Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://cr.elmerpub.com

Original Article

Volume 16, Number 1, February 2025, pages 44-52

Relationship Between Advanced Glycation End Products Tissue Accumulation and Frailty in Patients Undergoing Cardiac Rehabilitation

Figure 1. Flow diagram for enrolling patients. Phase II CR was performed on 1,000 consecutive patients with CVD. Of these, 48 patients were excluded as duplicate cases, and an additional 146 patients were not included because of insufficient SAF data. The final analysis included 806 patients. CR: cardiac rehabilitation; SAF: skin autofluorescence.

Figure 2. SAF level distribution. The SAF levels were 3.0 ± 0.6 a.u. for the mean and 2.9 a.u. for the median (interquartile range: 2.5 - 3.3 a.u.). The Shapiro-Wilk test of normality: P < 0.05. SAF: skin autofluorescence.

**Table 1.** The Comparison of Clinical Characteristics of Patients Between the High and Low SAF Groups
	Total (n = 806)	Low SAF (n = 368)	High SAF (n = 438)	P value
High SAF is defined as SAF levels ≥ 2.9. Frailty (1 - 20) is defined as ≥ 6 points of sub-total score of KCL. Frailty (1 - 25) is defined as ≥ 8 points of total score of KCL. Prefrailty (1 - 25) is defined as 4 - 7 points of total score of KCL. Data are shown as n (%), median (interquartile range), or mean value ± standard deviation. BMI: body mass index; CVD: cardiovascular disease; CR: cardiac rehabilitation; CHF: chronic heart failure; AMI: acute myocardial infarction; AP: angina pectoris; LVEF: left ventricle ejection fraction; eGFR: estimated glomerular filtration rate; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; SAF: skin autofluorescence; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; KCL: Kihon Checklist.
Basic characteristics
Age, years	67.0 ± 12.9	62.4 ± 13.7	70.9 ± 10.6	< 0.01
Male, n (%)	570 (70.7)	254 (69.0)	316 (72.2)	0.33
BMI, kg/m²	22.9 ± 3.8	22.7 ± 3.8	23.1 ± 3.7	0.10
Diabetes mellitus, n (%)	263 (32.6)	89 (24.2)	174 (39.7)	< 0.01
Hypertension, n (%)	505 (62.6)	218 (59.2)	287 (65.5)	0.07
Dyslipidemia, n (%)	400 (49.6)	172 (46.7)	228 (52.1)	0.13
Chronic kidney disease, n (%)	271 (33.6)	94 (25.6)	177 (40.4)	< 0.01
Atrial fibrillation, n (%)	141 (17.5)	81 (18.5)	60 (16.3)	0.42
Cancer, n (%)	104 (12.9)	43 (11.7)	61 (13.9)	0.34
Current smoking, n (%)	82 (10.2)	38 (10.4)	44 (10.1)	0.05
CVD at beginning of CR
CHF, n (%)	208 (25.8)	91 (24.7)	117 (26.7)	0.50
AMI, n (%)	55 (6.8)	24 (6.5)	31 (7.1)	0.75
AP, n (%)	30 (3.7)	11 (3.0)	19 (4.3)	0.31
Post open-heart surgery, n (%)	444 (55.1)	204 (55.5)	240 (54.8)	0.86
Aortic disease, n (%)	61 (7.7)	36 (9.8)	25 (5.7)	0.03
Peripheral artery disease, n (%)	8 (0.9)	2 (0.5)	6 (1.4)	0.23
Anthropometric data
Body fat percentage, %	22.7 ± 8.8	21.9 ± 8.6	23.4 ± 9.0	0.03
Lean body mass, kg	46.6 ± 9.6	47.1 ± 10.2	46.1 ± 9.1	0.13
Grip strength, kg	28.9 ± 9.0	29.8 ± 9.5	28.1 ± 8.4	0.06
Cardiac function indicator
LVEF, %	63 (52 - 70)	63 (53 - 70)	63 (52 - 69)	0.56
Laboratory data
Hemoglobin, g/dL	13.0 ± 1.9	13.4 ± 1.9	12.7 ± 1.9	< 0.01
Albumin, g/dL	3.9 ± 0.5	3.9 ± 0.5	3.8 ± 0.5	< 0.01
Creatinine, mg/dL	0.8 (0.7 - 1.0)	0.8 (0.6 - 0.9)	0.9 (0.7 - 1.1)	< 0.01
eGFR, mL/min/1.73m²	69.1 ± 26.9	75.3 ± 23.9	64.0 ± 28.2	< 0.01
TG, mg/dL	102 (74 - 139)	103 (73 - 145)	100 (76 - 132)	0.32
HDL-C, mg/dL	49.4 ± 15.5	49.5 ± 15.4	49.3 ± 15.6	0.85
LDL-C, mg/dL	99.9 ± 30.9	101.7 ± 31.9	98.4 ± 30.1	0.13
HbA1c, %	6.0 ± 0.9	5.9 ± 0.8	6.1 ± 1.0	< 0.01
BNP, pg/mL	88.2 (34.1 - 227.7)	71.6 (27.7 - 177.2)	100.1 (42.2 - 286.0)	< 0.01
SAF, a.u.	3.0 ± 0.6	2.4 ± 0.3	3.4 ± 0.5	< 0.01
Medication
Aspirin, n (%)	645 (80.2)	293 (79.8)	352 (80.6)	0.80
ACE-I/ARB, n (%)	267 (33.2)	115 (31.3)	152 (34.8)	0.30
β-blocker, n (%)	579 (72.0)	254 (69.2)	325 (74.4)	0.10
Calcium antagonist, n (%)	153 (19.0)	63 (17.2)	90 (20.6)	0.22
Loop diuretics, n (%)	601 (74.8)	277 (75.5)	324 (74.1)	0.66
Statin, n (%)	425 (52.9)	168 (45.8)	257 (58.8)	< 0.01
Oral hypoglycemic agent, n (%)	129 (16.0)	34 (9.3)	95 (21.7)	< 0.01
Insulin, n (%)	51 (6.3)	6 (1.6)	45 (10.3)	< 0.01
Frailty
Sub-total KCL score (1 - 20)	4.4 ± 3.3	4.2 ± 3.2	4.6 ± 3.3	0.05
Frailty (1 - 20), n (%)	260 (32.3)	108 (29.3)	152 (34.7)	0.11
Total KCL score (1 - 25)	5.9 ± 4.2	5.5 ± 4.1	6.2 ± 4.3	0.02
Frailty (1 - 25), n (%)	260 (32.3)	109 (29.6)	151 (34.5)	0.14
Prefrailty + frailty (1 - 25), n (%)	525 (65.1)	235 (63.9)	290 (66.2)	0.49

