HaemoDYNAMICs in Primary and Secondary Hypertension

Recruiting

• Conditions: Primary Hypertension; Secondary Hypertension; Renal Insufficiency; Aortic Stenosis
• Interventions: Drug: Nitroglycerin 0.25 mg (single dose, no longer given since January 2017); Dietary Supplement: Small milk casein-derived polypeptides (12 weeks daily, recordings completed 2011); Drug: Salbutamol 400 µg (single dose, no longer given since January 2017); Drug: L-arginine (10 min infusion, no longer given since January 2017); Drug: Bisoprolol (5 mg daily for 3 weeks, recordings completed 2011); Dietary Supplement: Liquorice (2 weeks, glycyrrhizin 290-370 mg daily, no longer given since 2012)

• Registration Number: NCT01742702
• Lead Sponsor: Tampere University

Brief Summary

The primary aim of the present study was to examine the haemodynamic changes in primary hypertension and secondary hypertension (renal diseases, endocrine diseases, obesity-associated hypertension) with a non-invasive haemodynamic measurement protocol utilizing radial pulse wave analysis and whole-body impedance cardiography in both supine position and during head-up tilt. For comparison, haemodynamics of subjects with chronic fatigue syndrome will also be recorded.

Detailed Description

Elevated blood pressure (BP) and related cardiovascular complications are the leading causes of morbidity and mortality in the modern world. In routine clinical practice, the haemodynamic status is commonly assessed by measuring heart rate and blood pressure at rest, which provides only limited information about functional haemodynamic status. In addition, the haemodynamic changes resulting in similar elevations of BP may differ substantially between patients and disorders.

Therefore, we investigated the haemodynamic changes in primary and secondary hypertension and in the control subjects with non-invasive radial pulse wave analysis and whole-body impedance cardiography. The method includes the determination of volume status using bioimpedance spectroscopy, determination of peripheral and central BP, cardiac function, vascular resistance, arterial compliance and indices of pulse wave reflection. Besides the measurements performed in the supine position, passive orthostatic challenge is included in the protocol to assess the upright functional haemodynamic status.

The repeatability and reproducibility of the protocol was first examined with a double-blind, randomized protocol in 35 subjects (methodological study group), and after that the administration of research drugs has been open-label. The effects of single doses of two largely endothelium-dependent agents, inhaled salbutamol and intravenous L-arginine, and one endothelium-independent agent, sublingual nitroglycerin, were investigated. However, challenges with the acute dosing of all medical compounds was terminated at the end of December 2016. Thereafter, the measurement protocol has included supine and upright recordings on the tilt-table, followed by supine measurements during paced breathing (15 breaths per minute for 5 minutes, 6 breaths per minute for 5 minutes) that modulate the autonomic nervous tone.

The study population has consisted of subgroups described below. The study protocol of each subgroup has been approved by the ethics committee of the Pirkanmaa Hospital District (Ethics committee ID's above), and the administration of research drugs has also been approved by the Finnish Agency for Medicines (EudraCT-numbers above).

Study Timeline

• Study Start: 2006-05-25
• Study First Submitted: 2012-11-29
• Study First Submitted QC: 2012-12-03
• Study First Posted: 2012-12-05
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-12
• Last Update Posted: 2021-08-19
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2000

Inclusion Criteria

• Independent, community-dwelling adults
• Hypertensive subjects (primary or secondary hypertension)
• Normotensive control subjects
• Subjects with aortic stenosis (subgroup "aortic stenosis")
• Participants of Ironman Triathlon competition

