Introduction

Obesity, defined as a body mass index (BMI) of 30 kg/m2 or higher in Caucasians, is a major public health crisis, with more than 700 million children and adults affected worldwide and a constantly increasing prevalence [1–4]. It is well established that obesity is an independent risk factor and predisposes to many comorbidities, including insulin-resistant states (i.e., metabolic syndrome, type 2 diabetes mellitus (T2DM)), various types of cancer, the, severity of COVID-19, and a wide spectrum of cardiovascular diseases (CVD), including coronary artery disease (CAD) and potentially peripheral artery disease (PAD) [2, 5–12].

PAD is a vascular disease caused mostly by atherosclerosis (other causes include connective tissue disease and vasculitis), defined as partial or complete stenosis of one or more arteries [13]. The prevalence of PAD ranges between 3%-10%, but it can be as high as 15%-20% among elderly patients, based on older data while the prevalence is higher now. More than 200 million people suffer from PAD worldwide, with symptoms varying from subclinical to severe lifestyle limitations [14, 15]. There are various classification systems, but the clinical presentation of PAD is usually classified by the Rutherford scale based on the patient's symptoms [16]. Asymptomatic PAD is defined as Rutherford Stage 0, while patients presenting with mild or moderate claudication, or walking-induced leg muscle pain relieved by rest, are classified as Stages 1 and 2, respectively. Stage 3 patients cannot complete standard treadmill exercise, while stage patients exhibit foot pain at rest, and at Stages 5 and 6 ulcers and/or gangrene [17–19]. PAD does not only affect patient’s quality of life but is associated with a 3‐ to 6‐fold increase in cardiovascular morbidity and mortality risk [13].

While associations of PAD with coronary or cerebrovascular atherosclerosis, hypertension, T2DM, smoking, Black race, and advanced age are well established, [15, 20, 21], the relationship with obesity is yet to be clarified. More than 65% of adults with PAD have also overweight (BMI 25-30 kg/m2) or obesity [22]. High fat mass is associated with declining of the ambulatory status and vascular health in patients with PAD and claudication [23]. However, studies in patients with overweight and mild obesity have identified better CVD related prognosis, compared to those within lean and underweight BMI range (18.5 to 25 and <18.5 kg/m2 accordingly) [4, 24]. This observation is known as the “obesity paradox”[24, 25, 26•]. Understanding the real meaning - beyond biases due to confounding variables – of this association can be particularly useful in further designing treatment strategies for patients with PAD [27, 28].

The purpose of this review is to present the current evidence for the association between obesity and PAD in terms of prevalence, pathophysiology, clinical phenotypes, and overall outcomes. Very few reviews and meta-analyses have been conducted regarding the association between obesity and PAD, and the current review offers a systematic presentation of all the major studies examining obesity and the risk of developing PAD and its implications for PAD outcomes.

Effect of Weight on Peripheral Artery Disease: Epidemiological Evidence and Controversy

A plethora of studies have examined the association between obesity and PAD [13] (Table 1). One of the major studies supporting a connection between obesity and PAD is a large cohort from Israel of over 10,000 men, which identified that those with new-onset intermittent claudication (IC) had a higher BMI (0.5 kg/m2) compared to men without IC [29]. Intriguingly, traditional indices of upper or lower body fat accumulation did not show any differences between groups [29]. In another study, Vogt et al. showed that upper body obesity, as assessed by the waist-to-hip ratio (WHR), and not BMI, was associated with an increased risk of developing PAD [30]. WHR was also shown to correlate with PAD in a group of non-insulin-dependent diabetic patients, while a Taiwanese study on patients with end-stage renal disease found that abdominal obesity was also independently associated with PAD [31, 32]. These findings could potentially be explained by the body fat distribution and the well-established detrimental effects of abdominal and visceral fat [33]. In a recent large-scale study, high BMI was associated with an increased risk of PAD only for women, suggesting a potential sex-specific underlying mechanism [34•]. In the same study, patients with overweight but not obesity (BMI 25–29.9 kg/m2) were shown to have the lowest prevalence of PAD compared to other BMI groups [34•].

Table 1 Main findings from studies examining BMI and/or other indices of obesity in relationship to PAD development risk
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Similarly interesting are other studies suggesting that a high BMI might be a protective factor against PAD [13, 35]. In the Framingham study, BMI was weakly associated with the development of IC in men, but weight showed an inverse relationship with the presence of PAD [35]. In women, an increased risk was recorded for the extremes (either low or high weights), while the overweight individuals in that study were found to have a lower risk as described before [34•]. A significant inverse association between BMI and ankle brachial pressure index (ABI) was shown in an analysis of the Edinburgh Artery Study [36]. A study from the Netherlands (Hoorn Study) and studies from the US in various ethnic populations have also shown a protective role of higher BMI against PAD [37–41]. Taiwanese subjects with a higher BMI were also shown to be at a significantly lower risk of PAD in a study of patients with diabetes mellitus [42]. More recently, a U-shaped relationship, i.e., a higher risk for PAD at the extremities of the BMI scale, was depicted in another study [43].

