**2. Results**

Seven hundred and fifty-one studies were detected by the search formula (shown in the method section), and four additional studies were identified through other sources and added in December 2018. Seven hundred and two studies were excluded following the screening algorithm (see Methods section). Full-text articles were assessed for eligibility. Thirty-six studies were excluded because no full-text article was available, the paper did not match the eligibility criteria, or it had limitations regarding the definition of PAOD or PD. Following application of the eligibility criteria, 17 studies out of the detected 755 studies were included in the qualitative synthesis. Nine studies demonstrated associations between PD and PAOD and two studies associations between tooth loss and PAOD. Six studies addressed the pathomechanism regarding PD as a trigger for PAOD and were included in the discussion. No study that dismissed an association was detected. Figure 1 summarizes the search-results using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

**Figure 1.** Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram, the detected studies regarding the pathomechanism were also inserted into the PRISMA diagram (represented by a dashed line).

### *2.1. Association between PD or Tooth Loss and PAOD*

The first study to demonstrate an association between PD and PAOD was a longitudinal study published by Mendez et al. in 1998 [16]. One thousand, one hundred and ten men were followed for up to 30 years, and a 2.27-fold increased incidence rate (95% CI: 1.32–3.9, *p* = 0.003) of developing PAOD was observed in men with clinically significant PD at baseline compared to men with no or only mild PD at baseline. Subsequently, an evaluation of the prospective Health Professionals Follow-up Study [17], which was based on 45,136 male health professionals free of cardiovascular diseases at baseline and 342 incidences of PAOD that had occurred during 12 years of follow-up, showed that incident tooth loss caused by PD was significantly associated with elevated risk of PAOD (relative risk (RR) for history of PD: 1.41, RR for any tooth loss during follow-up: 1.39, after controlling for traditional risk factors of cardiovascular disease) [17].

In a cross-sectional evaluation of data from the National Health and Nutrition Examination Survey (NHANES), 172 of 3585 participants were diagnosed to have PAOD. PD was significantly associated with PAOD with an odds ratio (OR) of over two in men and women [18]. Moreover, systemic markers of inflammation, such as C-reactive protein (CRP), white blood cell count, and fibrinogen, were also associated with PAOD and PD.

Munoz-Torres et al. [19] assessed the association between baseline number of teeth and recent tooth loss and the risk of PAOD in over 70,000 women participating in the Nurses' Health Study. During 16 years of follow-up, a significant association between incident tooth loss and the hazard of PAOD (hazard ratio (HR) = 1.31 95% CI: 1.00–1.71) could be demonstrated.

A recently reported meta-analysis that included a total of 4,307 participants from seven independent studies, confirmed these findings. The study showed a significantly increased risk of PD in PAOD patients compared with non-PAOD patients (RR = 1.70, 95% CI = 1.25–2.29, *p* = 0.01). PAOD patients also had more missing teeth than non-PAOD participants (weighted mean difference, WMD = 3.75, 95% CI = 1.31–6.19, *p* = 0.003), while no significant difference was found with respect to the clinical attachment loss between PAOD patients and non-PAOD participants (WMD = −0.05, 95% CI = −0.03–0.19, *p* = 0.686) [20].

Association between PD and PAOD was not only detected in cross-sectional and longitudinal studies, but also in several case-control studies. A strong association was observed by Soto-Barreras et al. [21] based on a small case-control study that included 30 patients with PAOD and 30 healthy controls. Patients with ≥30% of the teeth with an attachment loss ≥4 mm had a six-fold increased risk of PAOD compared to controls (OR = 8.18, 95% CI = 1.21 to 35.23, *p* = 0.031). The results also indicated that PAOD patients had higher CRP levels (*p* = 0.0413) and a higher mean decayed missing filled teeth (DMFT) index value (*p* = 0.0002) along with an elevated number of missing teeth (*p* = 0.0459) compared to the control group. The study also addressed the potential mechanism of the association. The CRP level was significantly higher (*p* = 0.0413), and there was also a difference in the decayed-missing-filled-teeth (DMFT) index (*p* = 0.0002), with a higher number of missing teeth (*p* = 0.0459) in the PAOD group compared to the control group. However, there were no significant differences regarding the frequency of bacteria in serum and subgingival plaque samples.

A strong association between PAOD and PD was also reported by Calapkorur et al. [22] who found an OR of 5.8 after adjusting for confounders (age, gender, diabetes, hypertension, and body mass index (BMI)) based on a case-control study including 40 patients with PAOD and 20 healthy controls. In a multicenter, population-based, case-control study that included 212 young women with PAOD and 475 healthy women from the Netherlands, PD was associated with PAOD with an OR of 3.0 (95% CI: 1.4–6.3) [23].

In a case-control, retrospective study based on chart reviews, Molloy et al. [24] evaluated self-reported systemic conditions and smoking history of 2006 selected patients attending the University of Minnesota dental clinics. In addition, the number of missing teeth and the degree of alveolar bone loss were recorded. After adjustments for age, sex, diabetes, and smoking, vascular disease and vascular surgery were significantly associated with alveolar bone loss and the number of missing teeth. The association could be demonstrated not only in people of mostly European descent but also in Asians. Ahn et al. observed an OR of 2.03 (95% CI: 1.05–3.93) for the association between severe PD and PAOD in a Korean community cohort of adults aged over 40 years (N = 1343) [25].

Chen et al. [26], observed that PD was significantly associated with PAOD (OR: 5.45, 95% CI: 1.57−18.89 after adjusting for age, gender, diabetes, and smoking) in a Japanese case-control sample of 25 patients with aorto-iliac and/or femoro-popliteal occlusive disease and 32 generally healthy patients who were employed as controls. Table 1 summarizes the results presented above.

**Table 1.** Summary of the strength of the association between PD or tooth loss and PAOD. RR = risk ratio; OR = odds ratio; HR = hazard ratio; WMD = weighted mean difference. \* PAOD patients had more missing teeth than non-PAOD participants. \*\* conditions that were significantly related to bone loss or number of missing teeth.

