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Introduction
Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease that leads to progressive joint deformity and disability.1 affecting approximately 1% of the population worldwide.2-9 Major cohort studies have demonstrated that patients suffering from RA are 3 to 5 times more likely to experience hospitalization for unrecognized, or silent myocardial infarction (MI) than age- and sex-matched controls.10,11 Therefore, patients suffering from RA are at a higher risk, ranging from 40 to 65%, to suffer from ischemic heart disease (IHD) without any recognized symptoms. However, before death, the patients were not aware of their cardiovascular risk.12-14
A wide range of literature including systematic reviews, meta-analyses and population-based studies with long and complete follow-ups, indicate that the causes of cardiovascular disease (CVD) in patients with many of the traditional cardiovascular risk factors (CVRF) such as hypertension, smoking, diabetes mellitus, obesity and hypercholesterolemia at baseline is similar amongst RA and non-RA patients.1,15 However, there is no consensus on the correlation between the presence of CVRF and ischemic heart disease as an outcome. Thus, CVD have become an important long-term end point for RA patients independent of traditional CVRF.16-21
In this setting, cardiovascular injury and mortality might be due to the presence of a chronic systematic inflammatory response.2 This is characterized by the release of high levels of pro-inflammatory substances (the cytokines, tumor necrosis factor alpha, interleukin-1, interleukin 2, and adhesion molecules), that causes endothelial dysfunction and the subsequent atherosclerotic disease.3 Evidence points that the chronic inflammation follows a pathogenesis pathway that occurs in RA and it would lead to increase atherosclerosis as a side effect while acting at a distance on the systemic vascular endothelium.4
Strategies that focus solely in the control of CVRF are inadequate since the distribution is generally the same but their impact results in different outcomes; and more relevant, symptoms remain silent for a long time. Consequently, to reduce such gap there is a need to assess IHD in patients with RA even if they have no symptoms and independent of the existence of cardiovascular RF to prevent and reduce cardiovascular mortality.
Objective
We aimed to evaluate myocardial perfusion in asymptomatic by gated single-photon emission computed tomography (g-SPECT) in a group of Mexican patients with rheumatoid arthritis.
Patients and methods
In this prospective observational study, we enrolled 91 consecutive patients with a previous rheumatoid arthritis clinical diagnose, and with at least one traditional cardiovascular risk factor. We excluded those patients with any history of angina or IHD. Patients were referred from the Rheumatology service to the Nuclear Medicine department from March to August 2015. All patients were asked their age, sex, years with RA diagnosis and prescribed treatment.
Assessments
Data were collected on traditional cardiovascular risk factors using established diagnostic criteria. Their body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m2). Diabetes mellitus was defined as a fasting plasma glucose level of 7.0 mmoles/liter (126 mg/dL) or a 2-hour glucose level of 11.1 mmoles/liter (200 mg/dL).5 Hypertension was defined as systolic blood pressure ≥ 140 mmHg and diastolic pressure ≥ 90 mmHg.6 Hypercholesterolemia was defined as a fasting plasma cholesterol level of 5 mmoles/liter (200 mg/dL) at baseline. Patients were considered cigarette smokers by current self-report.
In order to measure the activeness of rheumatoid arthritis, we used composite scores of the disease activity (DAS28 Score). DAS28 is validated index scale which provides a number from cero to 10; DAS28 > 5.1 means high disease activity, DAS28 = 3.2 to 5.1 moderate activity, DAS28 3.2 to 2.1 low disease activity, whereas a < 2.1 indicates remission.7 High sensitivity C-reactive Protein (hs-CRP) was quantified, where the reference range was as follows: low risk 1.0 mg/L, medium risk 1 to 3.0 mg/L and high risk above 3.0 mg/L.8 Also, erythrocyte sedimentation rate (ESR) was assessed assuming normal values as 0-22 mm/h for men and 0-29 mm/h for women.9
Nuclear screening
All 91 patients were non-invasively assessed trough gated single-photon emission computed tomography (g-SPECT), which is a non-invasive cardiovascular imaging technique.