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Exclusion Criteria

• Pregnancy
• Systolic blood pressure <90 mmHg
• Allergies to test compounds

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Methodological (recordings completed)	L-arginine (10 min infusion, no longer given since January 2017)	35 normotensive subjects who received research drugs (nitroglycerin, salbutamol, placebo resoriblet, placebo inhalation, L-arginine infusion, saline infusion) in a placebo-controlled, double-blinded manner
Liquorice (recordings completed)	Salbutamol 400 µg (single dose, no longer given since January 2017)	Normotensive subjects, daily liquorice ingestion (daily glycyrrhizin dose 290-370 mg) for 2 weeks, haemodynamic measurements before and after the intervention.
Methodological (recordings completed)	Salbutamol 400 µg (single dose, no longer given since January 2017)	35 normotensive subjects who received research drugs (nitroglycerin, salbutamol, placebo resoriblet, placebo inhalation, L-arginine infusion, saline infusion) in a placebo-controlled, double-blinded manner
Bisoprolol (recordings completed)	Nitroglycerin 0.25 mg (single dose, no longer given since January 2017)	Hypertensive subjects, bisoprolol 5 mg once daily versus placebo in a double-blind, cross-over protocol.
Bisoprolol (recordings completed)	Bisoprolol (5 mg daily for 3 weeks, recordings completed 2011)	Hypertensive subjects, bisoprolol 5 mg once daily versus placebo in a double-blind, cross-over protocol.
AERO-DYNAMIC (recordings completed)	Nitroglycerin 0.25 mg (single dose, no longer given since January 2017)	Subjects who had voluntarily decided to participate in a professionally coached marathon school (Varala Sports Institute, Tampere) were given the chance for haemodynamic recordings before, during and after the training protocol.
Liquorice (recordings completed)	Nitroglycerin 0.25 mg (single dose, no longer given since January 2017)	Normotensive subjects, daily liquorice ingestion (daily glycyrrhizin dose 290-370 mg) for 2 weeks, haemodynamic measurements before and after the intervention.
Bisoprolol (recordings completed)	Salbutamol 400 µg (single dose, no longer given since January 2017)	Hypertensive subjects, bisoprolol 5 mg once daily versus placebo in a double-blind, cross-over protocol.
Methodological (recordings completed)	Nitroglycerin 0.25 mg (single dose, no longer given since January 2017)	35 normotensive subjects who received research drugs (nitroglycerin, salbutamol, placebo resoriblet, placebo inhalation, L-arginine infusion, saline infusion) in a placebo-controlled, double-blinded manner
AERO-DYNAMIC (recordings completed)	Salbutamol 400 µg (single dose, no longer given since January 2017)	Subjects who had voluntarily decided to participate in a professionally coached marathon school (Varala Sports Institute, Tampere) were given the chance for haemodynamic recordings before, during and after the training protocol.
Liquorice (recordings completed)	Liquorice (2 weeks, glycyrrhizin 290-370 mg daily, no longer given since 2012)	Normotensive subjects, daily liquorice ingestion (daily glycyrrhizin dose 290-370 mg) for 2 weeks, haemodynamic measurements before and after the intervention.
Milk polypeptides (recordings completed)	Small milk casein-derived polypeptides (12 weeks daily, recordings completed 2011)	Daily ingestion of yoghurt containing small milk casein-derived polypeptides for 12 weeks versus placebo yoghurt.

Primary Outcome Measures

Name	Time	Method
Change in haemodynamic variables during the follow-up	baseline, ten years	Haemodynamic measurements are performed at baseline, and after approximately 10 years of follow-up
Cardiovascular events	ten years of follow-up	All cardiovascular events during follow-up

Secondary Outcome Measures

Name	Time	Method
Haemodynamic response to head-up tilt and research drugs	0, 5, 10, 15, 20, 25 and 30 minutes	Rapid haemodynamic responses are assessed during the same measurement session (the response to head-up tilt and to research drugs salbutamol, nitroglycerin and L-arginine)
Haemodynamic response to bisoprolol or dietary supplements (liquorice, milk casein-derived polypeptides)	baseline and after 2 weeks (liquorice); 3 weeks (bisoprolol), or 12 weeks (polypeptides)	The change in haemodynamic variables after daily consumption of liquorice (2 weeks); bisoprolol (3 weeks); small milk casein-derived polypeptides (12 weeks)
Haemodynamic changes induced by Ironman competition	Recordings within 2 hours after completion Ironman competition, 12-18 hours later, and within 1-4 before or 4-8 weeks after the competition	Recordings are performed during normal conditions (training peroid) and after completion of a full-length Ironman competition

Trial Locations

Locations (2)

Tampere University Hospital; 🇫🇮 Tampere, Southern Finland, Finland

Tampere University; 🇫🇮 Tampere, Southern Finland, Finland