Early Non‐Invasive Detection of Arterial Stiffness Related to Endothelial Dysfunction in Apical Periodontitis Patients: A Systematic Review and Meta‐Analysis

ABSTRACT

This systematic review and meta‐analysis evaluated the association between apical periodontitis (AP) and non‐invasive markers of arterial stiffness, including carotid intima‐media thickness (c‐IMT), endothelial flow reserve (EFR), flow mediated dilatation (FMD), carotid plaques and aortic atherosclerotic burden (AAB) in systemically healthy individuals. PubMed/MEDLINE, Cochrane, Scopus and EMBASE were searched. Quality assessment was done using the Newcastle‐Ottawa Scale. Six studies were selected, with two at low and four at moderate risk of bias. Five studies (two c‐IMT; three EFR) underwent meta‐analysis. Pooled analysis demonstrated that AP was significantly associated with increased c‐IMT (mean difference: 0.16 mm; 95% CI: 0.02–0.30; p = 0.01) and reduced EFR (mean difference: −0.30; 95% CI: −0.43 to −0.16; p < 0.0001). Heterogeneity was high for c‐IMT (I ² = 84%), and absent for EFR (I ² = 0%). Evidence quality was ‘low’ for c‐IMT and ‘moderate’ for EFR (GRADEpro). AP is associated with increased arterial stiffness.

Trial Registration: PROSPERO: CRD420251047888

1. Introduction

Apical periodontitis (AP) is defined as an acute or chronic inflammatory lesion situated at the apex of a tooth root, primarily caused by bacterial infiltration of the dental pulp due to dental caries or trauma [1]. A meta‐analysis [2] comprising 114 papers revealed that the prevalence of periapical radiolucency was substantially greater in patients with cardiovascular disease (CVD) (57%) than in healthy controls (35%). An umbrella review [3] which encompassed four systematic reviews identified a weak relationship between CVD and AP. Among the four systematic reviews, two [4, 5] identified a positive correlation between endodontic pathosis and CVD. Conversely, others [6, 7] came to the conclusion that insufficient data is present to establish a causal link between AP and CVD. Recent research [8, 9] has sought to establish a correlation between AP and surrogate markers of atherosclerosis by measuring the levels of hs‐CRP, IL‐1 and IL‐6 in healthy individuals. However, there are very few studies that used non‐invasive markers to assess the association between AP and CVD.

The dysregulation of arterial stiffness has been identified as a critical factor in the development of CVD, as it impairs the flexibility of the arteries, thus obstructing their ability to stretch or contract in relation to blood flow [10]. Endothelial dysfunction (ED) is the initial phase of arterial stiffness marked by compromised endothelial‐dependent vasodilatation. The loss of elastic properties in calcified great vessels results in increased afterload on the heart, thereby exacerbating heart failure. Arterial stiffness serves as an indicator of cardiovascular health in individuals who appear to be healthy [11]. The outcomes of arterial stiffness are categorized into two types: direct (structural) and indirect (functional). The direct outcomes encompass carotid plaques, carotid intima‐media thickness (c‐IMT), carotid artery calcification (CAC) and aortic atherosclerotic burden (AAB). Indirect measures include flow‐mediated dilation (FMD), endothelial flow reserve (EFR) and pulse wave velocity (PwV).

Coexistence of oral inflammatory diseases and CVD was identified in numerous dental investigations. The association between chronic periodontitis (CP) and CVD has garnered significant attention among oral infections. A recent meta‐analysis determined that non‐surgical periodontal therapy (NSPT) had some beneficial effects on c‐IMT and FMD, while the same was not observed for PwV. High heterogeneity and potential for bias preclude a definitive conclusion regarding the effectiveness of NSPT in enhancing arterial stiffness [12]. Another meta‐analysis, on the outcomes of arterial stiffness, demonstrated the association of periodontal disease with impaired FMD and increased c‐IMT [13]. Furthermore, interventional studies have shown that periodontal treatment can lead to improvements in EF and reductions in systemic inflammatory burden, supporting a potential causal relationship between oral inflammation and cardiovascular risk [14, 15]. Despite these advances, the majority of available evidence has focused on periodontal disease, with limited attention to other oral infectious‐inflammatory conditions such as AP. To date, no systematic review and meta‐analysis has specifically evaluated the association between apical periodontitis and non‐invasive markers of arterial stiffness, thereby highlighting a critical gap in the literature that the present study aims to address.

