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Keywords:

  • cardiovascular;
  • heart rate;
  • rheumatoid arthritis;
  • subendocardial viability ratio

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

Aim

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality. In the general population, an increased heart rate is associated with increased mortality. Only a few studies have investigated heart rate in RA patients and compared the results with patients that do not have RA (n-RA). Therefore, little is known as to whether an increased heart rate, at least in part, could explain the increased mortality found in RA patients. The aim of the present study was to investigate whether heart rate is increased in RA patients.

Methods

In this cross-sectional study, heart rate was determined in a total of 282 patients (131 RA, 151 n-RA). In addition, non-invasive pulse wave analysis of the radial artery was performed to determine cardiac ejection duration using the Sphygmocor apparatus. Furthermore, the subendocardial viability ratio (SEVR), a marker of cardiac workload, was investigated, whereby higher values indicate a more favorable supply/demand relationship for the myocardium. Patients using chronotropic drugs were not included in the study.

Results

Heart rate was virtually the same in RA patients (71.9 ± 11.2 beats/min [bpm]) as compared with controls (72.3 ± 11.7 bpm; > 0.05). Also SEVR (RA 144 ± 25% vs. n-RA 147 ± 27%; > 0.05) and ejection duration (RA 321 ± 24 ms vs. n-RA 318 ± 24 ms; > 0.05) were comparable between the groups.

Conclusion

It could not be shown that heart rate in RA patients differs significantly from heart rate in controls. Therefore, heart rate does not appear to explain or contribute to the increased cardiovascular risk found in RA patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

It is well established that rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality.[1, 2] It is believed that the premature and accelerated atherosclerotic processes found in RA patients are mainly driven by ongoing systemic inflammation.[3] It appears that traditional cardiovascular risk factors do have a lower impact on cardiovascular disease in RA patients as compared with the general population.[4] Besides other established risk factors, such as smoking, hypertension and cholesterol, one known cardiovascular risk factor is heart rate: the higher the heart rate, the higher the cardiovascular mortality.[5, 6] An increased heart rate affects the cardiovascular system in multiple ways. In the short term, an increased heart rate causes a higher energy demand of the myocardium. This may lead to myocardial ischemia.[7] In addition, a higher heart rate is associated with a shorter time of relaxation of the heart, which may decrease the time of coronary perfusion.[8] In the long term, heart rate leads to remodelling processes within the cardiovascular system: coronary heart disease patients with a higher heart rate show more significant calcification of their coronary vessels.[9] An increased heart rate is also associated with vascular dysfunction.[10] Going further, rupture of coronary plaques may be more frequent at a higher heart rate.[11] Finally, arrythmias are found more frequently in patients with an increased heart rate.[8]

Of interest, little is known as to whether RA patients do have a higher heart rate as compared with controls, which could in turn contribute to the increased mortality found in RA patients.

During systole blood is ejected from the left ventricle into the aorta and during diastole most of the myocardial perfusion takes place. An impaired relationship between energy-consuming myocardial contraction and oxygen supply may have detrimental effects on the cardiac system. The subendocardial viability ratio (SEVR) is a measure of myocardial perfusion relative to cardiac workload.[12-14] It provides a useful measure of the relationship between subepicardial/subendocardial blood flow and cardiac workload. Preliminary data suggest that estimation of SEVR by using applanation tonometry may provide a tool for the assessment of coronary flow reserve and coronary microcirculation.[15] A parameter which is closely related to heart rate and SEVR is ejection duration, as it reflects the time interval when blood is ejected into the aorta.

The aim of this study was to analyse the heart rate in RA patients with or without cardiovascular comorbidities and to compare the results with controls that do not have RA (n-RA group). This should allow for the interpretation of the results in the context of a ‘real world’ scenario. Additionally, we non-invasively investigated ejection duration and SEVR. This should provide an estimate on coronary flow reserve.15

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

Included in this cross-sectional analysis were patients with a diagnosis of RA according to the 1987 American College of Rheumatology (ACR) criteria.[16] Patients with early arthritis were not included. This exclusion criterion was based on the assumption that RA would have a detectable impact on the cardiovascular system only after a reasonable amount of time, therefore making it difficult to measure potential differences between the two groups at a very early state. In addition, patients using beta-blockers, ivabradine, cardiac glycosides or non-dihydropyridine-type calcium antagonists were excluded from the analysis because of their strong impact on heart rate.

