Publications
Documents & Other Announcements
Results:
107
Haplotype Targeting in Heart Failure Using a Biased Ligand β-blocker
Carroll, IA et al.
Sep 11, 2025
In the BEST pharmacogenetic substudy and in the GENETIC-AF trial ADRB1 (β1-adrenergic receptor) and ADRB2 (β2-AR) internalizing and internalization-resistant haplotypes affected heart failure (HF) and atrial fibrillation (AF) endpoints. Internalizing (ADRB1 Arg389Gly49, ADRB2 Gln27Arg16) haplotypes exhibited benefit with placebo treatment, while non-internalizing (ADRB1 Arg or Gly389Ser49, ADRB2 Gln27Gly16 or Glu27Gly16) haplotypes had enhanced treatment effects with bucindolol. The mechanism for efficacy enhancement of bucindolol in heart failure patients with the more prevalent, internalization-resistant haplotypes is presumably its biased ligand property, which was shown to activate the cardioprotective MAP kinase ERK1/2 pathway, either by internalizing resistant receptors or through internalization-independent phosphorylation of ERK1/2. Targeting internalization-resistant haplotypes produced an increase in therapeutic effectiveness that was equivalent to and additive with that conveyed by targeting ADRB1 Arg389 homozygotes. The result of adding internalization-resistant β1- and β2-AR haplotypes to β1 Arg389 pharmacogenetic targeting increases the percent of the population eligible for enhanced effects from 49 to 65%, and in certain subgroups increases treatment effects by 100% in comparison to no pharmacogenetic targeting.
Symptoms Burden as a Clinical Outcomes Assessment in Heart Failure Patients with Atrial Fibrillation
Carroll, IA et al.
Apr 13, 2025
Development and validation of a new primary endpoint for AF/HF clinical trials, Symptoms Burden of AF (SxBAF), which is 2-3x more efficient than time to first symptomatic event (thereby allowing for smaller sample sizes) and suited for efficacy detection with interventions that have long term AF prevention effects.
Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development
Müller-Calleja, N et al.
Mar 21, 2024
Lipid reactive aPLs recognize and bind to cell surface expressed endothelial protein C receptor, leading to complement activation tissue factor (TF) dependent proinflammatory signaling and thrombosis. In mice Inhibition of the TF coagulation initiation complex with rNAPc) prevented the prothrombotic effects of aPL derived from patients with COVID-19 and the aPL-induced proinflammatory and prothrombotic activation of monocytes.
An extensive β1-adrenergic receptor gene signaling regulates remodeling in dilated cardiomyopathies
Tatman, PD et al.
Aug 22, 2023
Gene expression data from transgenic mice overexpressing variants of β1-Ars were analyzed in concert with the gene expression effects of b-blockers on human HFrEF reverse remodeling. β1-AR signaling is connected to a large (N=430 genes) gene signaling network associated with forward and reverse ventricular remodeling, with major ontologic categories of genes identified.
Novel Tissue Factor Inhibition for Thromboprophylaxis in COVID-19: Primary Results of the ASPEN-COVID-19 Trial
Hess, CN et al.
Jun 29, 2023
Final results of the ASPEN trial, stopped at the end of Phase 2B for the need to make major design changes. Nonsignificant trends in favor of rNAPc2 on D-dimer levels were noted in both mild and severe COVID-19 patients, as well as numerically fewer thrombotic events (6 in rNAPc2, 9 in heparin). There were no safety issues. After analysis of the data sponsor and lead investigators were in discussions to design a trial comparing the combination of heparin and rNAPc2 to heparin alone, but these plans were abandoned on cessation of the pandemic.
Atrial Fibrillation and Heart Failure: Too Much Talk and Not Enough Action
Piccini, JP et al.
Apr 9, 2023
This is an editorial on Inciardi et al (https://doi:10.1016/j.jacep.2022.11.032) on HF phenotypes in the ENGAGE-AF TIMI trial, showing overall how HF adversely affected outcomes in AF patients. The author points out out that this is not new information, and investigators need to start doing something about AF/HF rather that writing descriptive papers on adverse outcomes.
Peripheral blood mononuclear cell tissue factor (F3 gene) transcript levels and circulating extracellular vesicles are elevated in severe coronavirus 2019 (COVID-19) disease
Girard, TJ et al.
Mar 1, 2023
In COVID-19 patients, tissue factor (Factor3, F3) transcript levels in circulating monocytes were increased by 5.2 fold and D-dimer levels were elevated.
Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination
Altman. NL et al.
Feb 8, 2023
This is an AHA and NIAID funded study investigating myocardial injury due to COVID-19 infection or mRNA vaccination for Covid. In the 7 Covid -19 and 4 mRNA vaccination patients investigated evidence of S (Spike protein) induced changes in gene expression were found, with a downregulation in mRNAs for ACE2, AGTR1 and the ACE2 co-receptor ITGA5, with upregulation in ACE. In both cohorts tissue factors were also upregulated and may have contributed to evidence of microthrombosis noted in myocardial biopsies of some patients in both groups.
Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure
Garlapati, V et al.
Dec 22, 2022
In myocardial infarction tissue factor activates the protease-activated receptor 2 (PAR-2) pathway in myeloid (immune) cells to activate the pro-fibrotic mediator TGF-β1, which increases fibrosis. In a mouse animal model of MI rNAPc2 prevented post MI fibrosis.
Rationale and design of a study to assess the safety and efficacy of rNAPc2 in COVID-19: the Phase 2b ASPEN-COVID-19 trial
Hess, CN et al.
Apr 1, 2022
Protocol paper for the ASPEN Trial, a comparison of the tissue factor inhibitor rNAPc2 to heparin (unfractionated or low molecular weight, formulation and dose according to local/site protocol) in patients newly diagnosed and hospitalized with COVID-19 infection who had an elevated D-dimer level; primary endpoint is D-dimer change from baseline to day8 or discharge. The trial is designed as a seamless Phase 2-3 trial, with a decision to convert to Phase 3 dependent on the outcome in approximately 160 randomized subjects.
Diagnosis-to-ablation time predicts recurrent atrial fibrillation and rehospitalization following catheter ablation
Chew, DS et al.
Feb 1, 2022
Duration of AF negatively influencing durability of successful catheter ablation was extensively demonstrated. Therefore, the therapeutic phenotypes of long AF and HF disease duration being refractory to therapy first demonstrated in the GENETIC-AF trial was also detected in catheter ablation.
Identification and characterization of an atypical Gαs-biased β2AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis
Kim, D et al.
Dec 2, 2021
Compound screening (40M library) for biased ligands that generate camp without engaging β-arrestin and producing desensitization identified a compound (“C1-S”) that generated cAMP on occupancy of human β2-ARs, without activating β-arrestin. Compared to albuterol C1-S did not produce desensitization and maintained smooth muscle relaxation on prolonged incubation.
Bucindolol Decreases Atrial Fibrillation Burden in Patients With Heart Failure and the ADRB1 Arg389Arg Genotype
Piccini, JP et al.
Jul 16, 2021
In a 69 patient substudy of GENETIC-AF atrial fibrillation burden measured by implanted devices was reduced by bucindolol compared to metoprolol succinate, by 36% (P=0.002) throughout the entire trial and by 55% (P <0.001) at the 180 day end of the trial. In the entire 257 patient efficacy cohort bucindolol reduced the use of therapeutic rhythm control interventions interventions (electrocardioversions, amiodarone or dofetilide administration, catheter ablation)by 32% (P=0.01). Also in the entire cohort the number of normal sinus rhythm ECGs was increased by 39% (P<0.001).
Patients With COVID-19 Have Elevated Levels of Circulating Extracellular Vesicle Tissue Factor Activity That Is Associated With Severity and Mortality—Brief Report
Rosell, A et al.
Dec 3, 2020
Extracellular vesicle tissue factor measured in 100 COVID-19 patients compared to controls revealed TF activity correlated with disease severity and D-dimer levels.
Bucindolol for the maintenance of sinus rhythm in a genotype-defined HF population
Piccini, JP et al.
Jul 1, 2019
GENETIC-AF trial, a bucindolol vs. metoprolol succinate Phase 2-3 seamless-design trial in ADRB1 Arg389Arg genotype Class I-III heart LVEF <0.50 patients with a history of symptomatic paroxysmal or <12 mos persistent AF in the past 6 months, with electrical cardioversion at the beginning of efficacy follow-up for subjects in AF. The primary endpoint was time to first symptomatic AF, atrial flutter or all-cause mortality (AF/AFL/ACM). The trial was stopped at midpoint based on a low Bayesian probability of success, with 267 patients having completed the 180 day follow-up period. By intention to treat the trial was neutral on the primary endpoint (HzR 1.01 (0.71, 1.42). However, a preplanned statistical analysis of variables associated with the primary endpoint that also interacted with therapy identified 2 entry criteria that predicted adverse outcomes (duration of AF or HF >12 years, AF presenting >2 years prior to HF presenting; total of 26% of the randomized population). On removal of patients with these characteristics the HzR in 196 subjects was 0.54 (0.33, 0.87) P=0.01). Entry criteria for the planned Phase 3 trial will exclude these 2 factors.
Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes
Parikh, KS et al.
Aug 13, 2018
At therapeutic doses (“high dose”) bucindolol in the BEST pharmacogenetic substudy exhibited marked differentiation of efficacy for decreasing all-cause mortality in subjects with an ADRB1 Arg389Arg genotype vs. Gly389 carriers, whereas all other β-blockers (from the ACTION-HF pharmacogenetics substudy, 58% carvedilol, 38% metoprolol) did not.
