Ahmed M. Adlan

Autonomic function and rheumatoid arthritis—A systematic review

OBJECTIVES Rheumatoid arthritis (RA) is a chronic inflammatory condition with increased all-cause and cardiovascular mortality. Accumulating evidence indicates that the immune and autonomic nervous systems (ANS) are major contributors to the pathogenesis of cardiovascular disease. We performed the first systematic literature review to determine the prevalence and nature of ANS dysfunction in RA and whether there is a causal relationship between inflammation and ANS function. METHODS Electronic databases (MEDLINE, Central and Cochrane Library) were searched for studies of RA patients where autonomic function was assessed. RESULTS A total of 40 studies were included. ANS function was assessed by clinical cardiovascular reflex tests (CCTs) (n = 18), heart rate variability (HRV) (n = 15), catecholamines (n = 5), biomarkers of sympathetic activity (n = 5), sympathetic skin responses (n = 5), cardiac baroreflex sensitivity (cBRS) (n = 2) and pupillary light reflexes (n = 2). A prevalence of ~60% (median, range: 20-86%) of ANS dysfunction (defined by abnormal CCTs) in RA was reported in 9 small studies. Overall, 73% of studies (n = 27/37) reported at least one of the following abnormalities in ANS function: parasympathetic dysfunction (n = 20/26, 77%), sympathetic dysfunction (n = 16/30, 53%) or reduced cBRS (n = 1/2, 50%). An association between increased inflammation and ANS dysfunction was found (n = 7/19, 37%), although causal relationships could not be elucidated from the studies available to date. CONCLUSIONS ANS dysfunction is prevalent in ~60% of RA patients. The main pattern of dysfunction is impairment of cardiovascular reflexes and altered HRV, indicative of reduced cardiac parasympathetic (strong evidence) activity and elevated cardiac sympathetic activity (limited evidence). The literature to date is underpowered to determine causal relationships between inflammation and ANS dysfunction in RA.

Low-Volume High-Intensity Interval Training in a Gym Setting Improves Cardio-Metabolic and Psychological Health

Background Within a controlled laboratory environment, high-intensity interval training (HIT) elicits similar cardiovascular and metabolic benefits as traditional moderate-intensity continuous training (MICT). It is currently unclear how HIT can be applied effectively in a real-world environment. Purpose To investigate the hypothesis that 10 weeks of HIT, performed in an instructor-led, group-based gym setting, elicits improvements in aerobic capacity (VO2max), cardio-metabolic risk and psychological health which are comparable to MICT. Methods Ninety physically inactive volunteers (42±11 y, 27.7±4.8 kg.m-2) were randomly assigned to HIT or MICT group exercise classes. HIT consisted of repeated sprints (15–60 seconds, >90% HRmax) interspersed with periods of recovery cycling (≤25 min.session-1, 3 sessions.week-1). MICT participants performed continuous cycling (~70% HRmax, 30–45 min.session-1, 5 sessions.week-1). VO2max, markers of cardio-metabolic risk, and psychological health were assessed pre and post-intervention. Results Mean weekly training time was 55±10 (HIT) and 128±44 min (MICT) (p<0.05), with greater adherence to HIT (83±14% vs. 61±15% prescribed sessions attended, respectively; p<0.05). HIT improved VO2max, insulin sensitivity, reduced abdominal fat mass, and induced favourable changes in blood lipids (p<0.05). HIT also induced beneficial effects on health perceptions, positive and negative affect, and subjective vitality (p<0.05). No difference between HIT and MICT was seen for any of these variables. Conclusions HIT performed in a real-world gym setting improves cardio-metabolic risk factors and psychological health in physically inactive adults. With a reduced time commitment and greater adherence than MICT, HIT offers a viable and effective exercise strategy to target the growing incidence of metabolic disease and psychological ill-being associated with physical inactivity.

