Decreased Psoas Muscle Computed Tomography Value Predicts Poor Outcome in Peripheral Artery Disease

Takayuki Sugai; Tetsu Watanabe; Yoichiro Otaki; Jun Goto; Ken Watanabe; Taku Toshima; Tetsuya Takahashi; Miyuki Yokoyama; Harutoshi Tamura; Satoshi Nishiyama; Takanori Arimoto; Hiroki Takahashi; Tetsuro Shishido; Masafumi Watanabe

doi:10.1253/circj.CJ-18-0726

Abstract

Background: The prognosis of peripheral artery disease (PAD) and comorbid sarcopenia is poor. Some reports indicate that the computed tomography (CT) value of skeletal muscle, which reflects intramuscular fat deposition as well as skeletal muscle mass, is considered a marker of sarcopenia. However, it remains unclear if skeletal muscle area and CT value are associated with poor outcomes in patients with PAD.

Methods and Results: Psoas muscle area and CT value were measured by manual trace at the level of the third lumbar vertebral body in 327 consecutive patients with PAD undergoing endovascular therapy (EVT). The endpoint was major adverse cardiovascular and limb events (MACLE). There were 60 MACLE during the follow-up period. Patients with MACLE had lower mean psoas muscle CT value than those without. However, there was no significant difference in total psoas muscle area between patients with and without MACLE. Kaplan-Meier analysis demonstrated that the lowest tertile of psoas muscle CT value was associated with the highest risk of MACLE. Multivariate Cox hazard analysis revealed that psoas muscle CT value was associated with MACLE after adjustment for Fontaine class, previous ischemic heart disease, prevalence of diabetes mellitus, brain natriuretic peptide, and serum albumin.

Conclusions: Psoas muscle CT value is a feasible predictor of MACLE in patients with PAD.

Peripheral artery disease (PAD) is an athero-occlusive disease of the lower limb arteries. Patients with PAD also show reduced muscle strength and physical activity.¹^,² Despite advanced medical therapy, patients with PAD have higher mortality than those without.³ Sarcopenia is defined as low muscle mass with low muscle strength or low physical performance.⁴ We have previously reported that malnutrition is associated with sarcopenia and causes poor prognosis in patients with PAD.⁵ Recently, it was reported that changes in not only skeletal muscle mass, but also in skeletal muscle quality are associated with impaired skeletal muscle function and poor prognosis of several types of cancer.⁶^–⁸ Intramuscular fat deposition is considered to be an important factor for degraded skeletal muscle quality,⁹ which is associated with systemic inflammation and inactivity.¹⁰^–¹³

Recently, skeletal muscle mass and intramuscular fat deposition evaluated on computed tomography (CT) were shown to predict poor outcome of several types of cancer.¹⁴^–¹⁶ It remains unclear, however, whether skeletal muscle mass and quality evaluated on CT are associated with poor outcome in patients with PAD.

The purpose of this study was therefore to determine whether skeletal muscle mass and intramuscular fat deposition evaluated on CT can predict major adverse cardiovascular and limb events (MACLE) in patients with PAD.

Methods

Subjects

This prospective study involved 327 consecutive patients admitted to the present hospital with PAD. PAD was diagnosed using the ankle brachial index (ABI) and contrast-enhanced CT. Endovascular therapy (EVT) was performed by experienced cardiologists according to the Trans-Atlantic Inter-Society Consensus II (TASC II) guideline recommendations. Fontaine classes II, III, and IV were defined as intermittent claudication, rest pain, and critical limb ischemia (CLI), respectively. Exclusion criteria included acute coronary syndrome (ACS) ≤3 months prior, malignant disease, and lack of arterial phase contrast-enhanced CT at the present hospital before EVT.

Measurements

Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or antihypertensive medication use. Diabetes mellitus (DM) was defined as glycosylated hemoglobin A1c (HbA1c) ≥6.5% (National Glycohemoglobin Standardization Program), or anti-diabetic medication use. Hyperlipidemia was defined as total cholesterol ≥220 mg/dL, triglyceride ≥150 mg/dL or anti-hyperlipidemic medication use. Venous blood samples were obtained in the early morning before the first EVT procedure. Serum albumin, total cholesterol, high-sensitivity C-reactive protein (hs-CRP), brain natriuretic peptide (BNP), blood lymphocytes, HbA1c, and fasting blood glucose were measured. Nutritional status was evaluated using the Controlling Nutritional Status (CONUT) score. CONUT score was calculated as previously reported.⁵ Patients with CONUT score 0–1 have a normal nutritional status; those with score 2–4 are at mild risk; those with score 5–8 are at moderate risk; and those with score 9–12 are at severe risk of malnutrition. Baseline activities of daily living (ADL) status was assessed using the Barthel index as previously reported.¹⁷ Impaired ADL was defined as Barthel index score ≤95.¹⁷