Increased risk of CVD in individuals with AP has been documented in few studies using both direct and indirect indicators of arterial stiffness [16, 17, 18, 19, 20]. Cotti et al. [16] evaluated the effect of AP on ED and concluded that AP was associated with ED documented by the reduced EFR. On the contrary, Bergandi et al. [17] found no significant difference between the AP and control groups in terms of EFR. A further study [18] showed that periapical lesions were significantly linked to higher c‐IMT values than the healthy controls. Our group also performed two studies [19, 20] and found significantly lower FMD and elevated c‐IMT in healthy patients with AP than in the control.

Despite emerging evidence suggesting a possible association between AP and CVD, the available literature remains inconclusive, with conflicting findings and limited use of objective, non‐invasive vascular markers. In particular, there is a lack of comprehensive synthesis of studies evaluating arterial stiffness and ED in patients with AP using standardized non‐invasive techniques. Therefore, the rationale of the present review is to address this critical gap by systematically evaluating and quantitatively synthesizing the existing evidence on the association between AP and surrogate markers of arterial stiffness. The aim of this systematic review and meta‐analysis is to assess whether the presence of AP is associated with alterations in non‐invasive markers of arterial stiffness, including c‐IMT, EFR, FMD, carotid plaques and AAB in systemically healthy individuals.

2. Methods

2.1. Protocol and Registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines [21]. Additionally, the research was a priori initiated and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database.

2.2. Review Question and Eligibility Criteria

Following the PICO framework of population, intervention, comparison and outcome, this review focused on addressing the following research question:

In adult patients (P), does the presence of AP (I/E), compared with its absence (C), alter the non‐invasive markers of arterial stiffness [O]? Description is given in Table 1.

TABLE 1.

The study was performed to address the following PICOS question.

Patients	Healthy human subjects (free from any systemic disease), regardless of age or gender limitations
Intervention (exposures)	Participants exhibiting one or more radiolucent periapical lesions identified through radiographic methods, including periapical radiographs, OPG or computerized tomography (CT)
Comparator	Controls could be represented by patients without any radiolucent periapical lesions
Outcomes	Arterial stiffness by means of non‐invasive markers like carotid plaques, carotid intima‐media thickness, aortic atherosclerotic burden, flow‐mediated dilation, endothelial flow reserve and pulse wave velocity
Study designs	Studies including randomized controlled trials, case–control studies, cohort studies and prospective clinical series were all considered for inclusion

2.3. Eligibility Criteria

The subsequent selection criteria were established in accordance with the research question:

Inclusion criteria:

1. Clinical studies including cross‐sectional, case–control, cohort or interventional designs published up to May 2025;

2. Studies involving adult participants (≥ 18 years) with clearly defined apical periodontitis diagnosed radiographically;

3. Studies including a comparison group without apical periodontitis;

4. Studies evaluating non‐invasive markers of arterial stiffness or ED, c‐IMT, EFR, FMD, carotid plaque or AAB;

5. Studies reporting sufficient quantitative data for analysis (e.g., mean ± standard deviation or equivalent).

Exclusion criteria:

1. Animal studies, in vitro studies, case reports, case series, editorials, letters, conference abstracts and review articles;

2. Studies without a control group or without clear differentiation between apical periodontitis and non‐apical periodontitis groups;

3. Studies involving participants with systemic diseases known to significantly influence cardiovascular outcomes (e.g., established cardiovascular disease, diabetes mellitus) unless analysed separately;

4. Studies lacking sufficient data for extraction or statistical analysis;

5. Duplicate publications or studies with overlapping datasets.

2.4. Information Sources and Search Strategy

An exhaustive search strategy was developed subsequent to the establishment of the PICO question and inclusion criteria. A bibliographic search was conducted across multiple databases, such as PubMed/MEDLINE, Cochrane, Scopus and EMBASE, without any limitations on language or time. In the manner outlined in Table S1, the electronic search strategy incorporated terms from the Medical Subject Headings (MeSH) and text words (tw). A search of the grey literature was also conducted; however, no relevant data was obtained (URLs: https://www.oclc.org/, https://opengrey.eu/ and https://scholar.google.com/; first 100 results; accessed on 21 May 2025).

