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Mitral Valve Prolapse?
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- autonomic nervous
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2010-11 HRV Papers Review (Subject: Immune system, AIDS,
and HRV)

Stimulated production of proinflammatory cytokines covaries inversely with heart rate
variability.
Psychosom Med.  2007; 69(8):709-16 (ISSN: 1534-7796)
Marsland AL; Gianaros PJ; Prather AA; Jennings JR; Neumann SA; Manuck SB
Behavioral Immunology Laboratory, Department of Psychology, University of Pittsburgh,
Pittsburgh, PA 15260, USA. marsland@pitt.edu

Editor’s note: Animal studies have shown that the autonomic nervous system plays a
significant role in regulating immune responses to inflammatory stimuli. This human study on
183 healthy adults provided initial human evidence that vagal activity is inversely related to
inflammatory competence, raising the possibility that vagal regulation of immune reactivity
may represent a pathway linking psychosocial factors to risk for inflammatory disease.

OBJECTIVE: To examine whether high-frequency heart rate variability, an indirect measure of
parasympathetic (vagal) control over variations in heart rate, is associated with immune
reactivity to an in vitro inflammatory challenge. Convergent evidence from the animal
literature shows that the autonomic nervous system plays a key role in regulating the
magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic
system inhibits the production of proinflammatory cytokines by activated
monocytes/macrophages and thus decreases local and systemic inflammation. As yet, no
direct human evidence links parasympathetic activity to inflammatory competence.
METHODS: We examined the relationship of variations in heart rate, recorded during paced
respiration, to lipopolysaccharide-induced production of the inflammatory cytokines
interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 among a community
sample of 183 healthy adults (mean age = 45 years; 59% male; 92% White, 7% African-
American). RESULTS: Consistent with animal findings, higher derived estimates of vagal
activity measured during paced respiration were associated with lower production of the
proinflammatory cytokines TNF-alpha and IL-6 (r = -.18 to -.30), but were not related to
production of the anti-inflammatory cytokine IL-10. These associations persisted after
controlling for demographic and health characteristics, including age, gender, race, years of
education, smoking, hypertension, and white blood cell count. CONCLUSIONS: These data
provide initial human evidence that vagal activity is inversely related to inflammatory
competence, raising the possibility that vagal regulation of immune reactivity may represent
a pathway linking psychosocial factors to risk for inflammatory disease.

Unique immunomodulation by electro-acupuncture in humans possibly via stimulation of the
autonomic nervous system.
Neurosci Lett.  2002; 320(1-2):21-4 (ISSN: 0304-3940)
Mori  H; Nishijo  K; Kawamura  H; Abo  T
Department of Acupuncture, Tsukuba College of Technology, Tsukuba 305-0821, Japan.

Editor’s Note: Clinical evidence has suggested that ANS regulates the immunologic
responses. This study divided the participants into three groups: (1) granulocytosis and
lymphocytopenia; (2) granulocytopenia and lymphocytosis; and (3) normal pattern.  The
authors found that acupuncture induced parasympathetic nerve stimulation and tended to
normalize the pattern of leukocytes.

Cumulative evidence suggests that immunologic responses are under the regulation of the
autonomic nervous system. Since acupuncture has recently been reported to modulate the
autonomic nervous system, we investigated the possibility that acupuncture eventually
modulates the immune system. In the present study, electro-acupuncture was applied in
young volunteer subjects. As for the proportions of granulocytes and lymphocytes in the
blood, there were three groups: (1) granulocytosis and lymphocytopenia; (2)
granulocytopenia and lymphocytosis; and (3) normal pattern. Interestingly, with the
administration of acupuncture, the status of subjects with relatively low levels of
granulocytes and high levels of lymphocytes shifted to Group 1, whereas that of subjects
with high levels of granulocytes and low levels of lymphocytes shifted to Group 2. In other
words, acupuncture tended to normalize the pattern of leukocytes. We confirmed that
acupuncture induced parasympathetic nerve stimulation, resulting in a decrease in the heart
rate. These results suggest possible mechanisms underlying how acupuncture ameliorates
the condition of patients with many chronic diseases.