CT Analysis

Arterial phase contrast-enhanced CT was performed before the first EVT in all patients. CT was acquired using a Somatom Definition Flash (Siemens Healthcare, Germany), Aquilion One (Canon Medical Systems, Japan), or Aquilion Prime (Canon Medical Systems) with 1-mm slice thickness, respectively. CT was analyzed using clinical picture archiving and communication systems (PACS) EV insite (PSP, Japan). Two physicians performed CT measurements. According to previous reports,¹⁸^,¹⁹ we measured area and the CT value of skeletal muscles and chose psoas muscles (Figure S1). Briefly, we first manually traced the skeletal muscle outline of 100 consecutive patients at the caudal end of the third lumbar vertebral body, and evaluated the inter-rater reliability (Table 1). Given that psoas muscle showed excellent inter-rater reliability, we used psoas muscle area and CT value in the following study.

Table 1. ICC for Muscle Area and CT Value

Parameter	Muscle area (mm²)			Muscle CT value (HU)
Parameter	Physician 1 (n=100)	Physician 2 (n=100)	ICC (95% CI)	Physician 1 (n=100)	Physician 2 (n=100)	ICC (95% CI)
Erector spinae muscle	4,055±1,089	3,399±763	0.594 (0.451–0.707)	35.0±17.5	35.3±17.0	0.923 (0.888–0.948)
Oblique muscle	3,850±1,055	3,575±912	0.771 (0.678–0.840)	25.0±13.8	25.0±15.0	0.911 (0.871–0.939)
Rectus abdominis muscle	711±227	667±244	0.477 (0.311–0.615)	22.6±20.5	16.9±21.3	0.669 (0.545–0.764)
Psoas muscle	1,194±337	1,131±340	0.934 (0.904–0.955)	44.3±7.4	44.2±6.6	0.926 (0.892–0.949)

Data given as mean±SD. CT, computed tomography; ICC, interclass correlation coefficient.

Endpoint and Follow-up

Subjects were followed using telephone interview or medical records twice yearly for a median period of 909 days (IQR, 375–1,583 days). There was no loss to follow-up. The endpoint was MACLE including cardiovascular death and rehospitalization due to stroke, ACS, heart failure, or amputation.

Statistical Analysis

Continuous data are expressed as mean±SD, and non-normally distributed data are expressed as median (IQR). Continuous and categorical variables were compared using t-test and chi-squared test, respectively. Data that were not normally distributed were compared using the Mann-Whitney U-test. Differences between the 3 groups were analyzed using analysis of variance (ANOVA) with Tukey’s post-hoc test. A Cox proportional hazard analysis was performed to identify the independent predictors of MACLE. Multivariate analysis using a forward stepwise Cox proportional hazards model was performed to evaluate the independent predictors of MACLE. Survival curves were constructed using the Kaplan-Meier method. P<0.05 was considered statistically significant. We calculated the net reclassification index (NRI) and integrated discrimination index (IDI) to measure the quality of improvement for correct reclassification following the addition of the psoas muscle CT value to the model. To examine the reliability of measurement of muscle area and CT value by manual trace, the interclass correlation coefficient (ICC) was used to evaluate the inter-rater reliability. All statistical analysis was performed using JMP version 12 (SAS Institute, Cary, NC, USA) and R 3.2.4 with additional packages, including Rcmdr, Epi, pROC, and PredictABEL.

Ethics

The study protocol was approved by the Ethics Committee of Yamagata University School of Medicine, and all participants provided written informed consent. All procedures were performed in accordance with the Declaration of Helsinki.

Results

Baseline Characteristics and Presence of MACLE

During the follow-up period, there were 60 MACLE including 6 cardiovascular deaths, 18 rehospitalizations due to heart failure and 8 due to ACS, 5 cerebrovascular events, and 23 amputations. Patients with MACLE had lower mean psoas muscle CT value than those without, but there were no significant differences in total psoas muscle area between patients with and without MACLE (Table 2). Patients with MACLE had a more severe Fontaine class than those without. Patients with MACLE also had a higher prevalence of DM, previous ischemic heart disease (IHD), hemodialysis, and higher rate of impaired ADL than those without. Patients with MACLE had higher hs-CRP and BNP, and lower serum albumin than those without.

