Israel Medical Association Journal

The interplay between post-traumatic stress disorder (PTSD) and autoimmunity is well known. One of the contributors leading to immune disorders is autonomic dysregulation, which is characterized by attenuated parasympathetic and elevated sympathetic systems. In this review, we described evidence regarding the relationship between stress, PTSD, autonomic dysfunction, and autoimmunity. Stress is a physiological response, which is functional for our being. The implication of dysfunction in stress response may be a cause of disease development. We described the fundamental role of the pathological high levels of stress in PTSD as a mediator factor that contributes to autonomic dysfunction, which as a result may lead to autoimmunity. Systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes are some of the autoimmune diseases PTSD patients are at higher risk of developing. Notably, some autoimmune diseases are shown to increase the susceptibility to develop PTSD, which may indicate a bidirectional influence. In addition, we elaborated on stress as a major component in both fibromyalgia and PTSD, as there are overlaps between the pathogenesis of fibromyalgia and PTSD. Underlying chronic low-grade inflammation, which characterizes PTSD patients, may be a potential target and biomarker in treating PTSD patients. We believe that chronic low-grade inflammation, high concentrations of cytokines, and other inflammatory biomarkers, which characterize PTSD patients, may be potential targets and biomarkers in the treatment of PTSD patients and part of the PTSD diagnostic criteria.

Pneumonia patients are susceptible to autonomic nervous system changes. Ultrashort HRV (usHRV) is the measurement of cyclic changes in heart rate over a period < 5 minutes.

Objectives: To describe usHRV in patients with pneumonia and assess the correlation with mortality.

Methods: We conducted a retrospective analysis, which included patients diagnosed with pneumonia in the emergency department (ED). UsHRV indices were calculated from a 10-second ED electrocardiogram and correlated with mortality utilizing logistic and Cox regressions.

Results: The study comprised 240 patients. Mortality rates over 30, 90, and 365 days were 13%, 18%, and 30%, respectively. usHRV frequency-domain parameters had significant univariate correlations with mortality. Normalized low frequency (LF) and high frequency (HF) were correlated with 30-, 90-, and 365-day mortality in an opposite direction (odds ratio [OR] 0.094, P = 0.028 vs. OR 4.589, P =0.064; OR 0.052, P = 0.002 vs. OR 6.975, P =0.008; OR 0.055, P < 0.001 vs. OR 7.931, P < 0.001; respectively). Survival analysis was conducted for a follow-up median period of 5.86 years (interquartile range 0.65–9.77 years). Univariate Cox proportional hazard regression revealed time-domain indices with significant correlation with survival (SDNN and RMSSD; hazard ratio [HR] 1.005, 1.005; P = 0.032, P = 0.005; respectively) as well as frequency-domain parameters (normalized LF, HF, LF/HF ratio, and total power; HR 0.102, 5.002, 0.683, 0.997, respectively; P < 0.001).

Conclusions: usHRV may predict mortality in pneumonia patients and serve as a novel risk stratification tool.

Background: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease.

Objectives: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged.

Methods: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls.

Results: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups.

Conclusions: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies

Abstract

Background: The relationship between autonomic nervous system (ANS) dysfunction and familial Mediterranean fever (FMF) is controversial. We recently reported normal heart rate variability (HRV), suggestive of normal ANS, in patients with uncomplicated FMF.

Objectives: To evaluate ANS function in colchicine non-responders by using the HRV tool.

Methods: The study group comprised 24 FMF patients suffering from recurrent FMF attacks despite treatment with a maximal colchicine dose. Electrocardiogram was measured under strict conditions and HRV parameters were calculated. Results were compared with age- and gender-matched unaffected controls.

Results: No statistically significant difference was found between the groups in any of the HRV parameters: maximal RR, minimal RR and average RR intervals, standard deviation of RR interval, square root of the mean squared differences of successive RR intervals, HRV triangular index, NN50, pNN50, and power spectral analysis parameters.

Conclusions: Although a small difference in HRV parameters in the current study cannot be entirely excluded, FMF patients in whom colchicine did not provide adequate symptomatic relief and who did not develop amyloidosis appear to have normal HRV parameters suggestive of normal ANS function, compared with healthy adults. 

Background: Familial dysautonomia is a genetic disease that affects the sensory and autonomic nervous systems with varying severity. The deep breath test is one of several measures used to assess the severity of autonomic diseases, but its value in familial dysautonomia has not yet been investigated.

Objectives: To determine the diagnostic value of the DBT[1] in patients with familial dysautonomia.