Table 1. The Comparison of Clinical Characteristics of Patients Between the High and Low SAF Groups

Total (n = 806)

Low SAF (n = 368)

High SAF (n = 438)

P value

High SAF is defined as SAF levels ≥ 2.9. Frailty (1 - 20) is defined as ≥ 6 points of sub-total score of KCL. Frailty (1 - 25) is defined as ≥ 8 points of total score of KCL. Prefrailty (1 - 25) is defined as 4 - 7 points of total score of KCL. Data are shown as n (%), median (interquartile range), or mean value ± standard deviation. BMI: body mass index; CVD: cardiovascular disease; CR: cardiac rehabilitation; CHF: chronic heart failure; AMI: acute myocardial infarction; AP: angina pectoris; LVEF: left ventricle ejection fraction; eGFR: estimated glomerular filtration rate; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; SAF: skin autofluorescence; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; KCL: Kihon Checklist.

Basic characteristics

Age, years

67.0 ± 12.9

62.4 ± 13.7

70.9 ± 10.6

< 0.01

Male, n (%)

570 (70.7)

254 (69.0)

316 (72.2)

0.33

BMI, kg/m²

22.9 ± 3.8

22.7 ± 3.8

23.1 ± 3.7

0.10

Diabetes mellitus, n (%)

263 (32.6)

89 (24.2)

174 (39.7)

< 0.01

Hypertension, n (%)

505 (62.6)

218 (59.2)

287 (65.5)

0.07

Dyslipidemia, n (%)

400 (49.6)

172 (46.7)

228 (52.1)

0.13

Chronic kidney disease, n (%)

271 (33.6)

94 (25.6)

177 (40.4)