2.5. Selection Process and Data Extraction

The titles and abstracts of the retrieved records were independently reviewed by the authors (N.C. and S.M.) in duplicate and without blinding. Articles that met the inclusion criteria were chosen, and the full texts of these papers were subsequently assessed to ascertain their eligibility for inclusion. Comparative analyses were performed between the lists of relevant studies, and a third reviewer (S.T.) was engaged to resolve any disputes.

The data collection was carried out utilizing a pre‐determined and piloted excel sheet (Microsoft Excel; Microsoft Corporation). Every study featured in this systematic review was meticulously recorded with particular details, such as the first author's name and publication year, the type of study design, the markers utilized for diagnosing arterial stiffness, the sample size of both experimental and control groups, the primary results including mean ± standard deviation, the level of significance (p value), the final conclusion, and lastly, the limitations of the study (Table 2). In instances of incomplete or absent data, the authors were reached out to for clarification.

TABLE 2.

Characteristics of included studies.

Study	Type of study	Country	Analysed parameter	AP/Control	Result	p	Conclusion	Limitation
Malvicini et al. (2024)	Cross‐sectional	Italy	c‐IMT	33/32	c‐IMT: AP—1.39 ± 0.22 Control—1.15 ± 0.21	0.000	AP is linked to a fivefold increase in the likelihood of developing carotid plaques and a 15‐fold increase in the odds of significant carotid intima‐media thickness.	1. Observational study design so difficult to establish cause‐effect relationship. 2. Study did not include any microbiological or immunological analysis. 3. The risk of residual confounding cannot be ruled out.
			Carotid plaque by NASCET method		Maximum NASCET (%): AP—0.12 ± 0.12 Control—0.03 ± 0.07	0.001
Bergandi et al. (2019)	Intervention study (data extracted was cross‐sectional)	Italy	EFR	21/20	AP—2.14 ± 0.49 Control—2.21 ± 0.67	0.758	AP may induce early vascular endothelial dysfunction without any macroscopic indication of a decrease in EFR.	1. Relatively small sample size.
Chauhan et al. (2019)	Cross‐sectional	India	c‐IMT	60/60	c‐IMT: AP—0.64 ± 0.12 Control—0.54 ± 0.08	< 0.05	Impaired FMD and increased c‐IMT in individuals with AP indicate a possible correlation between endodontic infection and cardiovascular disease.	1. FMD is observer depended and there are questions about the reproducibility and repeatability of FMD. 2. Values might be affected unobserved confounders.
			FMD		FMD (%): AP—4.9 ± 2.05 Control—9.74 ± 2.59	< 0.05
Cotti et al. (2015)	Cross‐sectional	Italy	EFR	41/40	AP—1.98 ± 0.33 Control—2.32 ± 0.48	< 0.05	Chronic inflammation in young subjects with AP may be associated with early endothelial dysfunction, as shown by the lower EFR.	1. Observational study design. 2. Residual confounding cannot be ruled out.
Petersen et al. (2014)	Retrospective cross‐sectional	Austria	Aortic atherosclerotic burden	389/142	AP—0.32 ± 0.92 mL Control—0.17 ± 0.51 mL	0.0001	CAP had a positive correlation with the aortic atherosclerotic burden. In regression models, the presence of CAP without endodontic therapy was identified as a more significant predictor than CAP with endodontic treatment.	1. The study's impact may be restricted by an uncontrollable bias that is common in retrospective studies. 2. The methodology employed to measure the aortic atherosclerotic load underrepresents the true extent of atherosclerosis, as it identifies only mature plaques, excluding the so‐called soft plaques.
Cotti et al. (2011)	Cross‐sectional	Italy	EFR	20/20	AP—2.08 ± 0.3 Control—2.4 ± 0.5	< 0.01	In young adults with AP, a low EFR may indicate the presence of an early endothelial dysfunction.	1. Relatively small sample size.

2.6. Quality Assessment

The approach used to evaluate the risk of bias and quality of each individual study was based on the Newcastle‐Ottawa Scale, which was modified by León‐López et al. [22] and specifically tailored for cross‐sectional research by Herzog et al. [23]. This scale was designed to correspond with the desired outcome, organizing the assessment items into two distinct domains: sample selection and outcome. Points were allocated (*) according to whether the required aspects were present or absent. The risk of bias criteria was explained in detail in Table 3. A 12‐point maximum score was set for the studies' evaluation. A score ranging from 0 to 4 points signifies a high risk of bias, a score from 5 to 8 points denotes a moderate risk of bias, and a score between 9 and 12 points reflects a low risk of bias.

