Cardiovascular Risk in the Rheumatic Disease Patient Undergoing Orthopedic Surgery
A hallmark of the rheumatic diseases, including systemic lupus erythematosis, spondyloarthritis, and rheumatoid arthritis, has been sustained inflammation, which typically targets the joint and may lead to joint destruction. Inflammation also plays a role in atherosclerotic cardiovascular disease, which is highly prevalent in patients with rheumatic diseases. Total joint arthroplasty, considered an intermediate cardiac risk procedure by the American College of Cardiology, maintains an important role in the management of rheumatic disease patients who progress to end-stage joints. The purpose of this article is to discuss the role of inflammation in cardiovascular disease, the prevalence of cardiovascular disease in patients with systemic rheumatic diseases, and the role of cardiovascular risk assessment when these patients undergo total joint arthroplasty.
KeywordsArthroplasty Rheumatic diseases Atherosclerosis Perioperative cardiac risk Cardiovascular risk Orthopedic surgery Coronary artery disease Inflammation Spondyloarthritis Rheumatoid arthritis Psoriatic arthritis Systemic lupus erythematosus
Inflammation is the defining feature of rheumatic diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA), and systemic lupus erythematosus (SLE). The contribution of atherosclerotic cardiovascular disease (ASCVD) to excess mortality in these inflammatory diseases is well established [1, 2, 3]. Chronic inflammation, a risk factor for ASCVD, appears to drive the increase in cardiovascular disease and excess mortality in patients with rheumatic disease. Since the joints are a major target of inflammation in the rheumatic diseases, it is unsurprising that orthopedic surgery plays a significant role in maintaining mobility in these patients. Current rates of total knee arthroplasty (TKR) and total hip arthroplasty (THR) are increasing dramatically , and 3 %–4 % of all knee arthroplasty (TKR) and hip arthroplasty (THR) performed are in patients with RA . In fact, 30 %–58 % of RA patients can expect to undergo total joint arthroplasty (TJR) over their lifetime of disease , while 4 % of SLE patients and 7 % of a psoriatic arthritis (PsA) cohort undergo arthroplasty [7, 8].
Cardiac events are a major perioperative complication in orthopedic surgery, and patients with underlying cardiac risk factors are at increased risk. The risk of perioperative myocardial infarction (MI) was 0.6 % in approximately 8,000 nonambulatory procedures, a risk that increased to 6.5 % in patients with underlying cardiac risk factors . The mortality after hip and knee arthroplasty surgery ranges from 0.4 % to 4.6 %, the variation dependent on primary total joint arthroplasty, as compared with revision procedures [10, 11]. In 4,315 patients undergoing major noncardiac surgery, Lee et al. reported a 2.1 % rate of major postoperative cardiac complications .
This article will discuss the role of inflammation in ASCVD, review the prevalence of ASCVD in patients with inflammatory arthritis and SLE, discuss the factors contributing to the risk of cardiac disease in patients with rheumatic disease, and review perioperative risk assessment in these patients. The appropriate preoperative evaluation and interventions to decrease cardiac risk via preoperative optimization will be discussed.
Coronary Artery Disease and Inflammation
The role of inflammation in coronary artery disease (CAD) is well established and is reflected in the models of risk prediction based on measurement of C-reactive protein (CRP), applicable in the absence of other traditional risk factors such as hyperlipidemia. The Jupiter trial demonstrated that major vascular events decreased by 44 % in those with normal low-density lipoprotein levels and CRP > 2 when randomized to receive rovustatin instead of placebo [12, 13]. CRP levels change quickly in response to acute events such as infection or surgery, with a serum half-life of 19 h. Although in a class of molecules referred to as acute phase reactants, CRP is elevated in chronic inflammatory conditions, including inflammatory arthritis , and is useful in monitoring the response to therapy. Composite scores such as the DAS-28 (disease activity score) and SDAI (Simplified Disease Activity Index) are objective outcome measures recommended for optimal RA management . They are calculated on the basis of clinical characteristics, including swollen and tender joint counts plus CRP, highlighting the integral role of CRP measurement as a determinant of disease activity in the setting of systemic inflammatory disease. Although CRP elevations are not specific, the inflammatory burden of many disparate conditions is reflected in the degree of elevation. For instance minimally invasive surgery raises CRP levels less than do open procedures used to perform the same lumbar spine fusion . Such inflammatory markers rise even higher in patients undergoing complex spine surgery and are associated with marked increases in cytokine levels, with multiple organ dysfunction reported as a complication . Although the consequences of anesthesia and surgery such as hypotension and anemia make well-defined contributions to ischemic risk, the role of inflammation is less well understood.