< 0.01

Atrial fibrillation, n (%)

141 (17.5)

81 (18.5)

60 (16.3)

0.42

Cancer, n (%)

104 (12.9)

43 (11.7)

61 (13.9)

0.34

Current smoking, n (%)

82 (10.2)

38 (10.4)

44 (10.1)

0.05

CVD at beginning of CR

CHF, n (%)

208 (25.8)

91 (24.7)

117 (26.7)

0.50

AMI, n (%)

55 (6.8)

24 (6.5)

31 (7.1)

0.75

AP, n (%)

30 (3.7)

11 (3.0)

19 (4.3)

0.31

Post open-heart surgery, n (%)

444 (55.1)

204 (55.5)

240 (54.8)

0.86

Aortic disease, n (%)

61 (7.7)

36 (9.8)

25 (5.7)

0.03

Peripheral artery disease, n (%)

8 (0.9)

2 (0.5)

6 (1.4)

0.23

Anthropometric data

Body fat percentage, %

22.7 ± 8.8

21.9 ± 8.6

23.4 ± 9.0

0.03

Lean body mass, kg

46.6 ± 9.6

47.1 ± 10.2

46.1 ± 9.1

0.13

Grip strength, kg

28.9 ± 9.0

29.8 ± 9.5

28.1 ± 8.4

0.06

Cardiac function indicator

LVEF, %

63 (52 - 70)

63 (53 - 70)

63 (52 - 69)

0.56

Laboratory data

Hemoglobin, g/dL

13.0 ± 1.9

13.4 ± 1.9

12.7 ± 1.9

< 0.01

Albumin, g/dL

3.9 ± 0.5

3.8 ± 0.5

< 0.01

Creatinine, mg/dL

0.8 (0.7 - 1.0)

0.8 (0.6 - 0.9)

0.9 (0.7 - 1.1)

< 0.01

eGFR, mL/min/1.73m²

69.1 ± 26.9

75.3 ± 23.9

64.0 ± 28.2

< 0.01

TG, mg/dL

102 (74 - 139)

103 (73 - 145)

100 (76 - 132)

0.32

HDL-C, mg/dL

49.4 ± 15.5

49.5 ± 15.4

49.3 ± 15.6

0.85

LDL-C, mg/dL

99.9 ± 30.9

101.7 ± 31.9

98.4 ± 30.1

0.13

HbA1c, %

6.0 ± 0.9

5.9 ± 0.8

6.1 ± 1.0

< 0.01

BNP, pg/mL

88.2 (34.1 - 227.7)

71.6 (27.7 - 177.2)

100.1 (42.2 - 286.0)

< 0.01

SAF, a.u.

3.0 ± 0.6

2.4 ± 0.3

3.4 ± 0.5

< 0.01

Medication

Aspirin, n (%)

645 (80.2)

293 (79.8)

352 (80.6)

0.80

ACE-I/ARB, n (%)

267 (33.2)

115 (31.3)

152 (34.8)

0.30

β-blocker, n (%)

579 (72.0)

254 (69.2)

325 (74.4)

0.10

Calcium antagonist, n (%)

153 (19.0)

63 (17.2)

90 (20.6)

0.22

Loop diuretics, n (%)

601 (74.8)

277 (75.5)

324 (74.1)

0.66

Statin, n (%)

425 (52.9)

168 (45.8)

257 (58.8)

< 0.01

Oral hypoglycemic agent, n (%)

129 (16.0)

34 (9.3)

95 (21.7)

< 0.01

Insulin, n (%)

51 (6.3)

6 (1.6)

45 (10.3)

< 0.01

Frailty

Sub-total KCL score (1 - 20)

4.4 ± 3.3

4.2 ± 3.2

4.6 ± 3.3

0.05

Frailty (1 - 20), n (%)

260 (32.3)

108 (29.3)

152 (34.7)

0.11

Total KCL score (1 - 25)

5.9 ± 4.2

5.5 ± 4.1

6.2 ± 4.3

0.02

Frailty (1 - 25), n (%)

260 (32.3)

109 (29.6)

151 (34.5)

0.14

Prefrailty + frailty (1 - 25), n (%)

525 (65.1)

235 (63.9)

290 (66.2)