TABLE 3.

The Modified Newcastle‐Ottawa Scale Risk of bias criteria parameters in detail.

Domain	Criteria	Points
Sample selection (maximum 6 points)
Representativeness of the sample (3 points)	Accurately depicts the mean in the target group (all participants or random selection)	3
	Somewhat indicative of the mean within the target group (non‐random sample)	2
	Designated cohort of users	1
	No description of sampling strategy	0
Assessment of CAP (2 points)	CAP diagnosed via CT or periapical radiography	2
	CAP identified using OPG	1
	Type of X‐ray not specified	0
Sample size (1 point)	Adequately justified (sample size calculation) OR entire population included with < 20% loss	1
	Sample size not justified	0
Outcome assessment (maximum 6 points)
Type of non‐invasive marker (3 points)	Assessment using whole‐body CT scan images	3
	Assessment using ultrasound images	2
	Assessment using PAT scan images	1
	Assessment method not described	0
Assessment of outcome (2 points)	Training and calibration with inter‐ and intra‐agreement values OR non‐operator dependent method	2
	Training and calibration provided without inter‐/intra‐agreement	1
	No mention of training or calibration	0
Number of observers (1 point)	Two or more examiners analysed ultrasound/CT images	1
	Only a single examiner	0

2.7. Data Synthesis and Meta‐Analysis

Initially, a synthesis of narrative data was conducted. Meta‐analyses were conducted when there were at least two studies employing comparable methodologies and yielding the same results. The combined effect was deemed significant with a p value < 0.05. Statistical software was used to create forest plots with a 95% confidence interval (CI) and heterogeneity (measured by the I ² statistic and Cochrane's Q test). The heterogeneity among trials was categorized, with slight heterogeneity indicated by values between 25% and 50%, moderate heterogeneity (50%–75%) and high heterogeneity (> 75%) [24]. The RevMan web software tool was utilized for the statistical analysis (Cochrane, RevMan).

2.8. Level of Evidence

The GRADEpro Guideline Development Tool (GRADEpro GDT, 2022) was utilized, and the evidence was classified as ‘very low’, ‘low’, ‘moderate’ and ‘high’. A low or very low amount of evidence means that the study results are not very reliable.

3. Results

3.1. Literature Search Process

The flow chart in Figure 1 presents a detailed literature search strategy employed in this study. Initially, 258 studies were identified through the primary search, from which 162 duplicates were excluded. Subsequent to the evaluation of titles and abstracts, an additional 86 studies were excluded. Subsequently, 11 studies underwent full‐text evaluation. After a meticulous examination, five studies were excluded based on the reasons outlined in Figure 1. Ultimately, six studies met the inclusion criteria for this systematic review, of which five were included in the meta‐analysis.

FIGURE 1.

PRISMA flow diagram of the study. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐analyses.

3.2. Characteristics of the Included Studies

Finally, the systematic review included six primary investigations. Out of which, five studies were cross‐sectional [16, 18, 19, 25, 26] and one study is an intervention [17]; however, cross‐sectional data was extracted from that study (Table 2). All included studies were written in English and published between 2011 and 2024. The inclusion criteria were not met by any randomized or non‐randomized controlled trials studies.

3.3. The Principal Findings From the Included Studies

The six studies included a total of 878 patients, of which 564 are cases having radiographic evidence of AP and 314 are healthy controls devoid of any radiographic periapical changes. Regarding the diagnosis of AP, five studies [16, 17, 18, 19, 25] used panoramic radiographs followed by periapical radiographs and one study [26] used retrospective CT scans to identify teeth with AP.

The level of arterial stiffness and ED was evaluated using different non‐invasive markers. Three studies utilized EFR [16, 17, 25], two studies used c‐IMT [18, 19], one study used AAB [26], one study used carotid plaque [18] and one study used FMD [19].

Bergandi et al. [17] failed to identify a statistically significant difference between the AP and control group (p = 0.758). The results of all other investigations were statistically significant.

3.4. Quality Assessment of Included Studies

The quality assessment findings for the selected studies are presented in Table 4. The Newcastle‐Ottawa Scale was employed to evaluate the risk of bias of the included studies. Four studies [16, 17, 18, 25] were categorized as exhibiting moderate risk of bias, whereas two studies [19, 26] were categorized as demonstrating low risk of bias. The cumulative total of the six studies was 45 points, signifying a moderate risk of bias overall.