The study was approved by the local ethics committee and is in accordance with the Helsinki Declaration. All patients and controls gave informed consent to participate in the study.

A total of 282 participants were included in this study, 131 of them having RA (consecutively recruited from the inpatient as well as outpatient clinic); 151 participants, recruited from the same department (specializing in rheumatology as well as in internal medicine), served as a control group (n-RA group). Patients with inflammatory rheumatic diseases other than RA were not included in the study. For each study participant co-morbidities and traditional cardiovascular risk factors were registered. Diabetes was diagnosed according to the guidelines of the Austrian Diabetes Association[17] or if the patient had any form of anti-diabetic medication. Smoking habits and history of former cardiovascular events were registered as provided by the study participants.

We evaluated disease duration, present and historically failed treatment with disease-modifying anti-rheumatic drugs (DMARDs), the presence of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), duration of morning stiffness and patient global assessment (PGA;100-mm visual analogue scale). In addition, tender joint count (TJC; 28 joints), swollen joint count (SJC; 28 joints) and the disease activity score 28 (DAS 28) were investigated in RA patients.[18]

Pulse pressure reading was performed after the patient had been lying in the supine position for several minutes using an automated oscillometric method (boso medicus, Bosch + Sohn GMBH, Jungingen, Germany; validated and certified by the German Society for Hypertension).[19]

Pulse wave analysis (PWA) was performed to determine heart rate, ejection duration and SEVR on the radial artery using applanation tonometry with a high-fidelity micro-manometer (SPC-301; Millar Instruments, Houston, TX, USA) as previously described.[19] In short, the aortic pressure waveform was derived from radial tonometry using a previously validated generalized transfer function relating radial to aortic pressure waveform within the integrated system software of the Sphygmocor apparatus (AtCor Medical, version 6.31, Sydney, NSW, Australia).[20, 21] Only high-quality data were used for the analyses. Each measurement was taken twice and the means were used for statistical analysis. Heart rate was calculated by the Sphygmocor software. The SEVR is a composite of two underlying determinates: it is calculated as the ratio of the area under the diastolic section (=integral pressure over time) of the derived aortic pressure waveform (diastolic time index, DTI) to the area under the systolic section of the waveform (tension time index, TTI). Lower values indicate an unfavorable supply/demand relationship for the myocardium. SEVR is independent from aortic pulse pressure, but it is inversely correlated with left ventricular pressure (i.e. a higher left ventricular end-diastolic pressure is associated with a lower SEVR).[12] Previously, a high inter-operator reproducibility of 2.7% could be demonstrated.[22] Ejection duration is the time period from the beginning of the rise of the central pulse pressure until the incisura in the pressure curve, reflecting the closing of the aortic valve, which also marks the boundary between systole and diastole.

Statistical analysis

In statistical analysis of indicator and metric variables the χ2 test was used. A P-value < 0.05 was accepted for statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

The baseline characteristics of all participants as well as the results are shown in Table 1. Patients were significantly older than controls and had higher cholesterol levels, but were less frequently diabetics and smokers. Heart rate was virtually the same in RA patients (71.9 ± 11.2 beats/min [bpm]) as compared with controls (72.3 ± 11.7 bpm; > 0.05). Also SEVR was comparable between the groups (RA 144 ± 25% vs. n-RA 147 ± 27%; > 0.05). This was also true for both determinates of the SEVR, the DTI (RA 3490 ± 475ms × mmHg vs. n-RA 3379 ± 592 ms × mmHg; > 0.05) and the TTI (RA 2484 ± 478 ms × mmHg vs. n-RA 2375 ± 499 ms × mmHg; > 0.05). Finally, ejection duration was virtually the same in both groups (RA 321 ± 24 ms vs. n-RA 318 ± 24 ms; > 0.05).