Image acquisition
The perfusion images were acquired in synchronization with the patient’s electrocardiogram (g-SPECT), this allowed us to study not only the left myocardial perfusion, but also the mobility, the systolic wall thickening and left ventricle ejection fraction (left myocardial function).
We utilized a gamma camera SIEMENS®-Symbia-S, with IQ-SPECT technology (dual head) and collimators SMATRZOOM with acquisition of 32 images (in 180o elliptical orbit from 45o right anterior oblique to 45o left anterior oblique, in step and shoot mode); allowing the use of radiotracer lower doses and the acquisition of high quality imaging in less time (4 minutes). Following the guidelines of the American Society of Nuclear Cardiology (ASNC)10American College of Cardiology (ACC),11 and American Heart Association (AHA),11 SPECT MPI was performed in a 1-Day protocol. The stress examination was done under physical or pharmacological with dipyridamole (according to the physical capacity and clinical condition of the patient). Technetium-99m sestamibi 8 mCi and 16 mCi were injected at rest and stress, respectively.
Image processing and data analysis
All g-SPECT myocardial perfusion imaging (MPI) studies were analyzed by two experienced nuclear cardiologist physicians who were blinded to perfusion results (Kappa intra e inter-observer 0.92). Reconstruction and image processing was generated in the usual levels: short axis, vertical long axis and horizontal long axis. For qualitative analysis, perfusion SPECT studies were assessed visually, using the 17-segment model which were rated based on the severity of perfusion defects in visual 5-point scale, where 0 denotes normal perfusion; 1 mild perfusion defect; 2 moderate defects; 3 severe perfusion defect and 4 denotes absence perfusion. Necrosis was indicated at the presence of a perfusion defect in the rest images, and was defined as transmural (severe defect or absence of perfusion) and nontransmural (moderate perfusion defect). Ischemia was indicated where the presence of a reversible defects, which refers to a perfusion defect present in stress that resolved at rest in the same segment, and was rated as mild, moderate and severe.
Statistical analysis
Descriptive data were generated for all variables. In order to test whether or not ischemia was statistically significantly associated with traditional CV risk factors and characteristics of RA, we calculated the relative risk, odds ratio and 95% CI. All analyses were carried out using SPSS, version 21.
Results
The sample consisted of 91 patients presenting RA diagnosis and without any history of angina or coronary artery disease. Eight were men and 83 women. Mean age was 59 ± 12, with a range of 27 and 84. The median number of years with diagnosis was 18.5 ± 7.9, the minimum number of years was 2 and the maximum was 36. Body mass index mean was 27.6 ± 4.8; 65 (71.4%) patients were obese, 17 (18.7%) classified as normal weight and 9 (9.1%) were overweight. The majority of patients (95.6%) underwent disease modifying antirheumatic drugs (DMARD) alone or combined with other modality of treatment. The median DAS28 score was 1.5 (IQR 1.0-5.2); 44 patients (48.4%) had a low severity, 29 (31.9%) had medium severity, and the remaining 18 (19.8%) had a high severity. According to the analyses of inflammation markers, hs-CRP mean was 11.14 ± 12.0 mg/L, whereas ESR mean was 26.5 ± 13.4 mm/h. Table I presents the distribution of clinical characteristics associated to RA, and risk factors, divided into two groups; with and without ischemia assessed by g-SPECT.
Table I: Characteristics of patients with RA with and without ischemia assessed by gated-SPECT.
In general, 22 (24.2%) patients presented ischemia when assessed by the g-SPECT.
The severity of the ischemia was mostly mild ischemia. The more frequent location of the myocardial perfusion alteration was in the territory of the anterior descending coronary artery (DA) as is presented in Table II.
Table II: Frequency of patients for each level and location of myocardial perfusion abnormalities.
LAD = Left anterior descending artery, LCX = Left circumflex coronary artery, RCA = Right coronary artery.
Numbers in parentheses are the % of the total number of ischemia cases.