TABLE 4.

Quality assessment of included studies using modified Newcastle‐Ottawa Scale.

Authors (year)	Study design	Selection			Outcome			Risk of bias
		Representativeness of the sample (Max 3)	Sample size calculation (Max 1)	Assessment of AP (Max 2)	Assessment of outcome (Max 2)	Type of marker used (Max 3)	No. of observers (Max 1)
Malvicini et al. (2024)	Cross‐sectional	*	*	**		**		Moderate
Bergandi et al. (2019)	Cross‐sectional	*		**	**	*	*	Moderate
Chauhan et al. (2019)	Cross‐sectional	*	*	**	**	**	*	Low
Cotti et al. (2015)	Cross‐sectional	*		**	**	*	*	Moderate
Petersen et al. (2014)	Cross‐sectional	*		**	**	***	*	Low
Cotti et al. (2011)	Cross‐sectional	*		**	**	*	*	Moderate

3.5. Meta‐Analysis for c‐IMT

Of the six studies available for qualitative analysis, results from two studies [18, 19] including 185 patients (93 with AP and 92 w/o AP) were available for meta‐analysis (Figure 2). c‐IMT was significantly higher in the AP group as compared to the control group (Z = 2.32; p = 0.01) with a pooled mean difference (95% CI) of 0.16 mm (0.02, 0.30). A random effects model was used as there was high heterogeneity among the studies (I ² = 84%; Tau² = 0.01) (Figure 2).

FIGURE 2.

A forest plot of comparison: AP versus control. (A) c‐IMT and (B) EFR.

3.6. Meta‐Analysis for EFR

In the meta‐analysis for EFR analysis, a total of 162 patients (82 with AP and 80 w/o AP) were included from three investigations [16, 17, 25] (Figure 2). The total aggregate effect was statistically significant (p < 0.0001), with a pooled mean difference (95% CI) of −0.30 (−0.43, −0.16) between the AP and control groups. The fixed effect model did not exhibit any heterogeneity among the studies (I ² = 0%).

3.7. Meta‐Analysis for FMD, Carotid Plaque and AAB

The absence of a minimum of two studies per parameter with adequate data precluded their incorporation into the meta‐analysis.

3.8. Level of Certainty of Included Studies

GRADE tool was used to assess level of certainty among individual studies. With respect to c‐IMT studies, the risk of bias was classified as ‘non serious’ and inconsistency was classified as ‘serious’ as studies are having I ² value of 84%. Regarding indirectness, it was termed ‘not serious’ as AP group directly represents the population without any selection bias and arterial stiffness was reliably evaluated. The imprecision domain was termed as ‘serious’ as the width of the confidence interval was > 50% of the calculated value. So, the overall level of certainty was deemed ‘low’ (Table 5). In case of EFR studies, all the domains were termed ‘not serious’ except imprecision, which was termed as ‘serious’. So, the overall level of certainty was deemed ‘moderate’ and evidence as ‘important’ (Table 5).

TABLE 5.

GRADE assessment of certainty level (GRADE Working Group).

In adult patients (P), does the presence of AP (I/E), compared with its absence (C), alter the non‐invasive markers of arterial stiffness [O]
Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Patients with AP	Healthy controls	Relative (95% CI)	Absolute (95% CI)
Carotid intima‐media thickness (assessed with: ultrasound; scale from 0 to 5)
2	Observational studies	Not serious	Very serious a	Not serious	Serious b	All plausible residual confounding would reduce the demonstrated effect	93	92	—	MD 0.16 mm higher (0.02 lower to 0.3 higher)	⨁⨁◯◯ Low	Important
Endothelial flow reserve (assessed with: peripheral artery tonometry; scale from 0 to 5)
3	Observational studies	Not serious	Not serious	Not serious	Serious b	All plausible residual confounding would reduce the demonstrated effect	82	80	—	MD 0.3 lower (0.43 higher to 0.16 lower)	⨁⨁⨁◯ Moderate	Important

Outcomes	Anticipated absolute effects c (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with healthy controls	Risk with patients with AP
Carotid intima‐media thickness (c‐IMT) assessed with: ultrasound Scale from 0 to 5	The mean carotid intima‐media thickness was 0.84 mm	MD 0.16 mm higher (0.02 lower to 0.3 higher)	—	185 (2 non‐randomized studies)	⨁⨁◯◯ Low	Patients with AP likely results in an increase in carotid intima‐media thickness.
Endothelial flow reserve (EFR) assessed with: peripheral artery tonometry Scale from 0 to 5	The mean endothelial flow reserve was 2.31	MD 0.3 lower (0.43 higher to 0.16 lower)	—	162 (3 non‐randomized studies)	⨁⨁⨁◯ Moderate	Patients with AP results in a reduction in endothelial flow reserve.