Cardiovascular autonomic neuropathy in HIV-positive African patients.
Minerva Cardioangiol.  2008; 56(4):417-28 (ISSN: 0026-4725)
Compostella C; Compostella L; D'Elia R
Institute of Infectious Diseases, University of Padua, Padua, Italy.

Editor’s note: Among African HIV-positive patients, about 30% showed cardiac autonomic
neuropathy, with lower HRV and higher heart rates correlated with lower lymphocytes
counts. . The authors suggest that all HIV –positive patients should be screened for
autonomic functions.

AIM: HIV infection causes cardiac autonomic neuropathy (CAN); little is known about the
relevance of CAN in sub-Sahara African patients, in spite of the highest prevalence of AIDS in
that population. The authors assessed prevalence rates of CAN in HIV-positive treatment-
naïve African patients and investigated the correlation between degree of immunodeficiency
and CAN. METHODS: Thirty HIV-positive patients and 11 HIV-negative controls underwent a
battery of cardiovascular autonomic function tests; the Ewing-Clarke score was calculated
along with the stage of severity of CAN. The patients' immunological status was evaluated by
CD4 T-lymphocytes counts. RESULTS: During paced respiration of normal depth, the
patients showed shorter baseline RR intervals (739.2+/-136.0 vs 846.2+/-88.7 ms; P<0.05),
with an inverse correlation with CD4 counts, and lower heart rate variability (85.3+/-73.0 vs
123.0+/-46.2 ms; P<0.02). Although patients with lower CD4 counts tended to present blunted
response to hand-grip and cold-face tests, no linear correlation was found between results of
cardiovascular reflex tests and CD4 counts. Eight patients (27%) obtained borderline Ewing-
Clarke scores; 9 patients resulted affected by early (6 pts, 20%) or intermediate (3 pts, 10%)
stage of CAN. CONCLUSION: Signs of HIV-related CAN are present in 30% of the African HIV+
patients observed, with no direct correlation to their immunological status. Based on the
relevance of the problem and the presence of signs of CAN even in newly diagnosed and
treatment-naïve patients, the authors suggest that all HIV-patients should be screened for
the presence of the complication, in view of the possible serious events associated with it.

Effects of footbathing on autonomic nerve and immune function.
Complement Ther Clin Pract.  2007; 13(3):158-65 (ISSN: 1744-3881)
Saeki Y; Nagai N; Hishinuma M
Nagano College of Nursing, 1694 Akaho, Komagane, Nagano 399-4117, Japan. yukaS@md.
tsukuba.ac.jp

Editor’s note: Footbathing could raise the activity of parasympathetic nerve, lower that of
sympathetic nerve, and significantly increase in white blood cell count and natural killer cell
cytotoxicity, suggesting an improved immune status.

The purpose of this study was to investigate the effects of footbathing on autonomic nerve
and immune function. Eleven healthy female volunteers (aged 22-24 years) undertook
footbaths at 42 degrees C for 10 min, with or without additional mechanical stimulation (air
bubbles and vibration). Autonomic responses were evaluated by electrocardiography and
spectral analysis of heart rate variability, and by measurement of blood flow in the sural
region. White blood cell (WBC) counts, ratios of lymphocyte subsets, and natural killer (NK)
cell cytotoxicity were used as indicators of immune function. Footbathing with mechanical
stimulation produced (1) significant changes in the measured autonomic responses,
indicating a shift to increased parasympathetic and decreased sympathetic activity and (2)
significant increases in WBC count and NK cell cytotoxicity, suggesting an improved immune
status. Because these physiological changes are likely to be of benefit to health, our findings
support the use of footbathing in nursing practice.


Cardiac autonomic dysfunction in AIDS is not secondary to heart failure.
Int J Cardiol.  2000; 74(2-3):133-7 (ISSN: 0167-5273)
Neild PJ; Amadi A; Ponikowski P; Coats AJ; Gazzard BG
Cardiac Department, Fazakerley Hospital, Liverpool, UK.

Editor’s note: Compared to healthy subjects, HRV was lower in patients with cardiovascular
diseases; HRV in AIDS patients was even lower, suggesting that HIV plays a role in
dysautonomia.

