Predictors of Total Mortality and Serious Arrhythmic Events in Non-Ischemic Heart Failure Patients: The Role of Galectin-3

Kochi, Adriano Nunes; Pimentel, Mauricio; Andrades, Michael; Zimerman, Tiago; Zimerman, Leandro Ioschpe; Rohde, Luis Eduardo

doi:10.36660/abc.20200353

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Original Article • Arq. Bras. Cardiol. 117 (3) • Sept 2021 • https://doi.org/10.36660/abc.20200353 copy

Predictors of Total Mortality and Serious Arrhythmic Events in Non-Ischemic Heart Failure Patients: The Role of Galectin-3

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Risk stratification remains clinically challenging in patients with heart failure (HF) of non-ischemic etiology. Galectin-3 is a serum marker of fibrosis that might help in prognostication.

Objective:

To determine the role of galectin-3 as a predictor of major arrhythmic events and overall mortality.

Methods:

We conducted a prospective cohort study that enrolled 148 non-ischemic HF patients. All patients underwent a comprehensive baseline clinical and laboratory assessment, including levels of serum galectin-3. The primary outcome was the occurrence of arrhythmic syncope, appropriate implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, or sudden cardiac death. The secondary outcome was all-cause death. For all statistical tests, a two-tailed p-value<0.05 was considered significant.

Results:

In a median follow-up of 941 days, the primary and secondary outcomes occurred in 26 (17.5%) and 30 (20%) patients, respectively. Serum galectin-3>22.5 ng/mL (highest quartile) did not predict serious arrhythmic events (HR: 1.98, p=0.152). Independent predictors of the primary outcome were left ventricular end-diastolic diameter (LVEDD)>73mm (HR: 3.70, p=0.001), exercise periodic breathing (EPB) on cardiopulmonary exercise testing (HR: 2.67, p=0.01), and non-sustained ventricular tachycardia (NSVT)>8 beats on Holter monitoring (HR: 3.47, p=0.027). Predictors of all-cause death were galectin-3>22.5 ng/mL (HR: 3.69, p=0.001), LVEDD>73mm (HR: 3.35, p=0.003), EPB (HR: 3.06, p=0.006), and NSVT>8 beats (HR: 3.95, p=0.007). The absence of all risk predictors was associated with a 91.1% negative predictive value for the primary outcome and 96.6% for total mortality.

Conclusions:

In non-ischemic HF patients, elevated galectin-3 levels did not predict major arrhythmic events but were associated with total mortality. Absence of risk predictors revealed a prevalent subgroup of HF patients with an excellent prognosis.

Keywords:
Heart Failure; Arrhythmias Cardiacs; Galectin-3; Apoptosis; Defibrillators, Implantable; Death Sudden; Mortality

		All patients (n=148)	Upper quartile GAL-3>22.5 ng/mL (n=36)	Lower quartiles GAL-3≤22.5 ng/mL (n=112)	p-value
Age (years)		54.8±12.7	63±9.3	52.2±12.6	<0.001
Male gender (%)		88 (59.5)	20 (55.6)	68 (61.3)	0.54
NYHA class (%)
	I	63 (42.6)	11 (30.6)	51 (46)	0.12
	II	59 (39.9)	15 (41.7)	44 (40)
	III	26 (17.6)	10 (28.8)	16 (14.4)
	IV	0	0 (0)	0 (0)
Etiology (%)
	Idiopathic	67 (45.3)	13 (36.1)	54 (48.6)	0.38
	Hypertensive	25 (16.9)	7 (19.4)	18 (16.2)
	Alcoholic	18 (12.2)	4 (11.1)	14 (12.6)
	Chagas disease	7 (4.7)	3 (8.3)	4 (3.6)
	Valvular	4 (2.7)	2 (5.6)	2 (1.8)
	Other	27 (18.2)	7 (19.5)	19 (17.1)
Physical examination
SBP (mmHg)		119.3±21.6	122.6±22.5	118.1±21.3	0.28
DBP (mmHg)		74.7±12.7	74.6±13	74.8±12.8	0.95
Laboratory tests
Hemoglobin (g/dL)		13.4±1.6	12.6±1.9	13.6±1.4	0.008
Lymphocytes (/mm³)		2099.2±848	1825±787	2193±852	0.02
Creatinine (mg/dL)		1.1±0.73	1.6±1.1	1.0±0.4	0.002
Sodium (mEq/L)		140±2.8	140±2.9	140±2.8	0.86
Potassium (mEq/L)		4.6±0.4	4.6±0.4	4.6±0.3	0.82
Uric acid (mg/dL)		7.5±2.2	8.6±2.4	7.1±2.1	<0.001
Glucose (mg/dL)		118±49.6	117.5±40.3	118.4±52.6	0.92
Total cholesterol (mg/dL)		180.6±42.6	188.4±42.6	177.3±41	0.16
LDL (mg/dL)		104.7±37.2	110.5±37.6	102.3±36.8	0.26
Galectin-3 (ng/mL)		19±9.4	31.6±10.7	14.9±10.7	<0.001
BNP (pg/mL)		116.4 (59.7–295)	158 (77–289)	106.6 (53–298)	0.30
NT-proBNP (pg/mL)		1145 (392–2590)	4776 (1549–15852)	741 (314–2291)	0.005
Echocardiography
	LVEF (%)	27.4±7.5	27.3±7.6	27.4±7.5	0.97
	Left atrium (mm)	47.3±6.6	48.7±7	46.9±6.4	0.15
	LVEDD (mm)	67.5±10.2	65.3±7	68.2±11	0.13
	LVESD (mm)	58.7±10.1	56.6±8.5	59.4±10.6	0.15
EKG
Atrial fibrillation		22 (14.9)	8 (22)	14 (12.6)	0.16
LBBB		60 (40.8)	18 (50)	42 (37.8)	0.46
24-hour Holter monitoring
NSVT (%)		54 (36.5)	12 (33.3)	42 (38.5)	0.57
NSVT>8 beats		11 (7.4)	1 (8.3)	9 (21.4)	0.54
Cardiopulmonary exercise testing
Peak VO₂ (mL/kg/min)		18±5.1	14.7±4.3	19±4.9	<0.001
VE/VCO₂ slope		41.5±11.7	44.3±12.5	40.8±11.5	0.14
EPB (%)		26 (17.5)	3 (8.3)	23 (20.5)	0.14
EPS (%)
No induction		129 (87.2)	34 (94.4)	94 (84.7)	0.10
SMVT		10 (6.8)	0	10 (9)
SPVT		5 (3.4)	1 (2.8)	4 (3.6)
Ventricular fibrillation		3 (2)	0	3 (2.7)
HV interval (ms)		52.6±10.4	54.2±11.3	52.2±10.1	0.34
Medication
Beta-blocker (%)		144 (97.3)	36 (100)	107 (96.4)	0.57
ACEi or ARB (%)		144 (97.3)	32 (88.9)	111 (99.1)	0.003
Spironolactone (%)		103 (69.6)	21 (58.3)	82 (73.9)	0.07
Digoxin (%)		121 (81.8)	31 (86.1)	90 (81.1)	0.49
Antiarrhythmic drug (%)		8 (5.4)	1 (2.8)	7 (6.3)	0.41

	Univariate analysis			Multivariate analysis
	HR	95%CI	p	HR	95%CI	p
Galectin-3 (for each 1 ng/mL)	1.003	0.97–1.04	0.877
Galectin-3>22.5 ng/mL	1.13	0.47–2.70	0.787
Atrial fibrillation	1.86	0.75–4.60	0.182
LVEF<20%	0.69	0.21–2.30	0.691
LVEDD>73 mm	4.13	1.91–8.90	<0.001	3.70	1.69–8.1	0.001
Peak VO₂<14.2 mL/kg/min	1.69	0.75–3.90	0.203
VE/VCO₂ slope>48.4	2.32	1.05–5.10	0.037
EPB	3.37	1.52–7.40	0.030	2.67	1.19–6.0	0.017
HV interval>59 ms	2.23	1.01–4.90	0.047
NSVT>8 beats	3.27	1.11–9.70	0.030	3.47	1.15–10.5	0.027
Positive EPS	1.58	0.54–4.60	0.403
Elevated natriuretic peptides	2.75	1.26–6.01	0.011

	Univariate analysis			Multivariate analysis
	HR	95%CI	p	HR	95%CI	p
Galectin-3 (for each 1 ng/mL)	1.024	0.99–1.05	0.057
Galectin-3>22.5 ng/mL	2.20	1.07–4.50	0.033	3.69	1.7–8.19	0.001
Atrial fibrillation	0.98	0.34–2.80	0.980
LVEF (for each 1%)	0.96	0.91–1.01	0.098
LVEF<20%	1.40	0.57–3.40	0.461
LVEDD>73 mm	3.02	1.44–6.30	0.003	3.35	1.53–7.34	0.003
Peak VO₂ (mL/kg/min)	0.92	0.86–0.99	0.042
Peak VO₂<14.2 mL/kg/min	1.20	0.53–2.70	0.656
VE/VCO₂ slope>48.4	1.92	0.89–4.10	0.092
EPB	2.91	1.36–6.20	0.006	3.06	1.38–6.77	0.006
HV interval>59 ms	2.80	1.36–5.80	0.005	1.98	0.95–4.13	0.068
NSVT>8 beats	3.31	1.26–8.70	0.015	3.95	1.45–10.73	0.007
Positive EPS	0.95	0.29–3.10	0.993
Elevated natriuretic peptides	3.44	1.67–7.06	0.001

Primary outcome (major arrhythmic events)
	All patients (n=148)	With event (n=26)	PPV% (95%CI)	NPV% (95%CI)
LVEDD>73 mm	36	13	36.1 (24.9–49)	88.3 (83.7–91.8)
EPB	26	10	38.4 (24.2–54.9)	86.8 (82.9–90)
NSVT>8 beats	11	4	36.3 (15.2–64.4)	83.7 (81.2–85.9)
Absence of all three	90	8		91.1 (85.4–94.8)
Secondary outcome (total mortality)
	All patients (n=148)	With event (n=30)	PPV% (95%CI)	NPV% (95%CI)
GAL-3>22.5 ng/mL	36	13	36.1 (24.6–49.4)	84.8 (80.1–88.5)
LVEDD>73 mm	36	12	33.3 (22.1–46.8)	83.9 (79.3–87.6)
EPB	26	10	38.4 (24.3–55.2)	83.6 (79.6–86.9)
NSVT>8 beats	11	5	45.5 (21.4–71.8)	81.4 (78.8–83.8)
HV interval>59 ms	35	13	37.1 (25.3–50.7)	84.9 (80.3–88.6)
Absence of all five	55	2		96.3 (85.2–99.0)

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