Note: GRADE Working Group grades of evidence: High certainty—we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty—we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty—our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty—we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Abbreviations: CI, confidence interval; MD, mean difference.

^a I ² value in the forest plot is very high, that is, 84%.

^b Confidence intervals > 50% of the calculated value.

^c The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

3.9. Publication Bias

The limited number of studies (< 10) precluded a quantitative assessment of publication bias.

4. Discussion

The findings of this systematic review and meta‐analysis indicate that AP is significantly associated with increased c‐IMT and reduced EFR, suggesting a potential link with early arterial stiffness, although the strength of this evidence remains limited by heterogeneity among included studies and methodological constraints. Multiple hypotheses have been put forth to explain the connection between AP and CVD, which include direct vascular injury brought on by endodontic pathogens, systemic inflammation and molecular mimicry. To measure this connection, various inflammatory markers (hs‐CRP, IL‐17) [27, 28] and non‐invasive markers measuring alterations in endothelial function and arterial distensibility have been recognized as critical predictors of CVDs, including atherosclerosis.

Both periodontitis and AP are characterized by chronic microbial infection and sustained local inflammation, which can lead to the systemic dissemination of inflammatory mediators. Elevated levels of biomarkers such as hs‐CRP, interleukin‐6 (IL‐6) and other pro‐inflammatory cytokines have been consistently reported in patients with periodontal disease and, with AP [27, 28]. These mediators play a critical role in endothelial activation, promoting oxidative stress, reduced nitric oxide bioavailability and subsequent ED.

Over time, this persistent inflammatory burden may contribute to vascular remodelling and progression of arterial stiffness, as reflected by changes in surrogate markers such as c‐IMT and EFR. Furthermore, periodontal intervention studies have demonstrated reductions in systemic inflammatory markers and improvements in endothelial function, supporting a causal link between oral inflammation and vascular health [14, 15]. Although the evidence linking biomarker dynamics specifically to AP remains limited, the shared inflammatory pathways with periodontitis support a biologically plausible mechanism connecting endodontic infection with early vascular alterations.

c‐IMT is increasingly acknowledged as a surrogate sign for the early identification of atherosclerosis. A review indicated that c‐IMT is a strong predictor of future vascular events, such as myocardial infarction (MI) and stroke [29]. Research demonstrates that every 0.1 mm increment in c‐IMT is associated with a 10%–15% increase in the risk of MI [30]. The guidelines from the European Society of Hypertension/European Society of Cardiology (ESH/ESC) confirm that a c‐IMT reading of more than 0.9 mm signifies asymptomatic organ damage [31]. The present systematic review revealed a mean c‐IMT values of 1 mm versus 0.84 mm in AP and control groups respectively, with a pooled mean difference of 0.16 mm (95% CI, 0.02–0.30 mm; p = 0.01). The c‐IMT values varied between the two studies [18, 19], exhibiting substantial heterogeneity of 84%. This might be due to differences in the target populations examined. One study [19] included younger male participants aged 18–40 years with strict exclusion of conventional cardiovascular risk factors, thereby minimizing confounding but limiting external validity, whereas the other study [18] reported older patients (both male and female) with the mean age of 56 years and more heterogeneous population, with an increased likelihood of residual confounding despite statistical adjustment. c‐IMT has the potential to enhance cardiovascular risk prediction in younger and middle‐aged populations, as opposed to individuals aged 55 years and older [32]. Vascular diameter changes associated with age were notably greater in older men, especially those aged > 50 years [33].

Beyond differences in age distribution, several methodological factors may account for the variability observed between these studies. Differences in diagnostic approaches for AP may also contribute to heterogeneity. While Chauhan et al. primarily relied on radiographic identification of periapical lesions, Malvicini et al. employed a more standardized approach incorporating clinical examination, radiographic assessment and calibrated PAI scoring, thereby enhancing diagnostic reliability. Furthermore, variations in vascular assessment protocols are notable. Chauhan et al. focused on early ED using FMD alongside c‐IMT, whereas Malvicini et al. adopted a more comprehensive evaluation of subclinical atherosclerosis, including carotid plaque assessment, stenosis grading and peripheral vascular indices. These differences reflect distinct pathophysiological stages—functional endothelial impairment versus structural vascular alterations—which may partly explain inconsistencies in observed associations.