Finally, a considerable proportion of studies did not document any significant, positive, or negative associations between either claudication or PAD and obesity [13, 44, 45]. In the Reykjavik study, a prospective population study, weight and BMI did not have an association with IC [46]. In the Framingham Offspring Study, BMI was associated with ABI level only for females, while no association between BMI and PAD was observed among elderly patients in two large Dutch studies [44, 47, 48].

Pathophysiological Links Between Obesity and Peripheral Artery Disease

Obesity is a diverse, multifaceted chronic disease that is linked to a plethora of comorbidities in still unclear ways, which could partially be attributed to genetic background. [10] To investigate the association between obesity and numerous conditions and possible causality, several genome-wide association studies (GWAS) have been performed, unveiling more than 300 single-nucleotide polymorphisms (SNPs). associated with various indices of obesity, including BMI, WHR, and other adiposity features [49]. Notably, in a Mendelian randomization study, exploring SNPs associated with higher BMI in 11,477 individuals of Chinese origin has shown that the presence of 14 SNPs associated with higher BMI may predispose to a higher risk of PAD, which implicates a genetic link and a causal association, at least in the examined population [50].

Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity [33]. However, a major driver of obesity-related comorbidities and health impacts is adiposopathy, defined as WAT dysfunction rather than just fat mass accumulation [10, 33, 51, 52]. WAT dysfunction includes adipocyte hypertrophy, impairments in lipid metabolism (reduced capacity to buffer the daily influx of dietary lipids), thereby contributing to ectopic fat accumulation, decreased adipose tissue blood flow, mitochondrial dysfunction, altered oxygenation, and a state of chronic low-grade inflammation [33, 53–55] (Fig. 1). Body fat distribution also plays a pivotal role in whole-body metabolism, CVD risk, and development [56]. Upper body fat (abdominal subcutaneous and visceral) accumulation has been linked to unfavorable effects, while gluteofemoral (lower body) fat has been shown to possess opposing, protective properties [33, 52, 57–59].

Fig. 1
figure 1

Characteristics of dysfunctional white adipose tissue, a major driver of the pathophysiological implications of obesity. (All images are originated from the free medical site http://smart.servier.com/ (accessed on February 8, 2023) by Servier licensed under a Creative Commons Attribution 3.0 Unported License)

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Numerous studies have indicated that abdominal fat deposition is associated with PAD [31, 60–62]. The presence of WAT inflammation in abdominal obesity is well established, and a pro-inflammatory phenotype of obese WAT could promote CVD development [63–68]. Hypertrophic WAT has an impaired capacity to store meal-derived fatty acids [69] and results in ectopic fat accumulation. The storage of excess lipids in non-adipose tissues in obesity is strongly associated with insulin resistance and atheromatous plaque formation [65, 70, 71]. Furthermore, hypertrophic adipocytes are characterized by a pro-inflammatory adipocytokine phenotype, which may further aggravate disease development [66, 72]. WAT inflammation is also determined by the infiltration of various populations of pro-inflammatory immune cells [73, 74] including macrophages [75–79]. All these cell populations and adipocytokine dysregulation could lead to further systemic vascular dysfunction and damage. A typical example of adipocytokine dysregulation in obesity is hypoadiponectinemia [80]. Plasma levels of adiponectin were significantly lower among patients with evidence of symptomatic PAD (intermittent claudication) than among those without [81]. These observations have driven the hypothesis that the pathophysiology of obesity and its complications, including its effect on PAD, is driven by WAT dysfunction rather than an increase in WAT mass alone and possibly relates to depot-specific fat accumulation, as reflected clinically by the WHR [33, 54, 64, 71, 82].

It is postulated that lower body WAT consists of cells with more anti-inflammatory properties [52]. In line with that hypothesis, interleukin-6 (IL-6) release (quantified by an arterio–venous difference technique model) showed a lower IL-6 release rate from femoral adipose tissue than from the corresponding abdominal tissue [57]. Perivascular fat could also play a role in disease development. For example, periaortic fat deposition is associated with PAD [83]. Based on the local differences in pro-inflammatory cytokine production and the influence of perivascular fat on disease development, there may be a beneficial effect of femoral adiposity and potentially a protective role for the arteries of the lower limbs [10, 49, 50]. Finally, observations from studies showing an increased risk of PAD for women [34•, 35, 47] could be attributed partially to the cardiometabolic transition occurring during and after the menopause, resulting in a re-distribution of the WAT and potentially a loss of the beneficial characteristics of the gluteofemoral fat [52, 84].