An examination of the current literature pertaining to CRP is instructive. Elevations in CRP level can predict mortality. A study measuring CRP levels in 5,811 patients at 1-year intervals was undertaken to better understand the association of CRP with risk of death. When CRP increased from <3 to >3, a 6.7-fold increase in the hazard ratio (HR) for death was observed. Moreover, when CRP decreased into the normal range, the HR for death was cut in half . When patients with inflammatory arthritis were similarly studied, the HR for death doubled when the CRP increased and decreased with a drop in CRP . High CRP levels measured in patients undergoing vascular surgery predicted a significant increase in long-term cardiac and all-cause mortality, as well as an increase in major cardiac events, although short-term events in the population with raised CRP levels did not increase . Worse long-term outcomes are also predicted after acute coronary syndromes when CRP is elevated [21•]. Although the role of CRP in accelerating atherosclerosis is unclear, the relationship appears strong, and there may be a role in up-regulation of adhesion molecules that promote atherogenesis . Therefore, patients presenting for surgery with active inflammatory disease would theoretically have an additional risk for perioperative cardiac complications.
RA is the most prevalent form of inflammatory arthritis, with numerous studies demonstrating an increase in the risk of MI [23, 24]; indeed, acute MI accounts for nearly 40 % of all deaths in this condition . Additionally, patients with RA report less angina, are more likely to experience asymptomatic MI, and experience more sudden death . Incidence rates for cardiovascular events in patients with chronic RA are as high as 3.97 [2, 27], and, despite the high prevalence of traditional cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, and cigarette smoking, the association between RA and cardiovascular events is independent of these risk factors [28, 29]. The chronic inflammatory milieu and inflammatory mediators such as CRP, TNFα, and interleukins appear to confer much of the incremental risk. In fact, the risk of MI conferred by RA is substantial and is estimated to be as great as the risk conferred by diabetes mellitus [30•].
Therapy of RA has been shown to decrease cardiac risk. Risk of MI was decreased by prolonged exposure to disease-modifying antirheumatic drugs (DMARDs)—in particular, methotrexate—which was also associated with a decreased prevalence of cardiovascular disease [35, 36]. Tumor necrosis factor antagonist (TNFα) use was associated with a reduced risk of cardiovascular events in RA patients in the large CORRONA registry. Moreover, when data from the British Society for Biologics Register was studied, RA patients responding to therapy within the first 6 months of TNFα use markedly reduced their risk of MI, as compared with nonresponders, reinforcing the concept that sustained inflammation and active RA is significant in CVD risk . Corticosteroids, however, particularly when administered in high doses, may increase cardiac risk and contribute to the development of cardiovascular risk factors such as hypertension and diabetes . Continuing therapy with methotrexate in the perioperative period has been well studied and does not increase surgical site infection and decreases disease flares. It is tempting to speculate that continuing methotrexate in the perioperative period may have cardiovascular benefit as well, although this has not been studied .
In patients with SpA, of which ankylosing spondylitis (AS) is the prototype, severe hip involvement and an increased risk of THR is associated with early onset of disease, more severe spine involvement, and sacroiliac disease . Up to 36 % of AS patients have hip involvement. Other consistently associated factors for severe hip involvement include persistent elevations of ESR and CRP, as well as poor function measured by AS-specific scales such as the Bath AS functional index and the Bath AS disease activity scale (BASDAI) [41, 42]. Total hip replacement is the most commonly performed orthopedic procedure in patients with AS, for the standard indications of relief of pain and improved function [43, 44].
Large population-based registry studies have revealed that ischemic heart disease, hypertension, and diabetes are increased in patients with AS [45•]. AS patients are at higher risk of stroke and MI, in spite of lower total cholesterol levels . Other cardiac risk factors such as smoking and metabolic syndrome are increased in AS patients, however [47, 48]. Although preclinical atherosclerosis as determined by CIMT, a surrogate marker of ASCVD, is increased in AS, this may reflect the increase in traditional risk factors, including BMI. However, disease duration has also been associated with arterial stiffness . Increased cardiac risk has been associated with elevations of CRP and Il-6, as well as higher disease activity scores, again supporting the role of systemic inflammation in cardiac risk in patients with inflammatory arthritis . Others, however, have not replicated these findings . Similar to patients with RA, patients at risk for destructive joint disease due to ongoing inflammation, who are likely to undergo arthroplasty, may also be at higher risk for ischemic cardiac disease.
