The main finding of our study was that high ankle %MAP acted synergistically with low ABI to improve the prediction of all-cause mortality in patients with type 2 DM. When these two indices were used in combination, ABI ≤ 0.90 and %MAP > 45%, predicted an approximately two-fold higher mortality risk than ABI > 0.90 and %MAP ≤ 45%. These results corroborate our previous study, which showed that high %MAP was a significant predictor of all-cause mortality [13]. The strength of the present study is that we demonstrated the synergy of ABI and %MAP for the prediction of mortality in a large sample of more than 5000 patients with type 2 DM. Furthermore, we used NRI and IDI to quantify the improvement of prediction. Because of the limitation to use only AUC or C-index for the risk prediction model, NRI and IDI were recommended to give complementary information for model performance [20]. Thus, a combination of %MAP and ABI appears to be more effective than ABI alone in predicting the risk of death, and this finding is important because global mortality from PAD is continually increasing [21].
PAD is associated with several atherosclerotic morbidities and is predictive of long-term cardiovascular events [3]. An occluded artery in a lower extremity will result in decreased blood flow, reflected by a decrease in systolic blood pressure and a flattened pulse volume waveform at the ankle [16, 17]. However, the ankle systolic blood pressure will be elevated in a noncompressible artery, and a false negative PAD diagnosis may occur when ABI alone is used for screening [22, 23]. Zahner et al. [24] reported that measuring the augmentation index of pulse waves in the radial artery helps improve PAD diagnosis. DM is closely associated with arterial stiffness [25, 26], and reportedly increases the risk of arterial stiffness by 1.8 times in a Chinese population [27]. In a study by Wukich et al., 42.7% of patients with DM and confirmed PAD had normal ABI values [28]. In contrast, a flattened pulse volume waveform in patients with DM was more closely associated with PAD than a low ABI value was, regardless of ankle arterial stiffness [29, 30]. The %MAP represents the percentage difference between the mean and maximum amplitude of the ankle pulse volume waveform [12]. A flattened waveform resulting from an occluded artery will increase the %MAP value, which is not strongly affected by noncompressible arteries [11, 30]. Therefore, the ankle %MAP might be a sensitive indicator of an occlusive artery with a noncompressible pattern, which is frequently observed in patients with DM [31]. The advantage of %MAP measurement in detecting arterial occlusion may explain why CVD-related mortality is markedly increased in patients with low ABI and high %MAP in the present study. In line with our study, %MAP was associated with CVD-related mortality in hemodialysis patients [32].
Arterial stiffness may involve extracellular destruction and cellular dysfunction of the vessel wall [33]. There are several potential mechanisms involved in the association between DM and arterial stiffness. First, glycation reactions during hyperglycemia can stiffen the arterial wall by inducing irreversible collagen cross-links [34]. Second, an overabundance of advanced glycation end products binding to their receptors on the vessel inner wall can activate a series of responses involving oxidation and inflammation [35]. An inflammatory process including the accumulation of macrophage and the activation of cell adhesion molecules can induce matrix metalloproteases to degrade the extracellular matrix and increase smooth muscle migration and proliferation [35, 36]. Oxidative stress can increase the vessel tone by impairing endothelial nitric oxide production and proliferating vascular smooth muscle cells [37-39]. Third, insulin resistance can increase the vessel tone by activating endothelin-1 and angiotensin II type 1 receptors [40, 41], and the Atherosclerosis Risk in Communities Study reported that insulin resistance was associated with arterial stiffness in patients with type 2 DM [42]. Arterial stiffness with high baPWV was also reported to be associated with new-onset DM [43]. Furthermore, a high prevalence of medial arterial calcification was reported in patients with DM [44, 45]. Noncompressible arteries are reportedly associated with mortality even in patients with high ABI [45, 46]. Therefore, the influence of noncompressible arteries on ABI must be considered in patients with type 2 DM.
In a previous study that enrolled 3004 Japanese participants, including 2598 (86%) with diabetes, the criterion of ABI < 0.9 predicted 20.4% of deaths within a mean follow-up duration of 4.4 years [47]. Notably, in the present study, the prediction of all-cause mortality was 21.1% with ABI alone and 38.0% with the combination of ABI and %MAP criteria. Although the C index was only 0.62 for predicting all-cause mortality in the combined ABI and %MAP model, it was still significantly higher than in the ABI alone model. Besides, the C index can reach to 0.72 by adding the common variables including age and sex in the model containing ABI and %MAP. Furthermore, Cox regression analysis confirmed that ABI accompanied by %MAP was superior to ABI alone in predicting the mortality of patients with type 2 DM.
The prevalence of PAD is increasing worldwide [48, 49]. Most patients with PAD are asymptomatic, but they have an elevated risk of mortality [48-50]. In Taiwan, annual screening for foot complications is recommended in the clinical guidelines and in the P4P program for patients with DM [14, 51]. In previous studies that have used the cutoff value of ABI ≤ 0.90, the prevalence of PAD in type 2 DM was approximately 10.0% in patients with a mean age of 63 years in Taiwan, 10.4% in Malay patients (mean age, 63 years) who lived in Singapore, and 9.5% in patients aged > 40 years in the US [52-54]. According to database of real-world clinical diagnosis, PAD was reported in 18.7% of patients with type 2 DM (mean age, 65 years) in the UK and in 13.6% of patients with type 2 DM (mean age, 66 years) in the US [55, 56]. In the present cohort, the prevalence of PAD was 8.4% when ABI ≤ 0.90 was the only criterion used, but the rate increased to 17.4% when the combination of ABI ≤ 0.90 and %MAP > 45% was used. In the Taiwan National Health Insurance database, under 2.2% of patients with DM and age ≥ 65 years have a diagnosis of PAD, indicating that the condition is greatly underdiagnosed in clinical practice [57]. Thus, the use of ABI along with the automatically reported ankle %MAP is an effective and convenient method for PAD screening and for prediction of mortality [10, 13].
The risk factors for abnormal ABI have been extensively investigated, but the specific risk factors for high %MAP are still not clear [58, 59]. In the present study, the risk factors significantly associated with %MAP at both ABI levels included age, CVD history, BMI, HbA1c, eGFR, UACR, baPWV, use of antiplatelet agents, type of oral antihyperglycemic drug taken, and type of hypertensive drug taken (Table 1). However, we did not include all cardiovascular risk factors in the present study; for example, it has previously been reported that higher HbA1c variability is associated with a higher %MAP [19]. Furthermore, this study has several limitations. First, all participants were from a single teaching hospital, and the results may not be generalizable to all populations with type 2 DM. Second, this was a retrospective study, and so we could not control the risk factors and treatments received during the follow-up period. Third, we did not apply anatomical assessments to confirm the lesions of PAD in the present study with a primary endpoint of all-cause mortality. Finally, the cutoff value of 45% for %MAP is based on the findings of previous studies [13]; we did not assess the normal range of %MAP in the present study.