Obesity Paradox or Sarcopenia and Frailty-related Symptoms and Outcomes in Underweight Elderly?

The “obesity paradox” is based on observations in patients with overweight or obesity and known PAD who had a better prognosis and fewer symptoms compared to their peers without overweight or obesity [85–87]. A partial explanation for this may be that a significant percentage of the underweight elderly patients suffered from frailty and sarcopenia. Sarcopenia is defined as an unintentional loss of lean muscle mass, frequently associated with aging [88]. Patients with sarcopenia and normal weight and with sarcopenia and obesity are two distinct sarcopenia groups [88, 89]. The preservation of muscle mass in collaboration with myokines and circulating hormones influences the progression of PAD [90]. Almost 25% of patients with intermittent claudication have sarcopenia, and those patients tend to have worse walking performance compared to their non-sarcopenic peers [91]. Mechanistic studies comparing elderly individuals with or without obesity and PAD identified that obesity decreased the time to claudication and delayed post-exercise hemodynamic recovery, suggesting that muscle metabolic demand, not the total workload, is responsible for the start of claudication and maximal exercise tolerance. Moreover, claudication duration might be responsible for the time needed to complete hemodynamic recovery after exercise [92]. Sarcopenia increases platelet dysfunction, promotes hypercoagulable states, and impairs wound healing through the expression of atherosclerotic cytokines [93, 94]. This pathophysiologic cascade can lead to amputation, major adverse cardiovascular events, major adverse limb events, and mortality [85, 95]. Other factors involved in the obesity paradox, but not linked directly to adiposity, could be attributed to the variation in vascular disease and atheromatous plaque morphology in coronary artery disease (CAD) versus PAD [96]. Thrombosis has a significant role in the pathogenesis of PAD as opposed to CAD, where weight, atherosclerosis is the predominant factor [97]. Another potential explanation is that patients with obesity and PAD receive more aggressive medical treatment and have better outcomes in some of the studies in comparison to patients with normal weight who might be less aggressively treated because of their overall lower risk factor profile [98–100]. Other cardinal pathophysiologic mechanisms related to obesity that could explain this phenomenon include higher energy reserves, inflammatory preconditioning, an anti-inflammatory immune profile, endotoxin neutralization, adrenal steroid synthesis, renin-angiotensin system activation, cardioprotective metabolic effects, and prevention of muscle wasting [25]. A summary of the potential factors explaining the complex relationship between obesity and PAD is depicted in Fig. 2.

Fig. 2
figure 2

Postulated pathophysiological mechanisms explaining the obesity paradox and discrepancies among studies. Panel A shows parameters within various adipose tissue depots and differences in histopathological level. Panel B presents potential cofounders that partially could explain the BMI subgroup differences regarding the association of obesity and PAD and clinical outcomes. BMI: body mass index; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; PAD: peripheral artery disease. (All images are originated from the free medical site http://smart.servier.com/ (accessed on February 8, 2023) by Servier licensed under a Creative Commons Attribution 3.0 Unported License)

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Finally, the potential pathophysiologic mechanisms and observations leading to the conclusion of an existing “obesity paradox” should be further examined, taking into account the methodological limitations of studies, such as the retrospective design, the potential selection bias (e.g., due to ethnicity, age, or sex), the use of BMI as an obesity index (which could lead to an underestimation of the impact of body composition and body fat distribution), and the inadequate adjustment for confounding variables [11, 25].

Impact of Obesity or Underweight Status on Disease Progression, Management, and Mortality in Patients With PAD

Various studies have examined the role of obesity in PAD progression. (Table 2). Therapeutic options for PAD include pharmacological management, lifestyle interventions (nutritional and exercise), and revascularization for cases that do not improve with standard management or for chronic limb-threatening ischemia (CLTI) [19].

Table 2 Main findings from studies examining the impact of obesity on disease progression and mortality in patients with PAD
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Weight loss effectively slows the course of atherosclerosis by improving risk factors such as diabetes, hyperlipidemia, hypertension, and adiposopathy [101]. Farah et al. showed that the walking capacity of over 100 patients with PAD fluctuated according to their comorbidities, with diabetes and CAD being independent predictors of decreased functional capacity [102]. Another study identified that patients who intentionally lost more than 5 pounds had a lower yearly drop in 6-minute walk distance, despite losing greater muscle in the calf area, compared to patients who gained weight [103]. A recent meta-analysis of weight-reduction studies including patients with established PAD showed that every 1kg loss of fat mass predicted a 0.01 m/s improvement in walking speed with the appropriate adherence to calorie restriction and physical activity [104]. All these implicate the benefit of weight loss interventions on the functional capacity of patients.

