A stepwise psychotherapy intervention for reducing risk in coronary artery disease (SPIRR-CAD) - rationale and design of a multicenter, randomized trial in depressed patients with CAD.

OBJECTIVE: Depressive symptoms are highly relevant for the quality of life, health behavior, and prognosis in patients with coronary artery disease (CAD). However, previous psychotherapy trials in depressed CAD patients produced small to moderate effects on depression, and null effects on cardiac events. In this multicentre psychotherapy trial, symptoms of depression are treated together with the Type D pattern (negative affectivity and social inhibition) in a stepwise approach. METHODS: Men and women (N=569, age 18-75 years) with any manifestation of CAD and depression scores ≥ 8 on the Hospital Anxiety and Depression Scale (HADS), will be randomized (allocation ratio 1:1) into the intervention or control group. Patients with severe heart failure, acutely life-threatening conditions, chronic inflammatory disease, severe depressive episodes or other severe mental illness are excluded. Both groups receive usual medical care. Patients in the intervention group receive three initial sessions of supportive individual psychotherapy. After re-evaluation of depression (weeks 4-8), patients with persisting symptoms receive an additional 25 sessions of combined psychodynamic and cognitive-behavioral group therapy. The control group receives one psychosocial counseling session. Primary efficacy variable is the change of depressive symptoms (HADS) from baseline to 18 months. Secondary endpoints include cardiac events, remission of depressive disorder (SCID) and Type D pattern, health-related quality of life, cardiovascular risk profile, neuroendocrine and immunological activation, heart rate variability, and health care utilization, up to 24 months of follow-up (ISRCTN: 76240576; NCT00705965). Funded by the German Research Foundation.

Associations between being overweight, variability in heart rate, and well-being in the young men.

Abnormalities of the autonomic nervous system have been repeatedly shown in hypertension. We studied the associations between being overweight, blood pressure, cardiac vagal tone as measured by variability in heart rate, and well-being in a large cohort of young men. We hypothesised an inverse correlation between body mass index and the variability in heart rate. Further, we assessed systolic and diastolic blood pressure as traditional indicators of cardiovascular risk. Exclusion criteria were the use of drugs or pharmaceuticals. The following data from 786 men with a mean age of 19.4 years (standard deviation = 1.4, with a range from 16 to 24 years) were analysed in a cross-sectional study: body mass index, sleep duration, sporting activities, psychological well-being, blood pressure, heart rate, and variability in heart rate. Despite the young age of the men in this study, increased values for the body mass index were already associated with a shift in sympathovagal balance trending towards sympathetic dominance. There was also a significant positive correlation between body mass index and systolic and diastolic blood pressure. A multiple stepwise regression analysis showed that significant factors, which were associated with variability in heart rate, were body mass index and sporting activities. In addition, sporting activity and sleep duration had a significant positive impact on psychological well-being. Even in young men, being overweight is associated with increased cardiovascular risk, especially an increased sympathetic and/or lowered cardiovascular tone and increased blood pressure. Our study gives additional motivation for the early prevention and treatment of obesity in childhood and adolescence.

Austrian Moderate Altitude Studies (AMAS): benefits of exposure to moderate altitudes (1,500-2,500 m).

OBJECTIVES: A considerable part of the millions of Alpine tourists suffer from pre-existing diseases (e.g., metabolic syndrome) and high daily stress levels. The main goal of the Austrian Moderate Altitude Study (AMAS) was to investigate (a) the consequences of an active vacation at moderate altitude on the key parameters of the metabolic syndrome (AMAS I) and (b) the effects of a short active vacation on adult progenitor cells, bio-psychological parameters, and heart rate variability (HRV). METHODS: During the AMAS I pilot study (n = 22; 1,700 m a.s.l.) and AMAS I main study (n = 71; 1,700 m a.s.l. and 200 m a.s.l.), the volunteers simulated 3-week coached hiking vacations. For AMAS II, healthy volunteers (n = 13) participated in a 1-week active holiday at 1,700 m. RESULTS: There were significant improvements of obesity, hypertension, dyslipidemia, and insulin resistance of AMAS I patients after the vacation. In AMAS II participants, we found an increase in circulating endothelial progenitor cells as well as improvements in bio-psychological and HRV parameters. CONCLUSIONS: Active vacations at moderate altitude are associated with a variety of positive health effects in persons with metabolic syndrome and in healthy subjects.