Regarding traditional cardiovascular risk factors, hypertension was the most common; found in 29 (31.9%) patients, followed by smoking found in 13 (14.3%) and lastly diabetes mellitus in 9 (9.8%). Table III shows the distribution of risk factors as well as the relative risk for ischemia and odds ratios. Smoking steroid treatment were statistically significant risk factors for presenting ischemia. Since the 95% CI for the rest of risk factors span 1.0, the odds of having a diagnosed risk factor and presenting ischemia do not reach statistical significance.
Discussion
The present study was designed to assess with a non-invasive cardiovascular imaging technique, the existence of ischemia in asymptomatic patients with rheumatoid arthritis and traditional cardiovascular risk factors. The development of quantitative methods in the attempt to diagnose IHD by nuclear imaging test, has provided a more objective measure, reducing operator bias compared with traditional diagnostic approaches.12 We have presented evidence to fill the gap for screening myocardial perfusion in patients with RA with more accuracy, since we have also presented the injured territory and the severity of the disease. These results support previous research regarding the non-relation between traditional CVRF and ischemia in this type of patients (5-9, 11-15). In fact, the most important clinically relevant finding of our study was that only one traditional CVRF, which was smoking, was statistically significantly associated with the presence of ischemia. The other significant relative risk, was treatment with steroids, which has also been topic of discussion because it has been related to endothelial dysfunction and atherosclerosis development.13 This means that neither the relevant clinical symptoms of the rheumatologic disease, as pain in articulations and inflammation evaluated with the DAS28 score, counted as a statistically significant association to the presence of ischemia. It is worth noting, that even when hs-CRP and ESR values were higher than the normal mean, there was not statistically significant correlation with ischemia. Therefore, the value of the myocardial perfusion assessment by g-SPECT is of enormous relevance, since it reveals the exact location and severity of myocardial perfusion defects, as a final outcome for asymptomatic patients (silent myocardial ischemia) with intermediate to high cardiovascular risk. This strategic diagnosis goes beyond what it is explained by traditional CVRF and the clinical rheumatologic disease’s characteristics. In fact, a striking observation is that our youngest patient; a woman aged 27, with two years of diagnosed RA and with DM as a risk factor, presented ischemia already.
Therefore, because the presence of myocardial perfusion defects could not be attributable to CVRF, we suggest that the abnormalities (ischemia or infarction) in gated-SPECT MPI can be explained by the persistence of a systemic inflammation PROCESS and endothelial dysfunction, as an inherent side effect of rheumatoid disease; explaining an accelerated atherosclerosis process.14
A non-invasive strategic diagnosis was possible because of the use of novel and updated software programs, which allow a non-invasive, automatic, quantitative, and without operator bias assessment of the left myocardial perfusion. Thus, the sensibility (90%) and accuracy (100%) of the method makes it a reproducible tool, since it allows the detection of perfusion abnormalities and the existence of functional coronary significant obstructions in the different anatomical territories (LAD, LCX and RCA), as well as the severity and the extension of the coronary artery disease.
In asymptomatic patients with suspicion or an intermediate to high risk to develop atherosclerotic coronary disease, as the case of patients with RA, g-SPECT technique is highly safe and reliable since it is credited for less than 1% of complications. In addition, it is the most used method in nuclear cardiology.
Conclusion
The present study will serve as a base for considering arthritis rheumatoid as a risk factor to develop atherosclerotic coronary artery disease. We have confirmed previous findings and have contributed additional evidence that suggests the need to explore CVD in patients with RA even if they have no symptoms and independently of the existence of cardiovascular risk factors to prevent and reduce cardiovascular mortality. We enhance the value of the g-SPECT as a non-invasive cardiovascular imaging evidence-based technique to perform strategic early assessments in asymptomatic patients with intermediate to high cardiovascular risk.
Limitations and suggestions
Due to the large prevalence of one or more cardiovascular risk factors within the Mexican population, more research is required to determine economic considerations and clinical implications to implement diagnosis protocols. Further investigation should focus on the role of steroid doses.