Table 2. PAD Patient Clinical Characteristics vs. Presence of MACLE

	All subjects (n=327)	MACLE (−) (n=267)	MACLE (+) (n=60)	P-value
Age (years)	73.5±8.8	73.2±9.0	74.7±8.1	0.237
Male	259 (79.2)	213 (79.7)	46 (76.6)	0.595
BMI (kg/m²)	22.1±3.5	22.2±3.4	21.5±3.7	0.124
Fontaine class (II/III/IV)	255/22/50	222/17/28	33/5/22	<0.001
Hypertension	269 (82.2)	223 (83.5)	46 (76.6)	0.222
Diabetes mellitus	160 (48.9)	121 (45.3)	39 (65)	0.005
Hyperlipidemia	184 (56.2)	157 (58.8)	27 (45)	0.052
Previous IHD	105 (32.1)	76 (28.4)	29 (48.3)	0.003
Previous CVD	63 (19.2)	53 (19.8)	10 (16.6)	0.566
Hemodialysis	61 (18.6)	41 (15.3)	20 (33.3)	0.002
Impaired ADL	76 (23.2)	54 (20.2)	22 (36.6)	0.008
EVT data
Iliac artery	203 (62.0)	179 (67)	24 (40)	<0.001
Femoropopliteal artery	183 (55.9)	150 (56.1)	33 (55)	0.868
Tibial or peroneal artery	59 (18.0)	36 (13.4)	23 (38.3)	<0.001
Stent	290 (89.7)	245 (92.8)	45 (76.2)	0.006
Pre ABI	0.57±0.19	0.58±0.18	0.54±0.24	0.176
Biochemistry
Albumin (g/dL)	3.74±0.52	3.8±0.46	3.38±0.61	<0.001
eGFR (mL/min/1.73 m²)	58.8±37.3	59.8±31.6	54.1±56.2	0.287
hs-CRP (mg/dL)	0.11 (0.048–0.345)	0.098 (0.045–0.260)	0.505 (0.093–1.030)	0.009
BNP (pg/mL)	44.2 (18.2–145.1)	36.8 (14.5–100.8)	146.4 (52.9–435.0)	<0.001
FBS (mg/dL)	119±42.2	117±40	129±49	0.043
HbA1c (%)	6.1±1.0	6.1±1.0	6.2±1.3	0.461
CONUT score (normal/mild/moderate-severe)	154/132/41 (47/40/12)	139/108/20 (52/40/7)	15/24/21 (25/40/35)	<0.001
Total psoas muscle area (mm²)	1,066±352	1,080±356	1,004±329	0.128
Psoas muscle CT value (HU)	45.7±6.4	46.7±5.7	41.0±7.4	<0.001
Medication
Aspirin	224 (68.5)	179 (67.0)	45 (75)	0.222
Clopidogrel	216 (66.0)	184 (68.9)	32 (53.3)	0.023
Cilostazol	111 (33.9)	89 (33.3)	22 (36.6)	0.623
ACEI and/or ARB	192 (58.7)	158 (59.1)	34 (56.6)	0.721
CCB	177 (54.1)	151 (56.5)	26 (43.3)	0.063
Statin	172 (52.6)	144 (53.9)	28 (46.6)	0.308

Data given as mean±SD, n (%), or median (IQR). ABI, ankle-brachial index; ACEI, angiotensin converting enzyme inhibitor; ADL, activities of daily living; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; CCB, calcium channel blockers; CONUT, Controlling Nutritional Status; CVD, cerebrovascular disease; eGFR, estimated glomerular filtration; EVT, endovascular therapy; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; hs-CRP, high-sensitivity C-reactive protein; IHD, ischemic heart disease; MACLE, major adverse cardiovascular and leg event; PAD, peripheral artery disease.

Psoas Muscle CT Value, Psoas Muscle Area and PAD Severity

Psoas muscle CT value was significantly lower in Fontaine class IV than in Fontaine classes II or III (Figure 1). Psoas muscle area was also significantly lower in Fontaine class IV than in Fontaine classes II or III. Mean psoas muscle CT value was inversely related to log hs-CRP (Figure 2). Psoas muscle CT value decreased with advancing malnutrition. Patients with impaired ADL had a lower mean psoas muscle CT value than those without.

Figure 1.

Fontaine class vs. (A) psoas muscle computed tomography (CT) value, and (B) psoas muscle area. *P<0.05.

Figure 2.

Psoas muscle computed tomography (CT) value vs. (A) log of high-sensitivity C-reactive protein (hs-CRP), (B) nutrition status, and (C) activities of daily living (ADL) status. ^#P<0.05 vs. normal; *P<0.05 vs. preserved ADL. CONUT, Controlling Nutritional Status.