The deep breathing test: median-based expiration-inspiration difference is the measure of choice.

Heart rate variability (HRV) has become an important parameter for the assessment of autonomic function in many areas of medicine. In particular, respiratory sinus arrhythmia measured during the deep breathing test (DBT) is often used. Results are usually expressed in common time-domain parameters. A "most preferred measure" has not yet been identified. We investigated the sensitivity of the DBT to the following anomalies: in-test variance; shifts of mean heart rate; premature ventricular contractions; and breathing rate deviations. Frequency and magnitude of the anomalies were determined in a set of real DBTs (n=514) and transferred to computer simulations to mimic realistic conditions. The sensitivity of standard deviation, mean circular resultant (MCR), root mean square of successive differences (RMSSD), and four types of expiration-inspiration (E-I) difference were quantified statistically. Median-based E-I differences, E-I ratio, and MCR were most resistant to the anomalies. E-I difference derived by median values should be used preferentially, providing the highest precision and independence from heart rate.

A pilot study on the effects of heart rate variability biofeedback in patients with depression and in healthy subjects.

Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in patients with depression. It was aim of the present study to assess the feasibility of using heart rate variability (HRV) biofeedback to treat moderate to severe depression. This was an open-label study in which 14 patients with different degrees of depression (13 f, 1 m) aged 30 years (18-47; median; range) and 12 healthy volunteers attended 6 sessions of HRV biofeedback over two weeks. Another 12 healthy subjects were observed under an active control condition. At follow up BDI was found significantly decreased (BDI 6; 2-20; median 25%-75% quartile) as compared to baseline conditions (BDI 22;15-29) in patients with depression. In addition, depressed patients had reduced anxiety, decreased heart rate and increased HRV after conduction of biofeedback (p < 0.05). By contrast, no changes were noted in healthy subjects receiving biofeedback nor in normal controls. In conclusion, HRV biofeedback appears to be a useful adjunct for the treatment of depression, associated with increases in HRV.

The effects of venlafaxine on autonomic functions in healthy volunteers.

Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition.

The effects of sildenafil on heart rate variability in healthy subjects.

The effects of sildenafil on heart rate variability were investigated in 20 healthy male subjects aged 24 (21 to 32) years (median; range). Subjects orally received single 100-mg doses of sildenafil and placebo under randomized double-blind crossover conditions on 2 separate study days. Time domain measures of heart rate variability were assessed under conditions of relaxed rest, metronomic breathing (6 cycles per minute), and bicycle ergometry before administration of sildenafil and placebo as well as 60 minutes afterwards. Sildenafil did not alter heart rate nor heart rate variability to a significant extent (P > 0.05).

The effects of acetylic salicylic acid on heart rate variability in healthy subjects.

In this placebo controlled double blind cross over study multiple daily dosing with 500 mg acetylic salicylic acid did not influence heart rate variability in 16 healthy male volunteers aged 25 (22-28) years (median; range) to a relevant extent (p > 0.05).

Acute effects of caffeine on heart rate variability in habitual caffeine consumers.

During the last years, heart rate variability (HRV) has become a promising risk factor for cardiovascular events. However, the effect of caffeine on HRV in habitual caffeine consumers has barely been investigated. Therefore, we treated 30 male habitual caffeine users in a randomized double-blinded crossover study design with either placebo, 100 or 200 mg caffeine orally and determined parameters of HRV under resting conditions and metronomic breathing. As result, we could not detect significant differences in HRV parameters up to 90 min after drug ingestion. We conclude that modest amounts of caffeine do not reveal negative nor positive effects on HRV within the first 90 min after drug ingestion in young and healthy habitual caffeine consumers. However, further research is necessary to determine the effects of caffeine on HRV in habitual caffeine users, healthy as well as suffering from diabetes, hypertension and postmyocardial infarction.