A Genotype-directed comparative Effectiveness TrIal of bucindolol and Toprol-XL for prevention of symptomatic Atrial Fibrillation/Atrial Flutter in patients with heart failure: Rationale and design of the GENETIC-AF Trial
Piccini, JP et al.
May 1, 2018
Rationale and design of the GENETIC-AF trial, emphasizing the need for better drug treatment in atrial fibrillation/heart failure, as well as the need for precision therapy.
Re-examination of the BEST Trial Using Composite Outcomes, Including Emergency Eepartment Visits
Shen, L et al.
Aug 5, 2017
In a re-analysis of BEST using the now standard primary endpoint of time to cardiovascular mortality or heart failure hospitalization (CVM/HFH) plus emergency department visits for worsening heart failure, bucindolol reduced this endpoint by 19% ((P <0.001) and the CVM/HFH endpoint by 20% (P <0.001).
Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis
Kotecha, D et al.
Dec 20, 2014
This is a per subject meta-analysis across 9 HF and one post-MI beta-blocker vs. placebo trial, primary endpoint of all-cause mortality in patients randomized in AF or sinus rhythm. For patients entering the trial in AF, of the 9 trials with enough evaluable events the lowest hazard ratio was for bucindolol in BEST (0.76 (0.54,1.06), compared to an overall HzR in all 10 trials of 0.85 (0.81, 1.12). The authors concluded that β-blockers do not reduce mortality in HF patients in permanent AF.
Race, Common Genetic Variation, and Therapeutic Response Disparities in Heart Failure
Taylor, MRG et al.
Dec 2, 2014
The marked African (AA)-vs. European-ancestry (EA) differences in common genetic variation within systems and heart failure drug targets is reviewed, highlighted by newly analyzed and reported data from the BEST Trial. For non-Blacks (95% were EA) bucindolol reduced the primary endpoint of all-cause mortality by 18% (hazard ratio 0.82 (0.70, 0.96), P=0.01), but in Blacks (23% of the randomized population) there was no benefit (HzR 1.17 (0.89, 1.53), P=0.27, interaction P vs. non-black= 0.02). This disparity was shown to be due to a higher prevalence of the ADRB1 Gly389 carrier genotype in AA, particularly in combination with ADRA2C Del carriers that had a 10 fold higher prevalence in AA, acting in concert with more advanced (Class IV) heart failure. In BEST within the same HF phenotype and the ADRB1 Arg389Arg genotype, bucindolol treatment effects vs. placebo were no different in AA vs. EA.
β-Adrenergic receptor-mediated transactivation of epidermal growth factor receptor decreases cardiomyocyte apoptosis through differential subcellular activation of ERK1/2 and Akt
Grisanti, LA et al.
Jul 1, 2014
In addition to ERK1/2 pathway of activation, Akt cardioprotective signaling is also promoted by β1-AR/EGFR signaling through internalized receptors.
Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation
Kao, DP et al.
Jan 27, 2014
For data in patients with permanent AF at entry into the BEST Trial (N=303), hazard ratios (HzRs) for all-cause mortality (ACM), ACM + HF hospitalization (HFH), and cardiovascular mortality + HFH were respectively 0.89 (0.60, 1.33), 0.82 (0.60, 1.11) and 0.80 (0.59, 1.09) compared to 0.87 (0.75, 1.02), 0.79 (0.70, 0.89) and 0.84 (0.75, 0.94) in subjects in sinus rhythm. In the largest number of events endpoint (ACM + HFH), subjects with AF and an ADRB1 Arg389Arg genotype (pharmacogenetic substudy) had a 77% reduction in event rate (P=0.038), compared to a 27% (P=0.039) reduction in subjects in sinus rhythm; patients with ADRB1 Gly389 genotypes had no reduction in ACM/HFH in either rhythm category. Unlike for other b-blockers with evaluable data, bucindolol’s effects in AF/HF are not different from SR/HF, with a strong pharmacogenetic pattern in both. In addition, bucindolol provided guideline defined rate control (ventricular rate ≤80 bpm) in 67% of the all-genotype cohort, and unlike carvedilol in the CIBIS-ELD study (see below, reference IIB2, Rau et al) bucindolol lowered HR more in AF subjects who had an ADRB1 Arg389Arg genotype (by 14.7 bpm) compared to Gly389 carrier patients (by 8.7 bpm), consistent with the favorable effect on Arg389 β1-ARs.
Prevention of Atrial Fibrillation by Bucindolol Is Dependent on the Beta-1 389 Arg/Gly Adrenergic Receptor Polymorphism
Aleong, RG et al.
Aug 1, 2013
Similar to the effect on AF, in subjects with an ADRB1 Arg389Arg genotype bucindolol reduced incident ventricular tachycardia or fibrillation (VT/VF) by 74% (P<0.0001), compared to by 40% (P = 0.09) in Gly389 carrier genotypes.