0.49

**Table 2.** Correlation Between SAF Levels and Clinical Parameters
	Total (n = 806)	Low SAF (n = 368)	High SAF (n = 438)
High SAF is defined as SAF levels ≥ 2.9. Frailty (1 - 20) is defined as ≥ 6 points of sub-total score of KCL. Frailty (1 - 25) is defined as ≥ 8 points of total score of KCL. Prefrailty (1 - 25) is defined as 4 - 7 points of total score of KCL. BMI: body mass index; LVEF: left ventricle ejection fraction; eGFR: estimated glomerular filtration rate; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; KCL: Kihon Checklist.
Basic characteristics
Age	0.34	< 0.01	0.21	< 0.01	0.10	0.04
Male	-0.07	0.04	-0.05	0.39	-0.09	0.06
BMI	0.08	0.02	0.03	0.57	0.08	0.10
Anthropometric data
Body fat percentage	0.07	0.05	-0.01	0.90	0.03	0.56
Lean body mass	-0.02	0.60	0.03	0.56	-0.04	0.41
Grip strength	-0.10	0.06	0.03	0.66	0.09	0.23
Cardiac function indicator
LVEF	-0.03	0.35	0.03	0.63	-0.06	0.25
Laboratory data
Hemoglobin	-0.21	< 0.01	-0.04	0.49	-0.57	< 0.01
Albumin	-0.20	< 0.01	-0.16	< 0.01	-0.15	< 0.01
Creatinine	0.32	< 0.01	0.06	0.27	0.36	< 0.01
eGFR	-0.33	< 0.01	-0.12	0.02	-0.34	< 0.01
TG	-0.01	0.74	-0.02	0.76	0.05	0.30
HDL-C	-0.09	0.01	-0.03	0.59	-0.20	< 0.01
LDL-C	-0.09	0.01	< 0.01	0.94	-0.11	0.02
HbA1c	0.21	< 0.01	0.07	0.17	0.14	< 0.01
BNP	0.25	< 0.01	0.06	0.23	0.30	< 0.01
Frailty
Sub-total KCL score (1 - 20)	0.14	< 0.01	0.04	0.41	0.20	< 0.01
Frailty (1 - 20)	0.12	< 0.01	0.03	0.51	0.17	< 0.01
Total KCL score (1 - 25)	0.14	< 0.01	0.03	0.54	0.16	< 0.01
Frailty (1 - 25)	0.10	< 0.01	0.05	0.36	0.12	0.01
Prefrailty + frailty (1 - 25)	0.07	0.04	0.02	0.67	0.12	0.01

Table 2. Correlation Between SAF Levels and Clinical Parameters

Total (n = 806)

Low SAF (n = 368)

High SAF (n = 438)

P value

High SAF is defined as SAF levels ≥ 2.9. Frailty (1 - 20) is defined as ≥ 6 points of sub-total score of KCL. Frailty (1 - 25) is defined as ≥ 8 points of total score of KCL. Prefrailty (1 - 25) is defined as 4 - 7 points of total score of KCL. BMI: body mass index; LVEF: left ventricle ejection fraction; eGFR: estimated glomerular filtration rate; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; KCL: Kihon Checklist.

Basic characteristics

Age

0.34

< 0.01

0.21

< 0.01

0.10

0.04

Male

-0.07

0.04

-0.05

0.39

-0.09

0.06

BMI

0.08

0.02

0.03

0.57

0.08

0.10

Anthropometric data

Body fat percentage

0.07

0.05

-0.01

0.90

0.03

0.56

Lean body mass

-0.02

0.60

0.03

0.56

-0.04

0.41

Grip strength

-0.10

0.06

0.03

0.66

0.09

0.23

Cardiac function indicator

LVEF

-0.03

0.35

0.03

0.63

-0.06

0.25

Laboratory data

Hemoglobin

-0.21

< 0.01

-0.04

0.49

-0.57

< 0.01

Albumin

-0.20

< 0.01

-0.16

< 0.01

-0.15

< 0.01

Creatinine

0.32

< 0.01

0.06

0.27

0.36

< 0.01

eGFR

-0.33

< 0.01

-0.12

0.02

-0.34

< 0.01

-0.01

0.74

-0.02

0.76

0.05

0.30

HDL-C

-0.09

0.01

-0.03

0.59

-0.20

< 0.01

LDL-C

-0.09

0.01

< 0.01

0.94

-0.11

0.02

HbA1c

0.21

< 0.01

0.07

0.17

0.14

< 0.01

BNP

0.25

< 0.01

0.06

0.23

0.30

< 0.01

Frailty

Sub-total KCL score (1 - 20)

