Cardiovascular disease is a well-described comorbidity in several inflammatory arthritides. It is probably best described in rheumatoid arthritis, where studies show that ischemic heart disease is a prevalent comorbidity [1–4]. In spondyloarthritis (SpA), ischemic heart disease is prevalent in Psoriatic Arthritis [5], but the data in axial SpA (AxSpA) are more controversial. This likely relates to several factors, including a younger group of patients studied and more study heterogeneity in the published literature. Structural heart disease, especially aortitis and lone aortic insufficiency, has been described in AS in the older literature, but the true prevalence of this is not clear. Several studies have described increased cardiovascular risk factors in SpA, including hypertension, metabolic syndrome and diabetes, and dyslipidemia. One should remember that though the topic of this paper refers to the population of AxSpA, the evidence primarily exists in ankylosing spondylitis (AS), with very little reported in non-radiographic disease or the general AxSpA population to date.

Defining cardiovascular disease

Cardiovascular disease outcomes are defined in several ways. One can assess for cardiovascular comorbidities that are really cardiovascular event risk factors. These include hypertension, hyperlipidemia, metabolic syndrome, and diabetes. However, one needs to be cautious in extrapolating these results to infer that more risk means more cardiovascular events. Another outcome is to assess for cardiovascular events including myocardial infarction (MI) and cerebrovascular events (CVA). One could also determine cardiovascular disease by assessing prevalence of coronary artery disease, peripheral vascular disease, and congestive heart failure. In addition, structural heart disease, including valvular heart disease and aortic disease, should be considered, especially in AS where they have been described in the literature, albeit in older smaller studies. Finally, one could determine if there is excess cardiovascular mortality.

Cardiovascular risk factors

Hypertension is a well-described comorbidity in AS. In a large cohort of more than 1000 AS patients, hypertension was self-reported in approximately 30 % at enrollment (mean age 41.1 years (SD = 13.6) [6]. Diastolic dysfunction, a complication of hypertension, has been studied in AS. A meta-analysis of 11 echocardiographic studies of 600 AS patients and 415 controls was performed to evaluate the prevalence of left ventricular diastolic dysfunction in AS [7]. The authors noted that there was an increase in diastolic dysfunction, though the clinical relevance of this finding was not clear. In a meta-analysis by Mathieu et al., an increased risk-ratio of metabolic syndrome and higher weighted mean intima-media thickness were found, despite no increased risk of events [8]. In a population-based Swedish study, the authors found an increased standardized morbidity rate ratio of both hypertension and diabetes in 935 AS subjects [9]. Dyslipidemia has been assessed in AS. In a small study of 45 AS patients (mean age 42 ± 11), increased disease activity was associated with a decrease in high-density lipoprotein (HDL) [10]. In a pooled analysis from two of the large 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitor randomized controlled trials (treating to new targets (TNT) and incremental decrease in endpoints through aggressive lipid lowering (IDEAL)) of 18,889 patient, 46 patients also carried the diagnosis of AS [11, 12]. AS patients were found to have lower baseline cholesterol levels than those without known inflammatory joint disease, and treatment led to a comparable decrease in lipid levels and a 20 % reduction in risk of cardiovascular disease (CVD) in both patients with/without inflammatory joint disease [13].

Cardiovascular events

An important outcome in AxSpA is cardiovascular events defined as myocardial infarction (MI) and cerebrovascular (CVA) events. These are more difficult endpoints, however, because cohorts of AS patients are often younger than other inflammatory arthritides and population-based studies or administrative data rely on accurate disease classification, which may be difficult to do comprehensively with newer classification criteria, where no ICD-9/10 code exists for non-radiographic axial SpA. Older classification criteria (modified New York criteria for AS) select for a more severe radiographic phenotype, potentially biasing data to not reflect the cardiovascular burden in the whole spectrum of disease. Studies that have been performed have been heterogeneous leading to inconsistent results. In 2011, a meta-analysis by Mathieu et al. showed that 3279 AS subjects compared to 82,745 controls displayed no increased risk of cardiovascular events (MI or CVA) [8]. Studies not represented in the meta-analysis include a population-based study by Szabo et al. in Quebec, which showed an increased age and sex-standardized prevalence ratio of CVA, ischemic heart disease, and peripheral vascular disease in 8616 AS subjects [14]. A Swedish population-based study by Bremander et al. showed an increased standardized morbidity rate ratio of ischemic heart disease (IHD) in 935 AS subjects [9]. Brophy et al. published a negative study for both cardiovascular and cerebrovascular events in 1686 AS subjects and 1,206,621 controls in Wales [15]. More recently, three papers were published using the same longitudinal Taiwanese administrative claim database. They showed there was an increased hazard ratio (HR) for both incident IHD and CVA events in addition to an increased HR for recurrent CVA in AS subjects compared to non-AS controls [16–18].

Structural heart disease

Aortitis, aortic dilation, and lone aortic insufficiency (AI) are rare but well-described comorbidities in AS. The aortic valve described similar to an enthesis and inflammation is thought to occur at its insertion points. Subsequently, the aortic wall behind and above the sinuses of Valsalva is affected. This leads to scarred, fibrotic, thickened, and shortened aortic valve cusps, inwards rolling of the edges and a dilated aortic root with secondary AI. In 1958, Graham et al. described the prevalence of AI in AS patients [19]. The authors noted that at 10 years of disease duration, 2 % of patients were found to have AI, while this increased to 12 % at 30 years. In a study by Berg et al., 91 patients with lone AI were studied [20]. The authors found that 15–20 % of these patients had an associated SpA. Of male patients with AI and a conduction defect, 88 % were human leukocyte antigen (HLA) B27 positive. In more recent studies, Szabo et al. used a population-based study design in Quebec, in 8616 AS subjects [14]. The authors found an increased age and sex-standardized prevalence ratio for both aortic and non-aortic valvular heart disease. In an echocardiography study of 24 AS patients with at least 10 years disease duration, two had AI, of which one was subclinical [21].

