in mothers of children with Attention Deficit-Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type in the Fagerström test; and a significant correlation between physiological anxiety in children with Attention Deficit Hyperactivity Disorder-combined type, with high and moderate maternal smoking level during pregnancy. In conclusion, data suggests, with caution a brain alteration of infants, induced by nicotine exposure during pregnancy in children with Attention Deficit Hyperactivity Disorder-combined type, and Attention Deficit Hyperactivity Disorder-hyperactive type.

Smoking and cessation-related attitudes among men who have sex with men in the country of Georgia.

Among men who have sex with men (MSM) in low- or middle-income countries, smoking and related factors have been understudied. We examined correlates of smoking status, level, and importance and confidence regarding quitting among 608 MSM in the country of Georgia recruited in June-September, 2016 (493 without HIV via peer referral in 3 Georgian cities; 115 with HIV via the National AIDS Center). Median age was 26 years, 78.6% reported current (past 30-day) alcohol use, and 22.4% reported past-year illicit drug use. Overall, 73.8% reported current smoking; of these, 87.1% smoked daily, mean cigarettes per day (cpd) was 19.8, 64.6% smoked ≤30 min of waking, and mean quitting importance and confidence were 6.8 and 6.4 (0 = not at all to 10 = extremely), respectively. Multivariable analyses indicated that current smoking correlated with past-month alcohol and past-year illicit drug use (p's < .001). Among smokers, cpd correlated with being older and smoking within 30 min of waking; greater quitting importance (≥7) correlated with higher education and no illicit substance use; and greater quitting confidence (≥7) was associated with fewer cpd, smoking ≤30 min of waking, and regional versus capital city residence. Given these findings, addressing tobacco and other substance use among MSM in Georgia is critical.

The Potential Epidemiological Impact of Coronavirus Disease 2019 (COVID-19) on the Human Immunodeficiency Virus (HIV) Epidemic and the Cost-effectiveness of Linked, Opt-out HIV Testing: A Modeling Study in 6 US Cities.

BACKGROUND: Widespread viral and serological testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present a unique opportunity to also test for human immunodeficiency virus (HIV) infection. We estimated the potential impact of adding linked, opt-out HIV testing alongside SARS-CoV-2 testing on the HIV incidence and the cost-effectiveness of this strategy in 6 US cities. METHODS: Using a previously calibrated dynamic HIV transmission model, we constructed 3 sets of scenarios for each city: (1) sustained current levels of HIV-related treatment and prevention services (status quo); (2) temporary disruptions in health services and changes in sexual and injection risk behaviors at discrete levels between 0%-50%; and (3) linked HIV and SARS-CoV-2 testing offered to 10%-90% of the adult population in addition to Scenario 2. We estimated the cumulative number of HIV infections between 2020-2025 and the incremental cost-effectiveness ratios of linked HIV testing over 20 years. RESULTS: In the absence of linked, opt-out HIV testing, we estimated a total of a 16.5% decrease in HIV infections between 2020-2025 in the best-case scenario (50% reduction in risk behaviors and no service disruptions), and a 9.0% increase in the worst-case scenario (no behavioral change and 50% reduction in service access). We estimated that HIV testing (offered at 10%-90% levels) could avert a total of 576-7225 (1.6%-17.2%) new infections. The intervention would require an initial investment of $20.6M-$220.7M across cities; however, the intervention would ultimately result in savings in health-care costs in each city. CONCLUSIONS: A campaign in which HIV testing is linked with SARS-CoV-2 testing could substantially reduce the HIV incidence and reduce direct and indirect health care costs attributable to HIV.

Improving the Delivery of Chronic Opioid Therapy Among People Living With Human Immunodeficiency Virus: A Cluster Randomized Clinical Trial.