Muscle metaboreflex and autonomic regulation of heart rate in humans

•  Heart rate increases during exercise due to withdrawal of cardiac parasympathetic tone and increased cardiac sympathetic nerve activity. •  We investigated the autonomic mechanisms whereby heart rate is regulated by the activation of metabolically sensitive skeletal muscle afferents (muscle metaboreflex). •  Heart rate responses elicited by partial flow restriction during leg cycling (enhanced metaboreflex activation) and post‐exercise muscle ischemia following leg cycling and handgrip (isolated metaboreflex activation) were evaluated under control (no drug), β‐adrenergic blockade and parasympathetic blockade conditions. •  We show that the muscle metaboreflex principally elevates heart rate by increasing cardiac sympathetic activity, and only following dynamic exercise with a large muscle mass (post‐exercise muscle ischemia following leg cycling) does the partial withdrawal of cardiac parasympathetic tone make a contribution to this heart rate response. •  These findings may have implications for patient populations in which alterations in skeletal muscle afferent sensitivity have been identified.

Association Between Corrected QT Interval and Inflammatory Cytokines in Rheumatoid Arthritis

Objective. Corrected QT (QTc) interval predicts all-cause and cardiovascular mortality and may contribute to the increased mortality risk in rheumatoid arthritis (RA). Animal experiments have shown that proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin 1 (IL-1)] can prolong cardiomyocyte action potential. We sought to determine whether elevations in circulating inflammatory cytokines were independently associated with QTc prolongation in patients with RA. Methods. One hundred twelve patients [median age 62 (interquartile range 17) yrs; 80 women (71%)] from a well-characterized RA cohort underwent baseline 12-lead electrocardiograms for QT interval measurement and contemporary blood sampling to assess concentrations of inflammatory markers including C-reactive protein (CRP), TNF-α, and interleukins (IL-1α, IL-1β, IL-6, IL-10). QTc was calculated using the Bazett (QTBAZ = QT ÷ √RR) and Framingham Heart Study (QTFHS = QT + 0.154 × [1 – RR]) heart rate correction formulas. Results. Inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) were positively correlated with QTBAZ (Spearman rank correlation coefficient rho = 0.199, 0.210, 0.222, 0.333; all p < 0.05). In multivariable regression analysis, these associations were all confounded by age except IL-10, where higher tertile groups were independently and positively associated with QTBAZ (β = 0.202, p = 0.023) and QTFHS (β = 0.223, p = 0.009) when compared to the lower tertile. CRP (per unit increase) was independently associated with QTBAZ (β = 0.278, p = 0.001), but not QTFHS. Conclusion. To our knowledge, ours is the first study demonstrating a contemporary link between inflammatory cytokines and QT interval in humans. Our results suggest that a lower inflammatory burden may protect against QTc prolongation in patients with RA. However, further studies are required to confirm the effects of pro- and antiinflammatory cytokines on QTc interval.

Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory condition associated with an increased risk of cardiovascular mortality. Increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity heighten cardiovascular risk, althogh whether such autonomic dysfunction is present in RA is not known. In the present study, we observed an increased sympathetic nerve activity and reduced cardiac baroreflex sensitivity in patients with RA compared to matched controls. Pain was positively correlated with sympathetic nerve activity and negatively correlated with cardiac baroreflex sensitivity. The pattern of autonomic dysfunction that we describe may help to explain the increased cardiovascular risk in RA, and raises the possibility that optimizing pain management may resolve autonomic dysfunction in RA.

Benefit-risk assessment of dronedarone in the treatment of atrial fibrillation.

Rhythm control in atrial fibrillation (AF) can be achieved using pharmacological therapy. Amiodarone is the most efficacious anti-arrhythmic agent; however, its use is limited due to an unfavourable safety profile, including pro-arrhythmia, thyroid, liver, skin and pulmonary complications. Dronedarone, which is structurally similar to amiodarone, was developed to try and achieve a favourable balance of efficacy and risk. Dronedarone has been evaluated in several large clinical trials, which have shown reduced mortality and hospitalization rates in patients with non-permanent AF. In patients with permanent AF and/or heart failure, dronedarone has been shown to cause increased mortality and morbidity and should not be used in these groups. Compared with amiodarone, dronedarone has fewer toxic effects (thyroid, skin, pulmonary) and, although less efficacious, may be used as first-line therapy for maintenance of sinus rhythm in patients with non-permanent AF. Clinicians must be vigilant in monitoring their patients to ensure they do not develop permanent AF or heart failure.

Neutrophil and Monocyte Bactericidal Responses to 10 Weeks of Low-Volume High-Intensity Interval or Moderate-Intensity Continuous Training in Sedentary Adults.