Conduction disease

Clinical conduction disease and asymptomatic electrodiagnostic findings have been described in the literature. It is thought that inflammation and fibrosis of the membranous portion of the interventricular septum may affect the atrioventricular node. Bergfeldt studied patients with pacemakers and found that 6.7 % of 223 men with permanent cardiac pacemakers had a diagnosis of AS [22]. In another study, the authors noted that the frequency of HLA B27 was increased in patients with complete heart block and pacemaker intervention regardless of clinical or radiological evidence of SpA [23]. In the 12 patients with complete heart block and HLA B27 related disease, 10 also had AI and seven had congestive heart failure [24]. In the Netherlands, Peeters et al. revisited this association in 35 unselected men with permanent pacemakers and idiopathic heart block [25]. Of these, one subject had AS and two had asymptomatic sacroiliitis, but none of the three were HLA B27 positive, suggesting that other factors besides HLA B27 were important in the pathogenesis of heart block. The HLA B27 frequency was higher in the pacemaker population than healthy controls (14 vs. 6 %) similar to the Swedish study. In a study of 210 AS patients who underwent a physical examination, blood tests, ECGs, and questionnaires, conduction disturbances were diagnosed in 10–33 % [26]. These were mostly first-degree atrioventricular block, QRS prolongation. Conduction abnormalities were associated with age, male gender, and higher weight but not with the presence of HLA B27 inflammation or disease activity, by bath ankylosing spondylitis disease activity index (BASDAI). This study is limited by selection bias as patients needed to reply to the invitation to participate, and most patients were treated at the time of the evaluation with 77 % on non-steroidal anti-inflammatory drugs (NSAIDs) and 20 % on tumor necrosis factor alpha inhibitors (TNFi), making interpretation of data regarding disease activity and inflammation difficult to perform. Dik et al. studied 130 AS patients and showed that 29 % had a prolonged QRS duration [27]. First-degree AV block was found in 4.6 %. These were young patients (mean age = 39.4 +/− 10.4) with disease duration <5 years.

Cardiovascular mortality

Studies addressing mortality in AS have shown that cardiovascular disease is a common cause. However, whether this is higher than non-AS subjects is less certain as few population-based studies have addressed this. Lehtinen studied 398 finish AS patients admitted to the hospital and followed for several decades [28]. Six of the 140 AS patients who died did so from a cardiovascular cause. In a study by Bakland et al., they studied 677 AS patients from their local hospital and compared them to matched population controls to estimate a standardized mortality ratio (SMR) [29]. They noted that circulatory disease was the most common cause of death, affecting 40 % of the 98 patients who died. Mok et al. studied several rheumatic diseases in the Hong Kong population and found that AS patients had an elevated SMR, though cardiovascular disease only accounted for 12 % of the cause of deaths [30].

Do our therapies modify cardiovascular outcomes?

Hypertension is a known side effect of non-steroidal anti-inflammatory drugs (NSAIDs). There are no studies suggesting this association in AS specifically, though hypertension is prevalent in the disease. If TNF inhibitors are NSAID sparing, might we change the prevalence of hypertension in AS patients? In a small study of 12 AS patients starting TNF inhibitors, endovascular function was studied [31]. The authors found that there was improvement in endothelial function by flow-mediated vasodilatation. Capkin et al. studied 28 active AS patients starting TNF inhibitors and found no improvement in arterial wall stiffness after 24 weeks despite clinical improvement and decrease in inflammation [32]. In a study by Mathieu et al., 49 AS patients starting TNF inhibitors showed no improvement in arterial stiffness at 6 or 12 months [33]. There are no studies assessing the effects of therapies on structural heart disease, as these would be difficult to perform with the relative rarity of valvular disease and aortitis.

Guidelines for cardiovascular management in axial spondyloarthritis

Guidelines for the management of cardiovascular disease in axial spondyloarthritis have been addressed in one published paper at the time of this submission. Peters et al. published the European league against rheumatism (EULAR) guidelines in all inflammatory arthritides in 2010 [34]. Rheumatoid arthritis was the basis for the majority of the evidence, though the committee suggested AS patients be screened per national guidelines on an annual basis (evidence level 3–4).

Summary

Cardiovascular disease is represented by cardiovascular risk factors, cardiovascular events, structural abnormalities, and conduction disease. The conclusions of the reviewed studies are variable, related to study heterogeneity, and the population studied. More recent studies have shown conduction disease may be common, but not clearly with complete heart block as was previously described. Ischemic heart disease may also be more common in some populations, though this needs further study. What has not been studied is the cardiovascular disease burden in those with the broader spectrum of AxSpA or non-radiographic AxSpA. This is important, because the data may not be generalizable to the entire spectrum; as we know, cardiovascular comorbidities are especially a risk in those with more active disease with higher inflammatory burden. It is interesting that the self-report of structural cardiac comorbidities is low in AS cohorts in the post-TNFi era and begs the question of whether therapies are preventing these complications in the treated population. Large population-based studies may determine whether the prevalence of these cardiac diagnoses have changed over the last several decades.