Research in Review

• Continuous progression of orthostatic tachycardia as a further feature of the postural tachycardia syndrome
• Increased plasma angiotensin II in postural tachycardia syndrome is related to reduced blood flow and blood volume
• Why most published research findings are false
• Contradicted and initially stronger effects in highly cited clinical research
• Renin-angiotensin-aldosterone system activity during head-up tilt testing in patients with vasovagal syncope

Pacing Clin Electrophysiol. 2005 Sep;28(9):975-9.

Continuous progression of orthostatic tachycardia as a further feature of the postural tachycardia syndrome.

Diehl RR.

Autonomic Laboratory, Department of Neurology, Krupp Hospital, Alfried-Krupp-Strasse 21, 45117 Essen, Germany. Rolf.Diehl@Krupp-Krankenhaus.de

BACKGROUND: The clinical diagnosis of the postural tachycardia syndrome (POTS) includes the demonstration of an upright heart rate (HR) of at least 30 beats per minute (bpm) above supine HR. The dynamic behavior of HR during the course of standing has not yet been studied systematically in POTS.

METHODS: HR and arterial blood pressure (ABP) were continuously monitored in 17 POTS patients and in 24 age-matched controls at rest and during an 11-minute phase of 80 degrees tilt.

RESULTS: ABP values at different time intervals of the protocol did not differ between the subgroups with the exception of higher diastolic pressures in POTS after 5 and 10 minutes of tilt. POTS patients showed a higher resting HR (80.6 +/- 17.0 bpm vs 67.8 +/- 10.9 bpm in controls, P < 0.05) and there was a continuous HR acceleration in the course of the 11-minute tilt phase. In control subjects, the tilt-induced HR increase was nearly completed after 1 minute with only a minimal further rise between minute 1 and minute 10 (from 83.7 +/- 11.5 to 85.3 +/- 11.9 bpm vs from 106.1 +/- 15.6 to 120.1 +/- 13.8 bpm in POTS).

CONCLUSIONS: Continuously progressing orthostatic tachycardia can serve as an additional criterion in the diagnosis of POTS. It may be related to the recently observed increased orthostatic capillary filtration rate in POTS.

PMID: 16176538

Clin Sci (Lond). 2005 Nov 1;

Increased plasma angiotensin II in postural tachycardia syndrome is related to reduced blood flow and blood volume.

Stewart JM, Glover JL, Medow MS.

Postural tachycardia syndrome (POTS) is associated with low blood volume, reduced renin and aldosterone. Angiotensin-II has not been investigated. Past work suggested that a subset of POTS, with increased vasoconstriction related to decreased bioavailable nitric oxide, had decreased blood volume. Angiotensin-II reduces bioavailable NO and is integral to the renin-angiotensin system. Thus, we investigated the relationship among blood volume, angiotensin-II, renin, aldosterone and peripheral blood flow in POTS. POTS was diagnosed by 70 o upright tilt. Supine calf blood flow measured by venous occlusion plethysmography was used to subgroup POTS patients. 23 POTS patients were partitioned among 10 with low blood flow, 8 with normal flow, and 5 with high flow. There were 10 healthy volunteers. Blood volume was measured by dye dilution. Biochemical measurements were performed supine. Blood volume was decreased in low flow POTS (2.14+/-.12 L/M 2) compared to control (2.76+/-.20 L/M 2) but not in other subgroups. PRA was decreased in low flow POTS (0.49+/-.12 vs 0.90+/-0.18 ng/ml/hr), while plasma angiotensin-II was increased (89+/-20 vs 32+/-4 ng/L), but not in other subgroups. PRA correlated with aldosterone (r=+0.71) over all subjects. PRA correlated negatively with blood volume (r=-0.72) in normal and high flow POTS but positively (r=+0.65) in low flow POTS. PRA correlated positively with angiotensin (r=+0.76) in normal and high flow POTS but negatively (r=-.83) in low flow POTS. Blood volume was negatively correlated to angiotensin II (r=-0.66) in normal and high flow POTS, and in five low flow POTS patients. The remaining five patients had reduced blood volume and increased angiotensin-II uncorrelated to blood volume. Data suggest that plasma angiotensin-II is increased in low flow POTS patients with hypovolemia which may contribute to local blood flow dysregulation and reduced NO bioavailability.