OBJECTIVE: Heart rate variability (HRV) is a marker of cardiovascular autonomic tone, and is
also known to be reduced in association with cardiac dysfunction. Abnormal autonomic
function tests are common in HIV infected individuals, but the contribution of heart disease
to such findings is not known. Spectral analysis of heart rate variability is a sensitive
technique for measurement of cardiovascular autonomic function, which also allows
differential assessment of parasympathetic and sympathetic components. The aim of this
study was to characterise the nature of autonomic dysfunction in patients with AIDS and to
compare our findings with those seen in HIV seronegative patients with established heart
disease. METHODS: HRV was measured prospectively by spectral analysis in 10 subjects
with dilated cardiomyopathy (age 45.7+/-6.9 years), 10 subjects with AIDS and no clinical
evidence of heart disease (age 37.9+/-5.4 years), and 10 healthy HIV seronegative controls
(age 41.7+/-13.9 years). RESULTS: All components of HRV were reduced in subjects with
cardiomyopathy (P<0.005), and markedly so in subjects with AIDS (P<0. 0001) compared with
controls. CONCLUSIONS: HIV infection may be associated with severe global autonomic
dysfunction, which is not related to heart disease

Central muscarinic cholinergic regulation of the systemic inflammatory response during
endotoxemia.
Proc Natl Acad Sci U S A.  2006; 103(13):5219-23 (ISSN: 0027-8424)
Pavlov VA; Ochani M; Gallowitsch-Puerta M; Ochani K; Huston JM; Czura CJ; Al-Abed Y;
Tracey KJ
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350
Community Drive, Manhasset, NY 11030, USA. vpavlov@nshs.edu

Editor’s note:  The authors discovered that TNF (a type of cytokines) production is regulated
by neural signals through the vagus (parasympathetic) nerve. Activation of this "cholinergic
antiinflammatory pathway" inhibits the production of TNF and other cytokines and protects
animals from the inflammatory damage caused by endotoxemia and severe sepsis.

TNF has a critical mediator role in inflammation and is an important therapeutic target. We
recently discovered that TNF production is regulated by neural signals through the vagus
nerve. Activation of this "cholinergic antiinflammatory pathway" inhibits the production of
TNF and other cytokines and protects animals from the inflammatory damage caused by
endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine
receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic
cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor
antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia.
Centrally administered methoctramine stimulated vagus-nerve activity measured by changes
in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not
abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral
muscarinic receptors on immune cells are not required for the cytokine-regulating activities
of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in
activating the cholinergic antiinflammatory pathway is of interest for the use of centrally
acting muscarinic cholinergic enhancers as antiinflammatory agents.

Power spectral analysis of heart rate variability in HIV-infected and AIDS patients.
Pacing Clin Electrophysiol.  2006; 29(1):53-8 (ISSN: 0147-8389)
Correia D; Rodrigues De Resende LA; Molina RJ; Ferreira BD; Colombari F; Barbosa CJ; Da
Silva VJ; Prata A
Infectious Diseases Division, Department of Internal Medicine, School of Medicine of the
Triangulo Mineiro, Uberaba, MG, Brazil. dalmo@mednet.com.br

Editor’s Note: Compared to normal subjects, HIV infected patients showed lower LF%及
LF/HF. Upon cold face tests, HF% and LF/HF were also lower. Upon bed-tilting tests, This
group showed a larger increase in LF%及LF/HF.  In contrast, HIV patients receiving highly
active antiretroviral therapy (HAART) behaved similarly to normal subjects.