Despite the inclusion of only two studies, a meta‐analysis was performed to provide a preliminary quantitative estimate of the association between apical periodontitis and c‐IMT, as individual studies may lack sufficient statistical power in this emerging field. Pooling the data allowed for a clearer assessment of the direction and magnitude of the effect. However, this approach has important limitations. The small number of studies restricts the robustness and generalizability of the findings and precludes meaningful assessment of publication bias. Furthermore, the high heterogeneity observed weakens confidence in the pooled estimate. Therefore, these results should be interpreted with caution and considered exploratory and hypothesis‐generating rather than definitive.

Carotid plaque is characterized as a localized formation within the innermost layer of a blood vessel that is at least 0.5 mm in thickness (or exceeds 50% of the surrounding intima‐media thickness, IMT), or any IMT value of 1.5 mm or above. c‐IMT serves as a biomarker for carotid atherosclerosis that may be monitored in younger individuals, whereas carotid plaque develops later in life [32]. In individuals exhibiting carotid plaques, the percentage of stenosis in the carotid artery was determined using the NASCET method, which differentiates between mild (0%–50%), moderate (50%–69%) and severe stenosis (≥ 70%) [34]. Malvicini et al. [18] assessed the correlation between carotid plaque and AP, revealing increased odds of carotid plaques in the AP group compared to the control group (OR = 4.07 [1.42, 11.71]; p < 0.01).

Peripheral arterial tonometry (PAT) is a novel, user‐friendly method that quantifies changes in finger pulse volume amplitude resulting from reactive hyperaemia following ischaemia of the upper limb for 5 min [35, 36]. Current evidence suggests that this technique may significantly impact cardiovascular research and CVD prevention [37]. The current study's results revealed a significant mean pooled difference of 0.30 (95% CI, 0.43, −0.16) in EFR utilizing PAT between the AP and control groups (p < 0.0001), with no observed heterogeneity (I ² = 0%) across the three studies. Out of three studies, Bergandi et al. [17] found no significant difference between the AP and control groups (2.14 ± 0.49 vs. 2.21 ± 0.67). However, the study indicated that AP group exhibited elevated blood levels of inflammatory markers of ED such as endothelin (ET)‐1, ICAM‐1 and E‐selectin indicating early vascular ED, despite the absence of visible macroscopic signs of reduced EFR. The EFR readings reported by Cotti et al. [16, 25] in AP group were 2.08 ± 0.3 and 1.98 ± 0.33 respectively. Although significantly lower than control group, the values were borderline for interpretation and did not fall within the pathological range of ED. For EndoPAT, the Reactive Hyperemia Index (RHI) cut‐off values are 1.67 and 2.10 (< 1.67 indicates abnormal, ≥ 1.67 and < 2.10 indicates borderline, and ≥ 2.10 indicates normal) [38]. In our meta‐analysis, the pooled mean EFR for the healthy and AP groups was 2.31 and 2.01, respectively, indicating that the healthy control group exhibited a normal EFR, but the AP group demonstrated an EFR within the borderline range, with a statistically significant difference between the two groups.

FMD is commonly used for evaluating nitric oxide‐induced ED and is linked to positive prognostic implications for cardiovascular events. FMD measures the endothelium's ability to promote vasodilation upon stimulation. Only one study examined FMD in patients with AP and observed considerably inferior FMD percentage compared to those without AP (4.9% ± 2.05% vs. 9.7% ± 2.59%, p < 0.05) [19]. A 1% decrease in FMD results in a 13% increase in the risk of subsequent cardiovascular events [39]. The odds ratio for estimated cardiovascular risk in patients with FMD (< 6%) is 2.81 relative to those with FMD (≥ 10%) [40]. A meta‐analysis of 22 studies [13] revealed that the diagnosis of periodontal disease correlated with a mean difference in FMD of 5.1% relative to controls (95% CI = 2.08–8.11).

