Ser49Gly Beta1-Adrenergic Receptor Genetic Polymorphism as a Death Predictor in Brazilian Patients with Heart Failure

Albuquerque, Felipe Neves de; Brandão, Andrea Araujo; Silva, Dayse Aparecida; Rocha, Ricardo Mourilhe; Bittencourt, Marcelo Imbroinise; Sales, Ana Luiza Ferreira; Spineti, Pedro Pimenta de Mello; Duque, Gustavo Salgado; Azevedo, Lucas Rangel de Souza; Pozzan, Roberto; Tura, Bernardo Rangel; Albuquerque, Denilson Campos de

doi:10.36660/abc.20190187

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Original Article • Arq. Bras. Cardiol. 114 (4) • Apr 2020 • https://doi.org/10.36660/abc.20190187 linkcopy

Ser49Gly Beta1-Adrenergic Receptor Genetic Polymorphism as a Death Predictor in Brazilian Patients with Heart Failure

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background The role of Ser49Gly beta1-adrenergic receptor genetic polymorphism (ADBR1-GP-Ser49Gly) as a predictor of death in heart failure (HF) is not established for the Brazilian population.

Objectives To evaluate the association between ADBR1-GP-Ser49Gly and clinical outcomes in individuals with HF with reduced ejection fraction.

Methods Secondary analysis of medical records of 178 patients and genotypes of GPRβ1-Ser49Gly variants, classified as Ser-Ser, Ser-Gly and Gly-Gly. To evaluate their association with clinical outcome. A significance level of 5% was adopted.

Results Cohort means were: clinical follow-up 6.7 years, age 63.5 years, 64.6% of men and 55.1% of whites. HF etiologies were predominantly ischemic (31.5%), idiopathic (23.6%) and hypertensive (15.7%). The genetic profile was distributed as follows: 122 Ser-Ser (68.5%), 52 Ser-Gly (28.7%) and 5 Gly-Gly (2.8%). There was a significant association between these genotypes and mean NYHA functional class at the end of follow-up (p = 0.014) with Gly-Gly being associated with less advanced NYHA. In relation to the clinical outcomes, there was a significant association (p = 0.026) between mortality and GPRβ1-Ser49Gly: the number of deaths in patients with Ser-Gly (12) or Gly-Gly (1) was lower than in those with Ser-Ser (54). The Gly allele had an independent protective effect maintained after multivariate analysis and was associated with a reduction of 63% in the risk of death (p = 0.03; Odds Ratio 0.37 – CI 0.15–0.91).

Conclusion The presence of β1-AR-GP Gly-Gly was associated with better clinical outcome evaluated by NYHA functional class and was a predictor of lower risk of mortality, regardless of other factors, in a 6.7-year of follow-up. (Arq Bras Cardiol. 2020; 114(4):613-615)

Heart Failure/mortality; Epidemiology; Polymorfism, Geetic; Receptors,Adreneic, beta; cardiovascular Dieases; Hospitalization; Epinephrine/therapeutic use; Cardiotoxicity

