Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Embryonic Expression of the Gax Homeodomain Protein in Cardiac, Smooth, and Skeletal Muscle

11 páginas, 7 figuras.-- et al.Abstract Gax is a homeobox-containing gene that has been detected in adult cardiovascular tissues and exhibits a growth arrest–specific pattern of expression in cultured vascular myocytes. To study the regulation of gax during development, we performed immunohistochemistry and in situ hybridization on mouse embryos. Gax was present in mesodermally and, as with other homeobox genes, neuroectodermally derived tissues. Early mesodermal protein expression was limited to the lateral plate and somitic mesoderm. Gax in the cardiac muscle lineage exhibited a biphasic pattern of expression. Expression was prominent in the heart tube of the earliest cardiomyocytes and remained prominent through the looping stage (day 12.5 post coitum [pc]) but fell below the threshold of detection in atria and ventricles by day 13.5 pc. At day 15.5 pc, Gax protein was again detectable but restricted to cells within the compact layer of the ventricular myocardium. Gax expression was also noted in smooth muscle cells as early as day 9.5 pc. In the skeletal muscle lineage, Gax protein was expressed at the onset of somitogenesis before the expression of the myogenic basic helix-loop-helix and MEF2/RSRF family proteins. Subsequently, it was noted at day 9.5 pc in premyogenic cells migrating into head, trunk, and limb buds. Gax was detected in myotomes, premuscle masses, and mature muscle groups. These data suggest an important developmental role for Gax in all muscle lineages.This study was supported by National Institutes of Health grants AR-40197 and HL-50692 to Dr Walsh and HL-02824 and HL-53354 to Dr Isner and by grants from the Muscular Dystrophy Association and the American Heart Association of Wisconsin to Dr Lyons.Peer reviewe

Five-Year Cardiovascular Outcomes after Infective Endocarditis in Patients with versus without Drug Use History

Background: Disparities in treatment and outcomes of infective endocarditis (IE) between people who use drugs (PWUD) and non-PWUD have been reported, but long-term data on cardiovascular and cerebrovascular outcomes are limited. We aim to compare 5-year rates of mortality, cardiovascular and cerebrovascular events after IE between PWUD and non-PWUD. Methods: Using data from the TriNetX Research Network, we examined 5-year cumulative incidence of mortality, myocardial infarction, heart failure, atrial fibrillation/flutter, ventricular tachyarrhythmias, ischemic stroke, and intracranial hemorrhage in 7132 PWUD and 7132 propensity score-matched non-PWUD patients after a first episode of IE. We used the Kaplan–Meier estimate for incidence and Cox proportional hazards models to estimate relative risk. Results: Matched PWUD were 41 ± 12 years old; 52.2% men; 70.4% White, 19.8% Black, and 8.0% Hispanic. PWUD had higher mortality vs. non-PWUD after 1 year (1–3 year: 9.2% vs. 7.5%, p = 0.032; and 3–5-year: 7.3% vs. 5.1%, p = 0.020), which was largely driven by higher mortality among female patients. PWUD also had higher rates of myocardial infarction (10.0% vs. 7.0%, p < 0.001), heart failure (19.3% vs. 15.2%, p = 0.002), ischemic stroke (8.3% vs. 6.3%, p = 0.001), and intracranial hemorrhage (4.1% vs. 2.8%, p = 0.009) compared to non-PWUD. Among surgically treated PWUD, interventions on the tricuspid valve were more common; however, rates of all outcomes were comparable to non-PWUD. Conclusions: PWUD had higher 5-year incidence of cardiovascular and cerebrovascular events after IE compared to non-PWUD patients. Prospective investigation into the causes of these disparities and potential harm reduction efforts are needed

Cardiac Magnetic Resonance Imaging of COVID-19-Associated Cardiac Sequelae: A Systematic Review

Background: Many COVID-19 survivors experience persistent COVID-19 related cardiac abnormalities weeks to months after recovery from acute SARS-CoV-2 infection. Non-invasive cardiac magnetic resonance (CMR) imaging is an important tool of choice for clinical diagnosis of cardiac dysfunctions. In this systematic review, we analyzed the CMR findings and biomarkers of COVID-19 related cardiac sequela after SARS-CoV-2 infection. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we conducted a systematic review of studies that assessed COVID-19 related cardiac abnormalities using cardiovascular magnetic resonance imaging. A total of 21 cross-sectional, case-control, and cohort studies were included in the analyses. Results: Ten studies reported CMR results 3 months after SARS-CoV-2 infection. Abnormal T1, abnormal T2, elevated extracellular volume, late gadolinium enhancement and myocarditis was reported less frequently in the >3-month studies. Eight studies reported an association between biomarkers and CMR findings. Elevated troponin was associated with CMR pathology in 5/6 studies, C-reactive protein in 3/5 studies, N-terminal pro-brain natriuretic peptide in 1/2 studies, and lactate dehydrogenase and D-dimer in a single study. The rate of myocarditis via CMR was 18% (154/868) across all studies. Most SARS-CoV-2 associated CMR abnormalities resolved over time. Conclusions: There were CMR abnormalities associated with SARS-CoV-2 infection and most abnormalities resolved over time. A panel of cardiac injury and inflammatory biomarkers could be useful in identifying patients who are likely to present with abnormal CMR pathology after COVID-19. Multiple mechanisms are likely responsible for COVID-19 induced cardiac abnormalities

Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study

BACKGROUND: Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension. METHODS AND FINDINGS: This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort. CONCLUSION: In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials