The Additional Prognostic Value of Ghrelin for Mortality and Readmission in Elderly Patients with Acute Heart Failure

Figures & data

Table 1 Baseline Characteristics of Elderly AHF Patients

Variables	No Events (N = 151)	Events (N = 90)	P value
General Characteristics
Age (year)	67.28 ± 13.27	70.78 ± 14.74	0.059
Male (N, %)	58 (38.4%)	36 (40.0%)	0.89
Smoking (N, %)	65 (43.0%)	38 (42.2%)	0.99
Alcohol (N, %)	24 (15.9%)	15 (16.7%)	0.86
Physical Exam
SBP (mmHg)	128.5 (114, 151)	128 (109, 145)	0.32
DBP (mmHg)	79 (69, 90)	74 (65, 85)	0.04
BMI (kg/m^2)	23.60 (20.68, 25.83)	21.68 (18.95, 25.31)	0.037
Heart rate (bpm)	88.5 (74, 104)	90 (80, 106)	0.18
RR (breaths/min)	20 (18, 22)	22 (20, 25)	<0.001
MNA-SF score	11 (8, 13)	9 (6, 12)	0.009
Laboratory data
ALT (U/L)	26 (18, 49)	27.5 (17, 50)	0.73
AST (U/L)	34 (21, 100)	35 (23, 66)	0.95
Albumin(g/L)	37 (34, 40)	36 (30, 39)	0.028
Prealbumin(mg/L)	177.7 (128.1, 207.0)	144.1 (104.1, 189.9)	0.025
Hemoglobin (g/L)	137 (118, 150)	126 (99, 145)	0.003
Creatinine (μmol/L)	82.5 (69, 116)	105.5 (82, 140)	<0.001
BUN (mmol/L)	6.5 (4.8, 8.4)	8.85 (6.0, 12.5)	<0.001
eGFR (mL/min)	74.37 (52.40, 100.85)	57.01 (40.12, 75.59)	<0.001
TG (mmol/L)	1.27 (0.99, 1.84)	1.19 (0.84, 1.63)	0.14
TC (mmol/L)	4.19 (3.57, 4.99)	3.75 (2.97, 4.73)	0.009
HDL-C (mmol/L)	1.02 ± 0.36	0.99 ± 0.37	0.51
LDL-C (mmol/L)	2.63 (2.16, 3.34)	2.19 (1.64, 3.03)	0.003
Instant blood glucose (mmol/L)	5.62 (4.78, 7.39)	5.42 (4.50, 6.86)	0.12
NT-proBNP (ng/mL)	3241 (1558, 7796)	8003 (2778, 15,136)	<0.001
Ghrelin (ng/mL)	0.97 (0.75, 1.20)	1.19 (1.07, 1.36)	<0.001
Serum sodium (mmol/L)	139 (136, 141)	137 (134, 140)	0.014
cTnI (ng/mL)	0.185 (0.03, 2.65)	0.13 (0.05, 0.96)	0.79
Echocardiographic data
LAD (cm)	4.07 (3.59, 4.59)	4.14 (3.43, 4.61)	0.90
LVEDD (cm)	5.04 ± 0.87	5.16 ± 1.05	0.46
LVEF (%)	53 (44, 58)	50.5 (40, 58)	0.43
Comorbidities
Hypertension (N, %)	93 (61.6%)	58 (64.4%)	0.68
Diabetes (N, %)	49 (32.5%)	30 (33.3%)	0.89
Dyslipidemia (N, %)	35 (23.2%)	16 (17.8%)	0.42
ASCVD (N, %)	52 (34.4%)	34 (37.8%)	0.68
CKD (N, %)	12 (7.9%)	13 (14.4%)	0.13
History of HF hospitalization (N, %)	54 (35.8%)	57 (63.3%)	<0.001
AHF stage
Bedside Clinical Classification (III~IV) (N, %)	83 (55.0%)	65 (72.2%)	0.009
AHF type
First occurrence (N, %)	61 (40.4%)	17 (18.9%)	<0.001
Decompensated CHF (N, %)	90 (59.6%)	73 (81.1%)	<0.001
AHF cause			0.35
CHD (N, %)	77 (51.0%)	42 (46.7%)
Hypertension (N, %)	25 (16.6%)	21 (23.3%)
DCM (N, %)	14 (9.3%)	12 (13.3%)
Valvular heart disease (N, %)	12 (7.9%)	3 (3.3%)
Others (N, %)	23 (15.2%)	12 (13.3%)

Note: Continuous variables were reported as mean ± deviation (SD) or median (upper and lower quartile), and categorical variables as percentages (%). P value < 0.05 is shown in bold type.

Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; RR, respiratory rate; MNA-SF, Mini Nutritional Assessment Short Form; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein protein cholesterol; cTnI, cardiac troponin I; LAD, left atrial dimension; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CHF, chronic heart failure; AHF, acute heart failure; CHD, coronary heart disease; DCM, dilated cardiomyopathy.

Figure 1 Association of ghrelin levels with (A) NT-proBNP levels and (B) MNA-SF scores.

Note: Pearson’s correlation analysis for the association of log ghrelin with log NT-proBNP levels (A), and log MNA-SF scores (B).
Abbreviation: MNA-SF, Mini Nutritional Assessment Short Form.