Table 1. Characteristics of participants and results of applanation tonometry
 RA (n = 131)n-RA (n = 151)P-value
Age, years54.3 (12.6)46.3 (11.4)< 0.001
Female, n (%)115 (87.8)137 (90.7)0.42
RA duration, years13.2 (9.2)  
RF positive (%)74  
ESR, mm/h25.8 (23.3)  
CRP, mg/dL1.8 (3.5)  
DAS 283.37 (1.6)  
TJC, n3.4 (5.8)  
SJC, n3.5 (4.7)  
Number of DMARDs, n (%)
08 (6.1)  
165 (49.6)  
256 (42.7)  
32 (1.5)  
Methotraxate94 (71.8)  
Sulfasalazine6 (4.6)  
Leflunomide16 (12.2)  
Hydroxychloroquine10 (7.6)  
Other traditional DMARD2 (1.6)  
TNF-inhibitor45 (34.4)  
Other biologics10 (7.6)  
Systolic BP, mmHg132.4 (20.2)128.6 (21.1)0.31
Diastolic BP, mmHg80.0 (10.9)77.5 (12.4)0.15
Former cardiovascular event4 (3.0)3 (2.0)0.57
Diabetes, n (%)2 (1.5)34 (22.5)< 0.001
Anithypertensive medication11 (8.2)25 (14.3)0.05
Smokers22 (16.8)43 (28.5)0.02
Former smokers27 (18.2)19 (13.2)0.11
Cholesterol, mg/dL216 (41)192 (49)0.025
Triglyzerides115.3 (56.5)126.0 (104.2)0.002
Heart rate (bpm)71.9 (11.2)72.3 (11.7)0.66
Ejection duration (ms)321 (24)318 (24)0.59
SEVR (%)144 (25)147 (27)0.65
DTI, ms × mmHg3490 (475)3379 (592)0.07
TTI, ms × mmHg2484 (478)2375 (499)0.34

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

Heart rate, a known risk factor for cardiovascular mortality, does not appear to be increased in RA patients as compared to controls. Thus, it is unlikely that heart rate plays a major role in explaining increased cardiovascular mortality in RA patients. These findings are underlined by the fact that ejection duration was also comparable between patients and controls. This is not surprising, as heart rate and ejection duration do show a linear relationship (with shorter ejection duration at higher heart rates).

As mentioned previously, several mechanisms contribute to the increased cardiovascular morbidity and mortality found in individuals with an increased heart rate.[5, 6] In a longitudinal study It could be demonstrated that an increase of the heart rate from baseline < 70 bpm to > 85 bpm over approximately 10 years is associated with an increased risk of death due to ischemic heart disease by a factor of 1.9 in comparison to patients with a heart rate of < 70 bpm at both measurements.[23]

RA is associated with an increased cardiovascular morbidity and mortality, which cannot be sufficiently explained by traditional cardiovascular risk factors.[1, 2] Elucidating the risk factors contributing to the increased risk for RA patients could be useful in developing strategies to reduce the burden of cardiovascular death in this particular patient group. Given our results, heart rate does not appear to explain or contribute to the increased cardiovascular risk found in RA patients. However, it should be emphasised that in our study traditional cardiovascular risk factors (such as diabetes and age) were not equally distributed between RA patients and controls. The high number of patients with diabetes in the control group is in part due to the fact that the control group was recruited from a department of internal medicine. The higher cholesterol levels in RA patients appear to reflect better control of the underlying disease rather than an increased cardiovascular risk, as is the case in the general population.[24] In addition, in our RA cohort there were a high percentage of female RA patients (87.8%). In theory, also this could have an influence on the results; probably results would be different in a cohort including more male RA patients. Keeping these limitations in mind, it appears very unlikely that reducing heart rates in RA patients, for instance with ivabradine, would have any additional effect as compared to patients without RA.[25]

A reduced SEVR is an indicator of an unfavourable state of substrate supply and demand during cardiac workload,[12-14] and it is associated with a reduced coronary flow reserve.[15] The latter is accompanied with a poor prognosis.[26] We did not find a reduced SEVR in RA patients. These findings argue against a significant skewed ratio of subepicardial/subendocardial blood flow and cardiac workload and therefore, they point in the direction that pressure-time-integrals in the myocardium are not deteriorated in RA patients. Given the fact that we have measured SEVR non-invasively by applanation tonometry, and therefore, only have an indirect clue of coronary flow reserve,[15] we cannot exclude that the direct measurement of coronary flow reserve (e.g. coronary catheterization) may yield different results.

In this study we investigated surrogate parameters of cardiovascular disease. Therefore, our data cannot give a final answer to the question of how heart rate influences mortality and/or cardiovascular events in RA patients. For that purpose, a large prospective, longitudinal study would be needed.

In conclusion, in this cross-sectional study we did not find an increased heart rate or impaired SEVR in RA patients as compared to controls. Our results point against a substantial role of heart rate as a significant cardiovascular risk factor in RA patients.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References
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