Few studies examined the association between obesity and functional decline in individuals with PAD. This was assessed with 6-minute walk performance; graded treadmills measured maximum walking distance (MWD) and initial claudication distance [105, 106]. A small study of 60 subjects showed that obesity and waist circumference were predictors of disease progression and were associated with the likelihood of major cardiovascular or revascularization events [106]. Another study that examined combinations of metabolic syndrome components found that abdominal obesity was predictive of unfavorable outcomes, including worsening IC symptoms and overall quality of life [32, 107]. Giugliano et al. showed that abdominal and, to a lesser degree, general obesity were associated with worse prognosis (CVD events), while Gardner et al. showed that patients with CLTI had a lower resting expenditure, a higher body fat percentage, and, compared to patients with IC only, a higher fat mass [108, 109].

The “obesity paradox” has potential implications for CLTI as well. Untreated or inadequately treated PAD may lead to CLTI or even amputation [110]. CLTI patients may have a much higher risk of amputation and mortality compared to those with claudication [88]. Although the one-year risk of limb loss is excessively high at 30% and the five-year all-cause mortality is 50% in patients with CLTI [111–113], higher BMI is associated with lower rates of mortality in patients with lower extremity ulcers [114].

Association of Obesity and Mortality in Patients With PAD

The GetABI study included 1,400 patients with established PAD, showing no correlation between obesity (BMI > 30 kg/m2) and mortality [115]. However, other studies did show a significant inverse correlation, with a Dutch and a Japanese study documenting that all-cause mortality was lower in patients with obesity compared to underweight individuals, although the overrepresentation of patients with chronic obstructive pulmonary disease and malnutrition, respectively, in the underweight group could have affected the results [116, 117]. Another study that assessed various manifestations of vascular disease, including CAD and PAD, showed that general adiposity was associated with an increased risk of vascular mortality for CAD, but the risk was lower in patients with PAD [118]. Two other large studies showed that obesity was associated with improved in-hospital outcomes, including mortality, compared to individuals without obesity [119• 120]. Again, this could have been confounded by the increased rates of frailty and sarcopenia in the group without obesity.

Impact of Obesity on Post-revascularization Outcomes

Revascularization is frequently performed in patients with ischemic ulcers or rest discomfort to avoid amputation [121]. Interestingly, Pacha et al. showed that patients with PAD and low BMI have worse in-hospital mortality (4.8% vs. 1.2%) and more adverse cardiovascular events (7.9% vs. 4.1%) after revascularization compared to their peers with normal BMI [122]. Another study that examined the long-term outcomes of over 1,000 CLTI patients after endovascular revascularization found that the 3-year overall survival rates were 33.3%, 61.2%, and 69.8% in the underweight, normal weight, and overweight/obesity groups, respectively. [123]. Those findings have been replicated by other studies [122–126] but there were also studies that failed to find a difference between the two groups [127, 128]. Finally, in a recent meta-analysis examining 12 studies, mortality among patients with PAD was higher in those who were underweight and lower in those with concomitant obesity [129••]. Interestingly, the authors of this meta-analysis concluded that obesity-related mortality was lower in individuals with PAD who had concurrent CAD than in those who did not have CAD [129••]. However, further research is necessary to validate these results and determine their long-term implications for individuals with CAD. This includes observing if increased monitoring and vigorous treatments in this patient population lead to a higher prevention of complications or if other physiological factors may play a role in mediating protection.

Conclusion and Future Perspectives

While there are a plethora of studies examining the detrimental effect of obesity on cardiovascular outcomes and in patients with PAD, there is also a significant body of literature suggesting improved outcomes following interventional treatments (revascularization) in patients with obesity and PAD compared to their peers without obesity. However, those studies identified the benefit in elderly patients, with COPD, frailty, and sarcopenia probably contributing to worse outcomes in the population without obesity. Larger prospective studies with a longer follow-up period examining the complex associations and adjusting for all those covariates, including ethnicity, sex, age, body fat distribution, and the overall degree of treatment of concurrent diseases, are needed to elucidate the complex association between obesity and PAD. Finally, further studies examining the impact of bariatric surgery [130] or novel medicinal treatments, like the dual incretin analogues [99], on PAD progression are warranted.