BACKGROUND: Chronic pain is prevalent among people living with human immunodeficiency virus (PLWH); managing pain with chronic opioid therapy (COT) is common. Human immunodeficiency virus (HIV) providers often diverge from prescribing guidelines. METHODS: This 2-arm, unblinded, cluster-randomized clinical trial assessed whether the Targeting Effective Analgesia in Clinics for HIV (TEACH) intervention improves guideline-concordant care compared to usual care for PLWH on COT. The trial was implemented from 2015 to 2018 with 12-month follow-up at safety-net hospital-based HIV clinics in Boston and Atlanta. We enrolled 41 providers and their 187 patients on COT. Prescribers were randomized 1:1 to either a 12-month intervention consisting of a nurse care manager with an interactive electronic registry, opioid education, academic detailing, and access to addiction specialists or a control condition consisting of usual care. Two primary outcomes were assessed through electronic medical records: ≥2 urine drug tests and any early COT refills by 12 months. Other outcomes included possible adverse consequences. RESULTS: At 12 months, the TEACH intervention arm had higher odds of ≥2 urine drug tests than the usual care arm (71% vs 20%; adjusted odds ratio [AOR], 13.38 [95% confidence interval {CI}, 5.85-30.60]; P < .0001). We did not detect a statistically significant difference in early refills (22% vs 30%; AOR, 0.55 [95% CI, .26-1.15]; P = .11), pain severity (6.30 vs 5.76; adjusted mean difference, 0.10 [95% CI, -1.56 to 1.75]; P = .91), or HIV viral load suppression (86.9% vs 82.1%; AOR, 1.21 [95% CI, .47-3.09]; P = .69). CONCLUSIONS: TEACH is a promising intervention to improve adherence to COT guidelines without evident adverse consequences.

Initiation of Antiretroviral Therapy in the Hospital Is Associated With Linkage to Human Immunodeficiency Virus (HIV) Care for Persons Living With HIV and Substance Use Disorder.

BACKGROUND: Studies have demonstrated benefits of antiretroviral therapy (ART) initiation on the day of human immunodeficiency virus (HIV) testing or at first clinical visit. The hospital setting is understudied for immediate ART initiation. METHODS: CTN0049, a linkage-to-care randomized clinical trial, enrolled 801 persons living with HIV (PLWH) and substance use disorder (SUD) from 11 hospitals across the United States. This secondary analysis examined factors related to initiating (including reinitiating) ART in the hospital and its association with linkage to HIV care, frequency of outpatient care visits, retention, and viral suppression. RESULTS: Of 801 participants, 124 (15%) initiated ART in the hospital, with more than two-thirds of these participants (80/124) initiating ART for the first time. Time to first HIV care visit among those who initiated ART in the hospital and those who did not was 29 and 54 days, respectively (P = .0145). Hospital initiation of ART was associated with increased frequency of HIV outpatient care visits at 6 and 12 months. There was no association with ART initiation in the hospital and retention and viral suppression over a 12-month period. Participants recruited in Southern hospitals were less likely to initiate ART in the hospital (P < .001). CONCLUSIONS: Previous research demonstrated benefits of immediate ART initiation, yet this approach is not widely implemented. Research findings suggest that starting ART in the hospital is beneficial for increasing linkage to HIV care and frequency of visits for PLWH and SUD. Implementation research should address barriers to early ART initiation in the hospital.

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel.

Importance: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. Objective: To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. Evidence Review: New evidence was collected since the previous International Antiviral (formerly AIDS) Society-USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. Findings: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. Conclusion and Relevance: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

Core Elements of a National COVID-19 Strategy: Lessons Learned from the US National HIV/AIDS Strategy.

COVID-19 has caused devastating health consequences and social inequities globally and in the United States. Unfortunately, the US has not developed a comprehensive National COVID-19 Strategy. In this editorial, we briefly review lessons about the development, structure, implementation and evaluation of the National HIV/AIDS Strategy (NHAS) for the US, and use these lessons to inform an initial proposal for a timely, dynamic, evidence-based, participatory, comprehensive and impactful National COVID-19 Strategy. Without such a strategy, the national response to the COVID-19 pandemic will remain uneven across jurisdictions and less than optimally impactful on disease-related mortality, short- and long-term morbidity, and health and social inequities.

Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial.

AIMS: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. METHODS AND RESULTS: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50-100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment-emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to -1.0%, P < 0.05) and circumferential strain (up to -3.3%, P < 0.01), decreased LA minimal volume index (up to -2.4 mL/m2 , P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo. CONCLUSIONS: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre-clinical findings of direct activation of LA contractility.