Psoas Muscle CT Value and Clinical Outcome

All patients were stratified into tertiles based on mean psoas muscle CT value. On Kaplan-Meier analysis, major adverse cardiovascular events (MACE), amputation, and MACLE increased with decreasing mean psoas muscle CT value (Figure 3). On univariate Cox hazard analysis, mean psoas muscle CT value, but not total psoas muscle area, was significantly associated with MACLE. Fontaine class, previous IHD, DM, hyperlipidemia, hemodialysis, ADL status, serum albumin, BNP, and hs-CRP were also associated with MACLE. On multivariate Cox hazard analysis mean CT value of psoas muscles was independently associated with MACLE after adjusting for Fontaine class, previous IHD, prevalence of DM, BNP, and serum albumin (model 1). Mean CT value of psoas muscles was also independently associated with MACLE after adjusting for hyperlipidemia, hemodialysis, ADL status, stent, Pre ABI, and hs-CRP (model 2; Table 3).

Figure 3.

Kaplan-Meier analysis for (A) major cardiovascular events (MACE), (B) amputation, and (C) major adverse cardiovascular and limb events (MACLE) vs. psoas muscle tertiles. CT, computed tomography.

Table 3. Predictors of MACLE in Patients With PAD

Variable	Univariate analysis			Multivariate analysis
	Univariate analysis			Model 1			Model 2
	HR	95% CI	P-value	HR	95% CI	P-value	HR	95% CI	P-value
Age^†	1.140	0.882–1.476	0.315
Male	0.710	0.400–1.344	0.280
BMI^†	0.770	0.583–1.017	0.067
Fontaine class (II vs. III–IV)	4.358	2.576–7.330	<0.001	2.326	1.257–4.267	0.007
Hypertension	0.750	0.416–1.450	0.375
Diabetes mellitus	1.859	1.099–3.227	0.020	1.384	0.789–2.454	0.248
Hyperlipidemia	0.545	0.323–0.910	0.020				0.787	0.441–1.402	0.416
Previous IHD	2.396	1.431–4.005	0.001	1.609	0.898–2.858	0.108
Previous CVD	0.962	0.458–1.820	0.911
Hemodialysis	2.561	1.463–4.348	0.001				1.485	0.742–2.825	0.254
ADL status (preserved vs. impaired)	2.117	1.229–3.562	0.007				1.064	0.568–2.043	0.848
Iliac artery	0.319	0.186–0.536	<0.001
Femoropopliteal artery	0.823	0.493–1.384	0.458
Tibial or peroneal artery	3.078	1.795–5.176	<0.001
Stent	0.339	0.189–0.646	0.002				0.684	0.340–1.496	0.328
Pre ABI	0.793	0.620–1.033	0.085				0.837	0.651–1.076	0.328
Biochemistry
Albumin^†	0.494	0.409–0.605	<0.001	0.607	0.465–0.811	0.001
eGFR^†	0.829	0.613–1.118	0.244
Log hs-CRP^†	2.128	1.607–2.847	<0.001				1.619	1.185–2.214	0.002
Log BNP^†	2.053	1.064–2.625	<0.001	1.150	0.840–1.570	0.376
Total psoas muscle area^†	0.754	0.568–1.007	0.057
Mean psoas muscle CT value^†	0.525	0.428–0.657	<0.001	0.784	0.617–0.955	0.045	0.699	0.548–0.889	0.003

^†Per 1-SD increase. Abbreviations as in Table 1.

Addition of Psoas Muscle CT Value

Model fit and discrimination improvement was evaluated with the addition of mean psoas muscle CT value to predictors such as Fontaine class, previous IHD, DM, BNP, and serum albumin. NRI and IDI were significantly improved by adding mean psoas muscle CT value to the predictors (Table 4).

Table 4. Effect of Addition of Malnutrition on the Prediction of MACLE

	Baseline model	+Psoas muscle CT value
C index	0.789	0.829 (P=0.011)
NRI (95% CI), P-value	Ref.	0.472 (0.202–0.7433), 0.0006
IDI (95% CI), P-value	Ref.	0.0556 (0.021–0.090), 0.0016

Baseline model included previous ischemic heart disease, diabetes mellitus, Fontaine class, albumin, brain natriuretic peptide. IDI, integrated discrimination index; NRI, net reclassification index. Other a bbreviations as in Table 1,2.

Discussion

The new findings of this study are as follows: both psoas muscle CT value and psoas muscle area were decreased with advancing Fontaine class. Mean psoas muscle CT value is associated with hs-CRP, malnutrition, and impaired ADL. Mean psoas muscle CT value is an independent prognostic factor after adjustment for confounding factors. The prediction model with mean psoas muscle CT value has improved prognostic capacity for patients with PAD.

