Adrenergic Polymorphisms and Survival in African Americans With Heart Failure: Results From A-HeFT

Johnson, Amber; Hanley-Yanez, Karen; Yancy, Clyde W.; Taylor, Anne L.; Feldman, Arthur M.; McNamara, Dennis M.

doi:10.1016/j.cardfail.2019.04.007

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…Indeed, as demonstrated by Ligget et al [ 104 ], while Leu41 carriers survived better than those presenting Gln41 variants, they exhibited a reduced response to β-blockers such as atenolol [ 107 ]. Conversely, another study among African Americans by Johnson et al [ 108 ] demonstrated that Leu41 negatively impacted on the survival of HF patients, but these effects seemed to be stabilized upon β-blocker usage. Together, these studies suggest the importance of patients’ genetic background and ethnicity, and how this drives the proper response to β-blocker therapy.…”

Section: Targeting β-Ar Signaling In Cardiovascular Disease: Grks Inh...mentioning

confidence: 99%

Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases

Liccardo

Arosio

Corbi

et al. 2022

JCM

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Sex differences in cardiovascular disease (CVD) are often recognized from experimental and clinical studies examining the prevalence, manifestations, and response to therapies. Compared to age-matched men, women tend to have reduced CV risk and a better prognosis in the premenopausal period. However, with menopause, this risk increases exponentially, surpassing that of men. Although several mechanisms have been provided, including sex hormones, an emerging role in these sex differences has been suggested for β-adrenergic receptor (β-AR) signaling. Importantly, β-ARs are the most important G protein-coupled receptors (GPCRs), expressed in almost all the cell types of the CV system, and involved in physiological and pathophysiological processes. Consistent with their role, for decades, βARs have been considered the first targets for rational drug design to fight CVDs. Of note, β-ARs are seemingly associated with different CV outcomes in females compared with males. In addition, even if there is a critical inverse correlation between β-AR responsiveness and aging, it has been reported that gender is crucially involved in this age-related effect. This review will discuss how β-ARs impact the CV risk and response to anti-CVD therapies, also concerning sex and age. Further, we will explore how estrogens impact β-AR signaling in women.

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Section: Targeting β-Ar Signaling In Cardiovascular Disease: Grks Inh...mentioning

confidence: 99%

Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases

Liccardo

Arosio

Corbi

et al. 2022

JCM

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“…In these patients, we found 50% less cGMP in the carriers of the T117S variant than the noncarriers (WT CYB5R3 form) ( Figure 8H ). We next extended these studies with a meta-analysis to determine the association of CYB5R3 T117S with event-free survival in self-identified Black individuals from the Genetic Risk Assessment of Heart Failure (GRAHF) study in African Americans, a genetic substudy of the African American Heart Failure Trial (AHeFT) (ClinicalTrials.gov NCT00047775) ( 41 , 42 ), and the Genetic Risk Assessment of Cardiac Events (GRACE) study, a single-center genetic outcomes registry from the University of Pittsburgh Medical Center ( 43 , 44 ). For the combined outcome analysis, subjects receiving fixed dose combination therapy of isosorbide dinitrate and hydralazine (FDC I/H) were excluded.…”

Section: Resultsmentioning

confidence: 99%

“…For analysis of the impact of the T117S genotype on clinical outcomes in chronic HFrEF, participants from 2 prospective genetic outcomes studies were combined. The GRAHF cohort was a genetic substudy of the AHeFT trial (ClinicalTrials.gov NCT00047775) ( 41 , 42 ). AHeFT was a placebo-controlled randomized trial of FDC I/H specifically in self-identified African Americans with chronic HFrEF.…”

Section: Methodsmentioning

confidence: 99%

Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death

Carew¹,

Schmidt²,

Yuan³

et al. 2022

Journal of Clinical Investigation

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Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.

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“…Variability in response to BBs among HF patients may, in part, be explained by interindividual genetic variability ( 8 , 9 ). Examples of such variations are the single nucleotide polymorphisms (SNPs) in beta-adrenergic signaling genes, such as ADRB1 and ADRB2 , which encode for the β 1 - adrenergic receptor (AR) and β 2 – AR, respectively.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers

Guerra

Lteif

Arwood³

et al. 2021

Pharmacogenomics J

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Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions ( P int = 0.043 and P int = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.

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Adrenergic Polymorphisms and Survival in African Americans With Heart Failure: Results From A-HeFT

Cited by 4 publications

References 31 publications

Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases

Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases

Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers

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