PMID: 16262605

PLoS Med. 2005 Aug;2(8):e124. Epub 2005 Aug 30.

Why most published research findings are false.

Ioannidis JP.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. jioannid@cc.uoi.gr

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

PMID: 16060722

Full Text: http://www.pubmedcentral.gov/articlerender.fcgi?tool=
pubmed&pubmedid=16060722

JAMA. 2005 Jul 13;294(2):218-28.

Contradicted and initially stronger effects in highly cited clinical research.

Ioannidis JP.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. jioannid@cc.uoi.gr

CONTEXT: Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted. Controversies are most prominent when high-impact research is involved.

OBJECTIVES: To understand how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether specific characteristics are associated with such refutation over time.

DESIGN: All original clinical research studies published in 3 major general clinical journals or high-impact-factor specialty journals in 1990-2003 and cited more than 1000 times in the literature were examined.

MAIN OUTCOME MEASURE: The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better controlled designs. The same analysis was also performed comparatively for matched studies that were not so highly cited.

RESULTS: Of 49 highly cited original clinical research studies, 45 claimed that the intervention was effective. Of these, 7 (16%) were contradicted by subsequent studies, 7 others (16%) had found effects that were stronger than those of subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely unchallenged. Five of 6 highly-cited nonrandomized studies had been contradicted or had found stronger effects vs 9 of 39 randomized controlled trials (P = .008). Among randomized trials, studies with contradicted or stronger effects were smaller (P = .009) than replicated or unchallenged studies although there was no statistically significant difference in their early or overall citation impact. Matched control studies did not have a significantly different share of refuted results than highly cited studies, but they included more studies with "negative" results.

CONCLUSIONS: Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

PMID: 16014596

Pol Merkuriusz Lek. 2005 Aug;19(110):136-8.

Renin-angiotensin-aldosterone system activity during head-up tilt testing in patients with vasovagal syncope

[Article in Polish]

Gajek J, Zysko D, Mazurek W.

Katedra i Klinika Kardiologii Akademii Medycznej we Wrociawiu. gajek33@interia.pl

The stimulation of renin-angiotensin-aldosterone (RAA) system during tilt table test is caused by sympathetic nervous system activation by orthostatic stress and a serotonin release as well. In healthy individuals increase of plasma renin activity during test with maximal values on the peak of the test was described.

OBJECTIVE: The aim of the study was to assess the activation of RAAS in patients with neurally mediated syncope during the tilt table test by means of plasma renin activity and serum aldosterone levels.

MATERIAL AND METHODS: The study was carried out in 31 patients aged 39.4 +/- 15.0 years (18 women and 13 men) with neurally mediated syncope during tilt test. Plasma renin activity was assessed in the baseline conditions, immediately after the test and 10 minutes after the test using radioenzymatic assay. Aldosterone concentrations were measured radioimmunologically, twice: after 30 minutes supine rest and after the syncope.

RESULTS: Plasma renin activity during supine rest was 2.2 +/- 2.4 ng/ml/h, rose after the syncope 2.5-fold to 5.2 +/- 4.5 ng/ml/h (p < 0.001 comparing to baseline) stayed on similar level approximately for the next 10 minutes--4.9 +/- 5.5 ng/ml/h (p = n.s.). In 11 patients (35%) 10 minutes after the test even further increase of PRA was observed. Serum aldosterone level increased significantly immediately after tilt test (90.0 +/- 72.9 vs 178.8 +/- 150.1 pg/ml, p < 0.01).

CONCLUSION: Authors showed, that in patients with NMS plasma renin activity increases and this increase lasts for 10 minutes after the syncope and the concentration of aldosterone increases immediately after tilt test.

PMID: 16245417

Research abstracts obtained from PubMed.

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