Intramuscular Fat Deposition on CT

Magnetic resonance imaging, ultrasonography, and CT have been used to non-invasively evaluate intramuscular fat deposition as a marker of skeletal muscle quality.²⁰ The CT value of human skeletal muscle is strongly correlated with intramuscular fat deposition.²¹ When the CT value decreases by 1 HU, intramuscular fat deposition increases by 1 g/100 mL.²¹ Although two methods to evaluate intramuscular fat deposition on CT have been reported,²²^,²³ the manual trace method is highly versatile because it can be measured with routine clinical PACS software without the need for additional equipment. Given that the psoas muscle outline is clearer than other skeletal muscles at the level of the third lumbar vertebral body, measurement of the psoas muscle by manual trace can be easily analyzed in a short time. In the present study, we demonstrate excellent inter-rater reliability in psoas muscle area and CT value by the manual trace method, which was consistent with the previous study.²⁴

Usefulness of Intramuscular Fat Deposition

Sarcopenia is defined as low muscle mass with low muscle strength or low physical performance.⁴ Sarcopenia has been shown to be a risk factor for poor prognosis in patients with PAD.²⁵ In that study, however, only skeletal muscle mass was noted, and skeletal muscle quality was not taken into consideration. To the best of our knowledge, the present study is the first to investigate the relationship between intramuscular fat deposition on CT as a marker of skeletal muscle quality and prognosis in patients with PAD. In this study, psoas muscle area was not associated with MACLE in patients with PAD. It has been reported, however, that a reduction of skeletal muscle mass is associated with MACLE in patients with PAD.²⁶ Although that study included only severe PAD patients with CLI, the present study extends these findings to include PAD patients with Fontaine class II–IV. In the present study, both psoas muscle CT value and psoas muscle area were decreased with advancing Fontaine class. Decreased psoas muscle CT value may occur before decreasing psoas muscle area with increasing PAD severity. In fact, intramuscular fat deposition reportedly occurs prior to skeletal muscle mass reduction.²⁷ Therefore, intramuscular fat deposition may be a more sensitive indicator than skeletal muscle mass reduction.

Malnutrition and Intramuscular Fat Deposition

In the present study, psoas muscle CT value was associated with malnutrition. Vitamin A deficiency is reported to cause intramuscular fat deposition.²⁸ We have previously reported that malnutrition was associated with poor prognosis in patients with PAD.⁵ Although we did not measure vitamin A, intramuscular fat deposition may result from malnutrition.

Inflammation and Intramuscular Fat Deposition

Elevation of inflammatory markers has been observed in healthy subjects with intramuscular fat deposition and patients with cancer.⁸^,¹⁰^,¹¹ Consistent with previous reports,²⁹ hs-CRP was associated with intramuscular fat deposition in the present study. Therefore, inflammation may also be involved in increasing intramuscular fat deposition in patients with PAD. Conversely, intramuscular fat deposition is reported to cause inflammation in animal models.³⁰ Inflammation may increase intramuscular fat deposition, which may cause further inflammation in patients with PAD.³¹

Physical Activity and Intramuscular Fat Deposition

Little is known about effective treatments to reduce intramuscular fat deposition in patients with PAD. Exercise training can reduce intramuscular fat deposition and inflammation, improve subsequent muscle strength,³²^,³³ and improve exercise capacity.³⁴^,³⁵ Given that intramuscular fat deposition was increased in patients with impaired ADL in the present study, exercise therapy may be useful to reduce intramuscular fat and improve prognosis.

Study Limitations

There were several limitations in this study. First, we measured muscle area and CT value at the level of the third lumbar vertebral body and did not evaluate lower limb muscle strength and atrophy. The relationship between psoas muscle CT value and lower limb muscle strength or atrophy remains unclear. Second, we measured psoas muscle CT value only once, prior to the first EVT. Therefore, we could not evaluate changes in intramuscular fat deposition after EVT or exercise therapy. Further study is needed to understand the relationship between intramuscular fat deposition and EVT or exercise therapy in patients with PAD.

Conclusions

Intramuscular fat deposition, as indicated by decreased psoas muscle CT value, predicts poor outcome in patients with PAD.

Acknowledgment

We would like to thank Editage (www.editage.jp) for English-language editing.

Disclosures

The authors declare no conflicts of interest.

Supplementary Files

Supplementary File 1

Figure S1. Representative computed tomography (CT) of skeletal muscle area and mean CT value measurement.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0726

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