Stretching increases heart rate variability in healthy athletes complaining about limited muscular flexibility.

An increase in muscular flexibility, as well as a significant beneficial effect on heart rate and heart rate variability (HRV), was observed in healthy male athletes after performing a standardized 15-minute stretching-program over a period of 28 days. We believe the HRV increase to be due, at least in part, to the improved vagal and/or diminished sympathetic control. Therefore, we recommend stretching as an effective and gentle technique for health protection.

The effects of St. John's wort extract and amitriptyline on autonomic responses of blood vessels and sweat glands in healthy volunteers.

St. John's wort extract is widely used and advertised as a "natural antidepressant" lacking autonomic side effects. This randomized, double-blind, placebo-controlled study compared the effects of St. John's wort extract on autonomic responses of blood vessels and sweat glands with those of amitriptyline and placebo. A randomized, double-blind, crossover study was performed in healthy male volunteers aged 22 to 31 years (25 +/- 3 years; mean +/- SD) years. Subjects orally received capsules with 255 to 285 mg St. John's wort extract (900 microg hypericin content), 25 mg amitriptyline, and placebo 3 times daily for periods of 14 days each with at least 14 days between. Vasoconstrictory response of cutaneous blood flow (VR) and skin conductance response (SR) following a single deep inspiration were employed as parameters of autonomic function. St. John's wort extract had no effect on VR and SR. In contrast, SR was diminished and the dilation phase of VR was prolonged following multiple dosing with amitriptyline (P < 0.05). Decreased electrodermal reactivity observed with amitriptyline reflects inhibition of acetylcholine at peripheral m3-cholinoreceptors, whereas prolongation of VR induced by the tricyclic drug may be due to sustained activation of central and/or peripheral sympathetic neurons.

Effects of olanzapine and clozapine upon pulse rate variability.

Based upon their in vitro receptor binding profiles, the atypical antipsychotics clozapine and olanzapine exhibit cholinergic receptor binding of similar potency. Data comparing the in vivo anticholinergic effects, however, of these neuroleptics upon neurocardiac control are sparse. The goal of this study was to compare the in vivo effects of clozapine and olanzapine upon neurocardiac control by assessment of the pulse rate variability (PRV) in schizophrenic patients and healthy controls. Twenty patients with schizophrenia (according to DSM-III-R criteria) treated with either clozapine (100-600 mg/day) or olanzapine (10-20 mg/day), and ten healthy controls, were recruited into the study. PRV was assessed by continuously recording the skin blood volume in the fingertip of the second digit under resting conditions and PRV parameters were calculated. When significant differences in PRV parameters between the patients and controls were detected by Kruskal-Wallis tests, Mann-Whitney tests were used to test for group differences between the olanzapine- and clozapine-treated patients. In comparison to the healthy controls, the PRV parameters of the clozapine- and olanzapine-treated schizophrenic patients were significantly reduced. Indeed the reduction of PRV was significantly greater in the clozapine-treated group compared to the olanzapine-treated group (P<0.05). Compared to the controls, only the clozapine-treated patients showed a significantly diminished low-frequency (LF)/high frequency (HF)-ratio, a PRV parameter reflecting sympatho-vagal balance. The significantly greater reductions in PRV parameters of the clozapine-treated compared to olanzapine-treated patients may be caused by clozapine's higher affinity for alpha(1)-adrenergic receptors in vivo compared with olanzapine. The similar LF/HF ratios of the healthy controls and olanzapine-treated patients suggests that the sympathetic-parasympathetic modulation of PRV remains relatively unchanged even during olanzapine treatment.

Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam.

OBJECTIVES: To evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DESIGN: Prospective, randomized clinical study. SETTING: University teaching hospital. PATIENTS: Forty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. INTERVENTIONS: Serial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). MEASUREMENTS AND MAIN RESULTS: The average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. CONCLUSIONS: Benzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the gamma-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.