Clinical Variable*		Total	Ser49Gly β1 Genetic Polymorphism

			Ser-Ser (n = 122)	Ser-Gly (n = 51)	Gly-Gly (n = 5)	p
Men n %		113 (63.5%)	79 (64.8%)	31 (60.8%)	3 (60.0%)	0.873
Follow-up (years)		6.7 ± 4.4
Duration of HF (months)		8.9 ± 6.1
Age (years)		64.4 ± 12.8
Skin Color	White	98 (55.1%)	76 (62.3%)	22 (43.1%)	0 (0.0%)	0.003
	Black	28 (15.7%)	20 (16.4%)	6 (11.8%)	2 (40.0%)
	Other	52 (29.2%)	26 (24.3%)	23 (45.1%)	3 (60.0%)
Etiology	CAD	56 (31.5%)	43 (35.2%)	12 (23.5%)	1 (20.0%)	0.093
	Idiopathic	42 (23.6%)	27 (22.1%)	13 (25.5%)	2 (40.0%)
	Hypert	28 (15.7%)	13 (10.7%)	13 (25.5%)	2 (40.0%)
	Alcohol	19 (10.7%)	12 (9.8%)	7 (13.7%)	0 (0.0%)
	Other	33 (18.5%)	27 (22.1%)	6 (11.8%)	0 (0.0%)
Baseline NYHA^†	I	47 (26.6%)	36 (29.8%)	9 (17.6%)	2 (40.0%)	0.334
	II	70 (39.5%)	50 (41.3%)	19 (37.3%)	1 (20.0%)
	III	47 (26.6%)	28 (23.1%)	17 (33.3%)	2 (40.0%)
	IV	13 (7.3%)	7 (5.8%)	6 (11.8%)	0 (0.0%)
	Mean	2.15 ± 0.9	2.05 ± 0.9	2.39 ± 0.9	2.0 ± 1.0	0.068
Baseline LVEF (%)		34.8 ± 10.7	35.3 ± 11.2	33.5 ± 8.1	37.4 ± 2.1	0.54
Hypert	n %	134 (75.7%)	88 (72.7%)	42 (82.4%)	4 (80.0%)	0.395
DM	n %	60 (33.7%)	39 (32.0%)	19 (37.3%)	2 (40.0%)	0.763
AF	n %	41 (24.0%)	29 (24.8%)	12 (24.5%)	0 (0.0%)	0.492
Lab	Hemoglobin (mg/dL)	13.2 ± 1.9	13.2 ± 2.0	13.1 ± 1.7	13.8 ± 2.2	0.734
	Sodium (mEq/L)	139.8 ± 3.4	139.9 ± 3.4	139.8 ± 3.3	139.0 ± 4.6	0.843
	Potassium (mEq/L)	4.47 ± 0.7	4.46 ± 0.7	4.52 ± 0.6	4.38 ± 0.5	0.836
	Creatinine (mg/dL)	1.41 ± 1.0	1.50 ± 1.1	1.23 ± 0.5	1.06 ± 0.2	0.199
Treatment	BB n %	173 (97.2%)	118 (96.7%)	50 (98.0%)	5 (100.0%)	0.828
	ACEI n %	79 (44.4%)	52 (42.6%)	23 (45.1%)	4 (80.0%)	0.255
	ARB n %	54 (30.3%)	37 (30.3%)	16 (31.4%)	1 (20.0%)	0.87
	Spiro n %	83 (46.6%)	52 (42.6%)	27 (52.9%)	4 (80.0%)	0.147
	Digox n %	47 (26.4%)	30 (24.6%)	15 (29.4%)	2 (40.0%)	0.631
	Low adherence n %	81 (46.0%)	52 (43.0%)	27 (54.0%)	2 (40.0%)	0.405
	Furosemide (dose-mg)	90.8 ± 64.3	97.3 ± 66.8	81.0 ± 59.8	55.0 ± 30.0	0.22

Clinical Variable^*		Total	Ser49Gly β1 Genetic Polymorphism

			Ser-Ser (n = 122)	Ser-Gly (n = 51)	Gly-Gly (n = 5)	p
Final NYHA	I	68	42	24	2	0.014
	I	38.2%	34.4%	47.1%	40.0%
	II	57	45	9	3
	II	32.0%	36.9%	17.6%	60.0%
	III	35	19	16	0
	III	19.7%	15.6%	31.4%	0.0%
	IV	18	16	2	0
	IV	10.1%	13.1%	3.9%	0.0%
	Mean	2.02 ± 1.0	2.07 ± 1.0	1.92 ± 1.0	1.6 ± 0.5	0.420
Final LVEF (%)		35.4 ± 13.3	35.1 ± 13.2	35.8 ± 13.4	39.6 ± 16.2	0.751
Hospital admission	n	74	54	18	2	0.55
Hospital admission	%	41.6%	44.3%	35.3%	40.0%
Death	n	67	54	12	1	0.026
Death	%	37.6%	44.3%	23.5%	20.0%
Hospital admission + Death	n	100	74	24	2	0.197
Hospital admission + Death	%	56.2%	60.7%	47.1%	40.0%

Variable	p	Odds ratio
Copy of Gly allele	0.030	0.37 (0.15–0.91)
Final NYHA	0.002	2.14 (1.32–3.45)
Final LVEF	0.002	0.94 (0.91–0.98)
Creatinine	0.051	1.52 (1.00–2.31)
Low adherence	0.346	1.50 (0.65–3.46))
Final HR	0.124	1.03 (0.99–1.07)

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[TFN1001] *Numerical variables are expressed as mean ± standard deviation; categorical variables expressed as [n e (%)]. Follow-up: follow-up time (in years); duration of HF: duration of disease course since the date of diagnosis (in years); CAD: Coronary Artery Disease; Hypert: Systemic Arterial Hypertension; NYHA: New York Heart Association Functional Class; LVEF: Left Ventricular Ejection Fraction; DM: Diabetes Mellitus; AF: Atrial Fibrillation; LBBB: Left Bundle Branch Block; Hb: Hemoglobin (in mg/dL); BB: Betablocker; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; Spiro: Spironolactone; Digox: Digoxin.^†Baseline NYHA class data were not available for 1 patient from the Ser-Ser group.