AAB was intended to quantify calcified plaques in the aorta using thoracic CT scans that were not especially designed for this quantification purpose. Calcification of the aorta and coronary arteries constitutes an independent risk factor for cardiovascular morbidity and death [41]. Petersen et al. [26] assessed the volume of the AAB in patients with at least one CAP lesion against those without CAP, revealing a significant difference (0.32 ± 0.92 mL vs. 0.17 ± 0.51 mL; p < 0.05). Consistent with this, another study [42] demonstrated that patients with at least one tooth impacted by CAP exhibited a higher atherosclerotic load (0.24 ± 0.6 mL) compared to those without CAP (0.51 ± 1.13 mL, p < 0.0001). The atherosclerotic burden was directly correlated with the number of teeth exhibiting CAP. However, the data are limited to two studies.

There is limited evidence with respect to intervention studies evaluating non‐invasive markers of arterial stiffness. Bergandi et al. [17] evaluated mean values of EFR across the control group, AP group at baseline and AP group at 2 and 12 months post‐treatment, and found no significant difference between the groups (p = 0.108). In another intervention study [20], a significant enhancement of FMD (4.84% ± 1.55% to 7.68% ± 2.08%) and reduction in c‐IMT (0.62 ± 0.11 to 0.59 ± 0.11 mm) was demonstrated at 12 months, before and after endodontic treatment (p < 0.05). This indicates that endodontic therapy may be helpful in reversing the early ED associated with arterial stiffness.

4.1. Strength and Limitations

The strengths include previously established and documented techniques, as well as strict compliance with PRISMA principles, supported by the Cochrane handbook. The studies analysed exhibited a low to moderate risk of bias, and the GRADE evaluation revealed level of evidence as ‘important’. This study also has some shortcomings including limited number of studies; and the observational character of the studies which is typically regarded as a low level of evidence. The findings of the present review should be interpreted in light of the methodological limitations of the included studies. Notably, the majority of studies were observational in nature, with a predominance of cross‐sectional designs. Such study designs inherently limit the ability to establish causal relationships between AP and non‐invasive cardiovascular risk markers. Furthermore, cross‐sectional studies are particularly susceptible to residual confounding, as multiple factors—including age, metabolic status, medication use, smoking, and other comorbidities—may independently influence systemic inflammatory and endothelial parameters. Although several studies attempted to adjust for these variables, the possibility of unmeasured or inadequately controlled confounders cannot be excluded. Therefore, while the observed associations are suggestive, they should be interpreted cautiously. The variation in imaging modalities represents another methodological limitation. Differences in sensitivity and specificity between conventional radiography and advanced imaging techniques such as CT may result in inconsistent detection of apical lesions. Likewise, variability in vascular imaging protocols (e.g., ultrasound‐based c‐IMT vs. CT‐derived measures) may introduce diagnostic heterogeneity. This inconsistency likely contributes to inter‐study variability and may partially explain the observed heterogeneity in the meta‐analysis.

4.2. Clinical and Research Implications

Non‐invasive assessments present opportunities for the direct or indirect measurement and monitoring of atherosclerosis in asymptomatic individuals. Consensus evidence remains insufficient for the adoption of these non‐invasive approaches in diagnosing subclinical manifestations of cardiovascular disease in AP patients. Specific study designs, such as prospective, multimodal longitudinal trials or randomized controlled trials that simultaneously assess inflammatory biomarkers (e.g., hs‐CRP, IL‐6) and vascular markers (c‐IMT, FMD) before and after endodontic treatment should be explored [43].

5. Conclusion

The present systematic review and meta‐analysis suggests a potential association between AP and alterations in non‐invasive markers of arterial stiffness, particularly c‐IMT and EFR. However, the strength of this evidence is limited by the small number of included studies, their predominantly observational design and the presence of methodological heterogeneity, including variations in imaging modalities and measurement techniques. The meta‐analytic findings—especially for c‐IMT based on only two studies—should therefore be interpreted with caution. Current evidence remains insufficient to establish a definitive conclusive relationship. Therefore, the results should be interpreted as preliminary associations rather than strong evidence of causality. Well‐designed prospective studies, standardized imaging protocols and larger sample sizes are required to validate these findings and clarify the clinical significance of this association.

Author Contributions

Nishant Chauhan: conceptualization, article screening, data extraction, writing – original manuscript, writing – review and editing. Shweta Mittal: methodology, article screening, writing – original draft, writing – review and editing. Sanjay Tewari: methodology, writing – final review and editing.

Funding

The authors have nothing to report.

Disclosure

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Literature search strategies for various databases using the following MeSH terms.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.