0.14

< 0.01

0.04

0.41

0.20

< 0.01

Frailty (1 - 20)

0.12

< 0.01

0.03

0.51

0.17

< 0.01

Total KCL score (1 - 25)

0.14

< 0.01

0.03

0.54

0.16

< 0.01

Frailty (1 - 25)

0.10

< 0.01

0.05

0.36

0.12

0.01

Prefrailty + frailty (1 - 25)

0.07

0.04

0.02

0.67

0.12

0.01

**Table 3.** Multivariate Regression Analysis With Clinical Parameters Correlated SAF Levels in All Patients and the High and Low SAF Groups
	β	P value	β	P value	β	P value
SAF: skin autofluorescence; BMI: body mass index; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; KCL: Kihon Checklist.
Multivariate analysis for all SAF group
Age	0.54	< 0.01	0.06	< 0.01	0.06	< 0.01
BMI	0.19	0.01	0.07	0.01	0.07	< 0.01
Creatinine	0.80	< 0.01	0.12	< 0.01	0.12	< 0.01
HbA1c	0.45	< 0.01	0.10	< 0.01	0.10	< 0.01
BNP	0.51	< 0.01	0.17	< 0.01	0.17	< 0.01
Sub-total KCL score (1 - 20)			0.06	0.29
Total KCL score (1 - 25)					0.06	0.26
Adjusted R²	0.24		0.24		0.24
Multivariate analysis for low SAF group
Age	0.16	< 0.01	0.16	< 0.01	0.16	< 0.01
Sub-total KCL score (1 - 20)			< 0.01	0.97
Total KCL score (1 - 25)					< 0.01	0.95
Adjusted R²	0.04		0.04		0.04
Multivariate analysis for high SAF group
Creatinine	0.57	< 0.01	0.56	< 0.01	0.56	< 0.01
HbA1c	0.36	< 0.01	0.35	< 0.01	0.35	< 0.01
BNP	0.52	< 0.01	0.48	< 0.01	0.50	< 0.01
Sub-total KCL score (1 - 20)			0.15	0.01
Total KCL score (1 - 25)					0.11	0.07
Adjusted R²	0.18		0.19		0.18

Table 3. Multivariate Regression Analysis With Clinical Parameters Correlated SAF Levels in All Patients and the High and Low SAF Groups

P value

SAF: skin autofluorescence; BMI: body mass index; HbA1c: hemoglobin A1c; BNP: brain natriuretic peptide; KCL: Kihon Checklist.

Multivariate analysis for all SAF group

Age

0.54

< 0.01

0.06

< 0.01

0.06

< 0.01

BMI

0.19

0.01

0.07

0.01

0.07

< 0.01

Creatinine

0.80

< 0.01

0.12

< 0.01

0.12

< 0.01

HbA1c

0.45

< 0.01

0.10

< 0.01

0.10

< 0.01

BNP

0.51

< 0.01

0.17

< 0.01

0.17

< 0.01

Sub-total KCL score (1 - 20)

0.06

0.29

Total KCL score (1 - 25)

0.06

0.26

Adjusted R²

0.24

Multivariate analysis for low SAF group

Age

0.16

< 0.01

0.16

< 0.01

0.16

< 0.01

Sub-total KCL score (1 - 20)

< 0.01

0.97

Total KCL score (1 - 25)

< 0.01

0.95

Adjusted R²

0.04

Multivariate analysis for high SAF group

Creatinine

0.57

< 0.01

0.56

< 0.01

0.56

< 0.01

HbA1c

0.36

< 0.01

0.35

< 0.01

0.35

< 0.01

BNP

0.52

< 0.01

0.48

< 0.01

0.50

< 0.01

Sub-total KCL score (1 - 20)

0.15

0.01

Total KCL score (1 - 25)

0.11

0.07

Adjusted R²

0.18

0.19

0.18