Neutrophils and monocytes are key components of the innate immune system that undergo age-associated declines in function. This study compared the impact of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on immune function in sedentary adults. Twenty-seven (43 ± 11 years) healthy sedentary adults were randomized into ten weeks of either a HIIT (>90% maximum heart rate) or MICT (70% maximum heart rate) group training program. Aerobic capacity (VO2peak), neutrophil and monocyte bacterial phagocytosis and oxidative burst, cell surface receptor expression, and systemic inflammation were measured before and after the training. Total exercise time commitment was 57% less for HIIT compared to that for MICT while both significantly improved VO2peak similarly. Neutrophil phagocytosis and oxidative burst and monocyte phagocytosis and percentage of monocytes producing an oxidative burst were improved by training similarly in both groups. Expression of monocyte but not neutrophil CD16, TLR2, and TLR4 was reduced by training similarly in both groups. No differences in systemic inflammation were observed for training; however, leptin was reduced in the MICT group only. With similar immune-enhancing effects for HIIT compared to those for MICT at 50% of the time commitment, our results support HIIT as a time efficient exercise option to improve neutrophil and monocyte function.

Cardiovascular autonomic regulation, inflammation and pain in rheumatoid arthritis

Background Rheumatoid arthritis (RA) is a chronic inflammatory condition characterised by reduced heart rate variability (HRV) of unknown cause. We tested the hypothesis that low HRV, indicative of cardiac autonomic cardiovascular dysfunction, was associated with systemic inflammation and pain. Given the high prevalence of hypertension (HTN) in RA, a condition itself associated with low HRV, we also assessed whether the presence of hypertension further reduced HRV in RA. Methods In RA-normotensive (n = 13), RA-HTN (n = 17), normotensive controls (NC; n = 17) and HTN (n = 16) controls, blood pressure and heart rate were recorded. Time and frequency domain measures of HRV along with serological markers of inflammation (high sensitivity C-reactive protein [hs-CRP], tumour necrosis factor-α [TNF-α] and interleukins [IL]) were determined. Reported pain was assessed using a visual analogue scale. Results Time (rMSSD, pNN50%) and frequency (high frequency power, low frequency power, total power) domain measures of HRV were lower in the RA, RA-HTN and HTN groups, compared to NC (p = 0.001). However, no significant differences in HRV were noted between the RA, RA-HTN and HTN groups. Inverse associations were found between time and frequency measures of HRV and inflammatory cytokines (IL-6 and IL-10), but were not independent after multivariable analysis. hs-CRP and pain were independently and inversely associated with time domain (rMMSD, pNN50%) parameters of HRV. Conclusions These findings suggest that lower HRV is associated with increased inflammation and independently associated with increased reported pain, but not compounded by the presence of HTN in patients with RA.

Sarcoidosis presenting as dilated cardiomyopathy

A 48-year-old lady presented with dyspnoea and chest pain. ECG showed sinus tachycardia with right bundle branch block and right ventricular strain. Echocardiography showed a dilated left ventricle with normal wall thickness and incoordinate septal motion with a globally poor systolic function (ejection fraction of 20%). Coronary angiography revealed normal coronary arteries. Cardiovascular magnetic resonance showed significant delayed enhancement following gadolinium contrast agent …

Acute hydrocortisone administration reduces cardiovagal baroreflex sensitivity and heart rate variability in young men

A surge in cortisol during acute physiological and pathophysiological stress may precipitate ventricular arrhythmia and myocardial infarction. Reduced cardiovagal baroreflex sensitivity and heart rate variability are observed during acute stress and are associated with an increased risk of acute cardiac events. In the present study, healthy young men received either a single iv bolus of saline (placebo) or hydrocortisone, 1 week apart, in accordance with a randomized, placebo‐controlled, cross‐over study design. Hydrocortisone acutely increased heart rate and blood pressure and reduced cardiovagal baroreflex sensitivity and heart rate variability in young men. These findings suggest that, by reducing cardiovagal baroreflex sensitivity and heart rate variability, acute surges in cortisol facilitate a pro‐arrhythmic milieu and provide an important mechanistic link between stress and acute cardiac events