Additional cardiac manifestations for AS include aortic valve disease and aortitis, with both inflammatory and degenerative features . Conduction disturbances have been described in AS [52, 53] associated with longer disease duration . Diastolic dysfunction has also been described .
There are no studies directly assessing perioperative risk in SpA patients. Estimation of risk is made difficult by the dependence of most risk assessment tools such as Framingham on cholesterol levels (Cooney), which are typically low in patients with active inflammatory disease.
PsA may take a severe destructive course with significant disability . Mortality in PsA is increased in severely affected hospital-based cohorts, while studies of community-based patients with milder disease have not duplicated those results . Similar to RA, death in PsA is most frequently due to cardiovascular disease, and predictors of increased mortality include an elevated ESR and evidence of radiologic damage at the time of presentation . The association of PsA with atherosclerosis and cardiac disease has been confounded by the increase in traditional cardiac risk factors such as smoking, hypertension, hyperlipidemia, and metabolic syndrome . The contribution of increased traditional cardiac risk factors in PsA is supported by the demonstration of an increase in CIMT in PsA patients, which was most significant in those patients with traditional risk factors, more than those with PsA alone. In fact, the increase in CIMT was strongly associated with abdominal obesity, hypertension, and BMI and was not associated with disease activity when multiple activity measures such as BASDAI or DAS28 were used . Although arthritis disease activity may not influence cardiac risk, severe skin disease, measured as a Psoriasis Skin Index (PASI) >20, has been a significant risk factor in other studies .
Systemic Lupus Erythematosus
Reference to the importance of CVD in the mortality associated with systemic lupus erythematosus has been made. While the observations of Urowitz et al.  remain of historical importance, the subsequent literature concerning this association has been extensive, confirming the increased prevalence of cardiovascular disease in SLE [25, 62]. As with RA, the increased risk also appears independently of traditional cardiovascular risk factors . In addition to this prevalence data, other studies serve to underscore this association. An analysis of data from the Framingham study reveals a 50-fold increase in rate of MI in women with SLE in the 35- to 44-year age range, as compared with age-matched controls . Similarly, the SLE-related risk for MI is reported as 2.67 . Furthermore, when this relationship was examined measuring CIMT as a marker for ASCVD with B-mode carotid ultrasound, the increase in carotid plaque in woman with SLE, as compared with controls, was confirmed; the prevalence of carotid plaque in SLE was 37 %, as compared with 15.2 % of age-matched controls (Fig. 1) [38, 65]. A similar investigation employing electron-beam computed tomography to screen for the presence of CAD added to these findings . Although the prevalence was higher in every age group studied, the difference was particularly striking in the youngest age group; plaque was 5.6 times as high among patients <40 years of age, as compared with control subjects, in this age group. Moreover, in multivariate analysis using age, hypertension, diabetes, fasting cholesterol, smoking practices, and lupus status as predictors, only age (Odds ratio (OR), 2.4 per 10 years), the presence of lupus (OR, 4.8 per 10 years), and a higher serum cholesterol level (OR, 1.1 per 10 mg per deciliter) were independently associated with the development of atherosclerosis. When compared with patients without carotid plaque, patients with plaque formation were older, had longer duration of disease and more disease-related damage, and were less likely to have positive autoantibody tests or to have been aggressively treated. Longer duration of corticosteroid therapy is also among the important potentiating influences in SLE .
Utilizing electron-beam computed tomography to screen for the presence of coronary artery calcification, total coronary calcium scores in patients with SLE were compared with those in matched controls . Coronary artery calcification was more frequent in patients with lupus; the mean coronary calcification scores were 68.9 in those with lupus versus 8.8 in those without. Coronary artery calcification occurred at a younger age in lupus patients and increased with increasing age. Moreover, the presence of asymptomatic atherosclerosis and the presence of coronary artery calcification could not be predicted by the presence or absence of traditional cardiovascular risk factors or by measures of disease activity, observations well supported from data derived from numerous studies [1, 68, 69, 70].
