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

Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration

AbstractThe notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin− c-kitPOS cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing ∼70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair

Abstract 429: The Failing Senescent Heart Contains a Pool of Functionally Competent Progenitor Cells

A critical question concerns whether myocardial aging affects uniformly all cardiac progenitor cells (CPCs) or a subset of functionally competent CPCs persists in the senescent heart suggesting that these cells may be activated to form new contracting myocardium. CPCs isolated from the heart of rats at 3, 12, 16 and 24 months were found to express IGF-1-IGF-1R, HGF-c-Met and the components of the renin-angiotensin system (RAS). Although mRNA for angiotensinogen and AT1-receptors decreased in old CPCs, the quantity of these proteins did not vary with aging. Renin mRNA increased at 12 and 16 months and returned to baseline at 24 months. Additionally, Ang II synthesis was 3-fold higher in old than in young CPCs and this difference persisted after ligand activation. Conversely, a decrease in IGF-1R, IGF-1 and HGF mRNA, and IGF-1R and c-Met proteins occurred in old CPCs. Baseline values for IGF-1 secretion were similar in young and old CPCs, but in response to ligand stimulation IGF-1 synthesis was 8-fold higher in young CPCs. HGF did not vary. Collectively, these results indicate that aging led to an increase in RAS function and a decrease in IGF-1-IGF-1R and HGF-c-Met function in CPCs. However, whether these aging effects involved the entire CPC pool remained unknown. Based on the expression of the senescence-associated protein p16 INK4a and telomere length, CPCs in the old heart consisted of two subsets: a large compartment of p16 INK4a -positive CPCs with short telomeres and a small pool of p16 INK4a -negative CPCs with long telomeres. CPCs expressing IGF-1-IGF-1R and HGF-c-Met were consistently negative for p16 INK4a while p16 INK4a was detected in CPCs positive for Ang II and AT1-receptors. Therefore, the ability of IGF-1 and HGF to induce CPC proliferation was attenuated but not abolished in old CPCs which also showed a modest 29% decrease in telomerase activity. Ang II stimulated apoptosis in both young and old CPCs but oxidative DNA damage was higher in old cells. Studies in vivo were then performed documenting that CPCs can be activated in the old heart by the local injection of growth factors. By this strategy, the senescent heart phenotype was partially corrected and the improvement in cardiac hemodynamics resulted in prolongation of maximum lifespan. </jats:p

Abstract 704: Cardiac Progenitor Cell Aging Is Responsible for Organ Aging

To establish whether the aging cardiomyopathy is dictated by depletion of the cardiac progenitor cell (CPC) pool and accumulation of old myocytes, we measured first the number of CPCs in rats at 4, 12, 20 and 28 months of age. CPCs are lineage-negative cells that express the stem cell antigens c-kit, MDR-1 and/or Sca-1. Unexpectedly, from 4 to 28 months, the number of CPCs in the heart increased ~3-fold. The increase in mitotic index of CPCs in the old heart indicated enhanced activation of CPCs which resulted in an increased number of myocyte progenitors and precursors and ultimately differentiated cardiomyocytes. These observations were at variance with the concomitant accumulation of p16 INK4a -positive-myocytes and the 6-fold increased rate of myocyte apoptosis in the senescent heart pointing to defects in the CPC compartment with aging. Activation and differentiation of old CPCs may generate a myocyte progeny that rapidly reaches senescence. To evaluate the biological age of CPCs, we measured two parameters of cellular aging: the senescence-associated protein p16 INK4a and telomere length. From 4 to 28 month, p16 INK4a -positive-CPCs increased from ~6% to ~81% resulting in a sharp decrease in the number of functionally-competent CPCs. Telomere length was measured by Q-FISH in cytospin preparations of c-kit-positive-cells collected from hearts at 3 and 27 months. In old hearts, the distribution of telomere length in CPCs, myocyte progenitors-precursors and developing myocytes was shifted to the left towards shorter telomeres. Average telomere length in old CPCs, myocyte progenitors-precursors and developing myocytes was 30%, 38% and 52% shorter than in the corresponding young cell populations, respectively. Importantly, 55% of old CPCs and 15% of young CPCs had telomeres less than 8 kbp and were p16 INK4a -positive. Thus, telomere attrition in CPCs with age leads to the generation of a myocyte progeny that rapidly acquires the senescent phenotype. However, nearly 16% of the old CPC pool had telomeres greater than 14 kbp pointing to a relevant growth reserve of the senescent myocardium. In conclusion, CPC aging with reduction in telomeric length dictates the formation of a senescent progeny which conditions organ aging and failure. </jats:p

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)