BACKGROUND: In HIV-infected patients the risks for cardiovascular disease are
multifactorial. Autonomic dysfunction has been detected in the early phase of HIV infection
as well as in AIDS patients with advanced cardiomyopathy. METHODS: Forty AIDS patients
receiving highly active antiretroviral therapy (HAART), 40 HIV+ naïve of HAART, and 40
control subjects were studied. Computerized analysis of heart rate variability was performed
using an analog to digital converter. R-R intervals were obtained from a standard ECG,
recorded in DII lead in supine rest and after the cold-face and tilt tests. The series of R-R
intervals were assessed in time and frequency domains using an autoregressive algorithm.
RESULTS: There was no difference regarding to mean values of R-R intervals and variance in
baseline. The normalized power of the low-frequency (LF) component and the low-
frequency/high-frequency (HF) ratio (LF/HF) was significantly decreased in the HIV group.
Responses of normalized HF and LF/HF ratio during the cold-face test were significantly
decreased in the HIV group, as compared to the control. During the tilt test, a higher
augmentation of normalized LF and the LF/HF ratio was observed in the HIV group compared
with the control. The AIDS group was similar to the control in baseline and after cold-face
and tilt tests. CONCLUSION: The HIV group presented in baseline conditions, a shift of
cardiac sympathovagal balance, an exacerbated response of the LF component during the tilt
test, and an ineffective cardiac vagal response to the cold-face test suggesting sympathetic
and parasympathetic dysfunction. AIDS patients receiving HAART did not present these
autonomic alterations.

Heart rate variability in human immunodeficiency virus-positive individuals.
Int J Cardiol.  2004; 94(1):1-6 (ISSN: 0167-5273)
Mittal CM; Wig N; Mishra S; Deepak KK
Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
110029, India.

Editors’ note: AIDS patients are known to exhibit lower HRV. This study observed that
patients infected by HIV but without AIDS also showed lower HRV parameters. The results
suggest that close follow-up on autonomic nervous functions for these patients are
warranted

BACKGROUND: Heart rate variability (HRV) is a marker of cardiac autonomic tone.
Depressed HRV has been reported in patients with AIDS. We conducted this study to find out
if HRV is depressed in human immunodeficiency virus (HIV)-positive individuals without AIDS.
METHODS: We studied prospectively HRV by spectral analysis of short-term
electrocardiography (ECG) monitoring in 21 HIV-positives (33+/-11 years) and in 18 healthy
volunteers (31+/-9 years). None of the HIV-positives had any clinical evidence of autonomic
or cardiac dysfunction. Echocardiography was also performed in HIV-seropositives to rule
out left ventricular (LV) systolic dysfunction. All these individuals did not have any evidence
of AIDS. RESULTS: Mean CD4+ lymphocyte count was 426+/-166/mm(3). The ejection fraction
(EF%) of HIV patients was 62.4+/-6.4. The total power of HRV was reduced significantly in HIV-
positive individuals (p<0.00001). All the components of HRV were reduced. CONCLUSIONS:
HRV is reduced in HIV-seropositive individuals in early stages of infection as well without any
clinical evidence of autonomic dysfunction. This may serve as an early marker of future
global sympatho-vagal imbalance.

Heart rate variability in patients with Sjögren's syndrome.
Clin Rheumatol.  2000; 19(6):477-80 (ISSN: 0770-3198)
Tumiati B; Perazzoli F; Negro A; Pantaleoni M; Regolisti G
Santa Maria Nuova Hospital, Reggio Emilia, Italy. brunotum@tin.it

Editors’ note: Sjogren’s syndrome (dry eyes and dry mouth) is a chronic auto-immune
disease. The authors in this study found that patients with Sjogren;s syndrome showed a
lower heart rate, a higher HRV, a lower LF/HF.  Overall, the parasympathetic dominance in
these patients seemed to protect the heart in consistent with the general finding that lower
incidence of sudden death was associated with this disorder

Heart rate variability (HRV) gives information about sympathetic parasympathetic autonomic
balance. Our purpose was to determine whether HRV is abnormal in patients with Sjögren's
syndrome. In 16 patients with Sjögren's syndrome and 30 matched controls, a short time
analysis of HRV was performed for both the frequency and the time domain. In the time
domain, patients tended to display a slower heart rate, greater R-R variability and higher
standard deviation of the mean (SDNN) than did healthy subjects, but the differences were
not statistically significant. In the frequency domain the spectral measures of HRV showed a
slight reduction of LF and an increase of HF; as a result, the ratio between high and low
frequencies, representative of sympathovagal modulation, was significantly reduced. Our
data suggest an increase in the parasympathetic control of heart rate in patients with
Sjögren's syndrome. This predominance in vagal tone could exert a protective and
antiarrhythmic role in patients with primary Sjögren's syndrome, and may be relevant with
reference to the lower incidence of sudden death in this disorder compared to other major
autoimmune diseases.