Figure 2 Association of NT-proBNP and ghrelin levels with acute heart failure events.

Note: Penalized cubic spline curves based on the Cox regression model (adjusted by age, sex, smoking status, BMI, RR, heart rate, SBP, DBP, hemoglobin, eGFR, bedside clinical classification, MNA-SF score, serum sodium, and history of HF hospitalization) were used to examine the association of log transformed NT-proBNP (A) and ghrelin (B) levels with AHF adverse events. Solid lines indicate lnHRs, and dashed lines indicate 95% confidence intervals (CI).

Table 2 C-Statistic Comparisons Between Models

Variables	ΔC-Statistics	SD	P value
Model 1 vs 2	0.0935	0.0296	0.0070
Model 1 vs 3	0.0378	0.0212	0.0744
Model 2 vs 4	0.0206	0.0102	0.0439
Model 3 vs 4	0.0763	0.0229	0.0009

Note: Model 1 (reference) included respiratory rate, eGFR, serum sodium, and history of HF hospitalization. Model 2, Model 1 + log NT-proBNP; Model 3, Model 1 + log ghrelin; Model 4, Model 1 + log NT-proBNP + log ghrelin. DeLong test was used to compare the C-statistics of each model.

Abbreviation: SD, standard deviation.

Table 3 Risk Reclassification with Ghrelin Addition

Predicted risk Reference model	Reference model + log ghrelin
	< 30%	≥ 30% to < 60%	≥ 60%	Total
Patients who did not experience AHF events
< 30%	84	11	0	95
≥ 30% to < 60%	17	30	4	51
≥ 60%	1	2	2	5
Total	102	43	6	151
Patients who experienced AHF events
< 30%	16	8	0	24
≥ 30% to < 60%	4	46	7	57
≥ 60%	0	1	8	9
Total	20	55	15	90
NRI (95% CI): 14.42% (2.25%, 26.6%), P = 0.02026; NRI (no events): 3.31%, NRI (events): 11.11%; IDI (95% CI): 5.64% (3.18%, 8.11%), P = 0.00001.

Notes: Reclassification tables are separated for absent AHF events and present AHF events, with rows indicating risk categories based on the reference model (RR, eGFR, serum sodium, and history of HF hospitalization). Columns indicate new risk stratifications after adding log ghrelin to the reference model, or reference model with log NT-proBNP. Green numbers reflect patients who changed risk category in a beneficial direction by adding log ghrelin, while blue numbers reflect patients reclassified in the inappropriate direction. Patients in grey boxes have the same predicted risk with both models. AHF events: composite events of all-cause mortality and/or readmissions due to HF.

Abbreviations: NRI, net reclassification index; IDI, integrated discrimination index; AHF, acute heart failure.

Table 4 Risk Reclassification with Dual Addition of NT-proBNP and Ghrelin

Predicted risk Reference model + log NT-proBNP	Reference model + log NT-proBNP + log ghrelin
	< 30%	≥ 30% to < 60%	≥ 60%	Total
Patients who did not experience AHF events
< 30%	114	5	0	119
≥ 30% to < 60%	6	15	2	23
≥ 60%	0	0	9	9
Total	120	20	11	151
Patients who experienced AHF events
< 30%	15	4	0	19
≥ 30% to < 60%	1	27	8	36
≥ 60%	0	1	34	35
Total	16	32	42	90
NRI (95% CI): 10.45% (1.34%, 19.56%), P value: 0.0246; NRI (no events): -0.0067%; NRI (events): 11.11%; IDI (95% CI): 3.60% (1.59%, 5.60%), P value = 0.00043.

Notes: Reclassification tables are separated for absent AHF events and present AHF events, with rows indicating risk categories based on the reference model (RR, eGFR, serum sodium, and history of HF hospitalization). Columns indicate new risk stratifications after adding log ghrelin to the reference model, or reference model with log NT-proBNP. Green numbers reflect patients who changed risk category in a beneficial direction by adding log ghrelin, while blue numbers reflect patients reclassified in the inappropriate direction. Patients in grey boxes have the same predicted risk with both models. AHF events: composite events of all-cause mortality and/or readmissions due to HF.

Abbreviations: NRI, net reclassification index; IDI, integrated discrimination index; AHF, acute heart failure.

Figure 3 ROC curves of each model for acute heart failure events.

Note: Model 1 (reference) includes RR, eGFR, serum sodium, and history of HF hospitalization; Model 2, Model 1 + log NT-proBNP; Model 3, Model 1 + log ghrelin; Model 4, Model 1 + log NT-proBNP + log ghrelin.

Figure 4 Kaplan–Meier curves of AHF event risks according to models with dual addition of log ghrelin and log NT-proBNP.

Note: AHF events: all-cause mortality and/or readmission due to heart failure.
Abbreviation: AHF, acute heart failure.

Figure 5 Kaplan–Meier curves of AHF events risk according to NT-proBNP and ghrelin levels.

Note: NT-proBNP median level: 3980ng/mL, ghrelin median level: 1.07ng/mL. AHF events: all-cause mortality and/or readmission due to heart failure. Cumulative event-free probability was compared by log rank test.
Abbreviation: AHF, acute heart failure.