Methods: Eight patients with familial dysautonomia and eight healthy volunteers were examined by electrocardiography for 1 minute at rest and during forced deep breathing. The following values were recorded: maximum expiratory and minimum inspiratory heart rate and the difference between them (ΔE/I), standard deviation of the heart rate values, interbeat intervals, and E/I[2] ratio. Spectral power analysis of heart rate variability was also performed.

Results: The patients with familial dysautonomia showed a lesser change in heart rate in response to the change in breathing pattern than the controls. Mean values in the study group were significantly higher for minimal inspiratory heart rate and significantly lower for ΔE/I, heart rate standard deviation and E/I ratio, indicating a non-flexible heart response and abnormal parasympathetic function. These findings were supported by power spectral analysis.

Conclusions: Patients with familial dysautonomia have a significantly disturbed response to physiological stimuli. The DBT may serve as a reliable means to quantify autonomic dysfunction in this patient population.

Fibromyalgia syndrome is a chronic, painful musculoske­letal disorder of unknown etiology and/or pathophysiology. During the last decade many studies have suggested autonomic nervous system involvement in this syndrome, although contradictory results have been reported. This review focuses on studies of the autonomic nervous system in fibromyalgia syndrome and related disorders, such as chronic fatigue syndrome and irritable bowel syndrome on the one hand and anxiety disorder on the other, and highlights techniques of dynamic assessment of heart rate variability, It raises the potentially important prognostic implications of protracted autonomic dysfunction in patient populations with fibromyalgia and related disorders, especially for cardiovas­cular morbidity and mortality.

Background: Articular cartilage is incapable of undergoing self-repair since chondrocytes lose their mitotic ability as early as the first year of life. Defects in articular cartilage, especially in weight-bearing joints, will predictably deteriorate toward osteoarthritis.  No method has been found to prevent this deterioration. Drilling of the subchondral bone can lead to fibrocartilage formation and temporary repair that slowly degrades. Animal experiments indicate that introducing proliferating chondrocytes such as cultured articular chondrocytes can reliably reconstruct joint defects.

Objectives: To describe our clinical experience in culturing and transplanting autologous chondrocytes. 

Methods: Biopsies were obtained from 10 patients, aged 18–45, undergoing a routine arthroscopy in which a cartilage defect was identified with indications for cartilage transplantation. The biopsies were further processed to establish chondrocyte cultures. ACT was performed in 8 of the 10 patients because of persistent symptoms for at least 2 months post-arthroscopy. All patients (6 men and 2 women) had a grade IV cartilage defect in the medial or lateral femoral condyle, and three had a defect in the trochlear region as well. Biopsies were removed from the lateral rim of the superior aspect of the femur, and cells were cultured in a clean room. Following a 2 order of magnitude expansion, cells were implanted under a periosteal flap.

Results: The eight patients implanted with autologous cells were followed for 6 months to 5 years (average 1 year). Complaints of giving-way, effusion and joint locking resolved in all patients, and pain as assessed by the visual analogue score was reduced by an average of 50%. Follow-up magnetic resonance imaging studies in all patients revealed that the defects were filled with tissue having similar signal characteristics to cartilage.

Conclusions: Chondrocyte implantation is a procedure capable of restoring normal articular cartilage in cases with isolated joint defects. Pain can be predictably reduced, while joint locking and effusion are eliminated. The effect on osteoarthritis progression in humans has not yet been elucidated.

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ACT = autologous chondrocyte transplantation

Background: Spectral analysis of heart rate variability has been shown to be a reliable non-invasive test for quantitative assessment of cardiovascular autonomic regulatory responses, providing a window reflecting the interaction of sympathetic and parasympathetic tone. Alterations in autonomic function are associated with a variety of physiologic and pathophysiologic processes and may contribute substantially to morbidity and mortality. Our previous study shows that patients with post-traumatic stress disorder have significantly lower HRV compared to controls, reflecting a basal autonomic state characterized by increased sympathetic and decreased parasympathetic tone.

Objectives: To apply this tool to PTSD patients treated with selective serotonin re-uptake inhibitors in order to assess the impact of such treatment on the autonomic dysregulation characterizing these patients.

Methods: Standardized heart rate analysis was carried out in nine PTSD patients treated with SSRI agents and compared to that in a matched control group of nine healthy volunteers and in nine untreated PTSD patients, based on a 15 minute resting electrocardiogram.

Results: Our preliminary results show that the HRV parameters indicating autonomic dysregulation, which characterize PTSD patients at rest, are normalized in responding patients by use of SSRIs. Neither the clinical implications of these findings nor their physiological mechanisms are clear at present, although we presume that they reflect a central effect, since the peripheral autonomic effects of SSRIs are relatively negligible.   

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HRV = heart rate variability

PTSD = post-traumatic stress disorder

SSRI = selective serotonin re-uptake inhibitor