A recent study using the National Inpatient Sample database analyzed pooled hospital discharge data (>5 million hospitalizations, 1998–2002) and showed that all-cause postoperative mortality was significantly higher among women with SLE, as compared with those without SLE. Stratified according to their risk for cardiovascular events, patients undergoing low- and high-risk procedures had worse outcomes. Curiously, those undergoing intermediate risk surgery did not, a relevant finding since most orthopedic surgery falls into the intermediate category [71•]. However, when arthroplasty was specifically addressed, SLE mortality was higher, an effect most marked in emergency surgery .
Perioperative Cardiac Risk Assessment
The overall frequency of serious adverse events, including MI and death, after hip or knee arthroplasty has been assessed in studies by review of medical records and analysis of prospectively collected databases. In one such study utilizing information on 10,244 patients, the overall frequency of serious complications was 2.2 %, with the rate of MI of 0.4 % and of death 0.5 % . Taking a population-based approach, in another large study, total cardiac events after arthroplasty, including MI, arrhythmia, and congestive heart failure, were 6.9 % of 1,195 THA and 6.7 % of 1,606 TKA . Risk factors identified in both studies included older age and male gender. Using case control methodology, risk factors for cardiac events identified include a history of arrhythmia, CAD, or valvular cardiac disease . While cardiac risk and cardiac disease are clearly elevated in patients with SLE and inflammatory arthritis, demonstration of adverse events in the perioperative setting has not been consistent. The odds ratio for early (within 90 days) complications after arthroplasty is 1.53 for RA, including death and pulmonary embolus [75, 76]. However, when perioperative cardiac events and mortality after elective surgery were compared between RA patients, diabetes mellitus patients, or unaffected controls, RA was not associated with an increase in perioperative cardiac risk or mortality, and patients were less likely to have a perioperative cardiovascular event than were patients with diabetes mellitus [77•]. For SLE, a study of postoperative in-hospital mortality, based on 1,500,000 hospital discharges contained in the National Inpatient Sample, revealed an OR = 3.8 for death in SLE after elective THR and an OR = 4.2 for THR after fracture. RA did not increase postarthroplasty mortality in this study . There has been no systematic assessment of perioperative cardiac complications in PsA or AS.
In the American College of Cardiology/American Heart Association algorithm for determining perioperative risk, total joint arthroplasty is rated as an intermediate risk procedure, associated with a 1 %–5 % risk of serious cardiac events such as cardiac death or nonfatal MI. However, taking the foregoing discussion into account, prudence suggests treating rheumatic disease as an independent risk factor, along with other traditional indicators, including a history of ischemic heart disease, compensated or prior heart failure, cerebrovascular disease, diabetes mellitus, and renal insufficiency. The dependence of traditional risk assessment tools on cholesterol levels decreases the usefulness in inflammatory disease patients, where these values are typically low in states of high disease activity . Assessment of functional capacity by history requires the ability to achieve activity levels of greater than or equal to four metabolic equivalents (METs), a level achieved by walking up the stairs or up a hill or by performing housework. Patients with rheumatic diseases are frequently limited in their activity, however, and history may not provide an adequate functional assessment. Noninvasive cardiac testing may then be helpful for management, particularly in the presence of one to three additional traditional risk factors. Consideration of heart rate control with beta blockade and initiation of therapy with statins may also be appropriate in some circumstances.
In summary, cardiac disease is highly prevalent and may be clinically silent in patients with a chronic inflammatory rheumatic disease. Atherosclerotic cardiovascular disease contributes to the increased mortality in patients with these conditions. Although the risk of cardiac disease is as high in RA as in patients with diabetes, no significant increase in perioperative cardiac complications in RA have been described [77•]. For SLE, where the risk of CAD is 50 times that of age-matched controls, postarthroplasty mortality is increased and is highest in nonelective arthroplasty . There are no studies addressing perioperative cardiac events in AS or PsA. Furthermore, none of the studies referenced are prospective, and the exclusion of patients with active disease at highest risk may have influenced these outcomes. In closing, given the role played by inflammation in the genesis of CAD, coupled with its putative part in the excess CV mortality of those with chronic inflammatory rheumatic disease, it is our thesis that these patients should be regarded as high-risk surgical candidates, an underappreciated and novel point of view for the perioperative literature. Furthermore, it is tempting to speculate that the inflammatory response elicited by major surgery, including total joint arthroplasty, might be mitigated by the continuation of DMARD therapy, a notion counter to current practice.
Compliance with Ethics Guidelines
Conflict of Interest
C. Ronald Mackenzie has served as a committee chair for the American College of Rheumatology.
Susan M. Goodman declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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