HaemoDYNAMICs in Primary and Secondary Hypertension (DYNAMIC)

Non-Invasive HaemoDYNAMICs in Primary and Secondary Hypertension: the DYNAMIC-study

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.

Study Overview

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

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 Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

Study Locations

• Finland
  • Southern Finland
    • Tampere, Southern Finland, Finland, 33014
      • Recruiting
      • Tampere University
      • Contact: Ilkka H Pörsti, MD, PhD, Professor; Phone Number: +358 40 5486507; Email: ilkka.porsti@tuni.fi
      • Contact: Elina J Hautaniemi, PhD; Email: elina.hautaniemi@tuni.fi
      • Principal Investigator: Ilkka Pörsti, Professor
    • Tampere, Southern Finland, Finland, 33521
      • Recruiting
      • Tampere university Hospital
      • Contact: Elina J Hautaniemi, PhD; Email: elina.hautaniemi@tuni.fi
      • Contact: Ilkka H Pörsti, Professor; Email: ilkka.porsti@tuni.fi
      • Principal Investigator: Ilkka Pörsti, MD, PhD, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult hypertensive and normotensive subjects who were treated in Tampere University Hospital clinics of internal medicine or cardiology, or visited medical doctors as outpatients at occupational health care providers in the Pirkanmaa Hospital District.

Patients with primary aldosteronism from all University clinics (Helsinki, Turku, Kuopio, Oulu) in Finland, who were referred to Tampere University Hospital for adrenal vein sampling.

Patients with acromegalia from all University clinics (Helsinki, Turku, Kuopio, Oulu) in Finland.

Participants of Ironman Triathlon competition.

Description

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

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

8

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DYNAMIC (ongoing); Subjects with primary or secondary hypertension and normotensive control subjects. In addition haemodynamic recordings to 50 subjects suffering from chronic fatigue syndrome will be performed.
AERO-DYNAMIC (recordings completed); 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.	Drug: Nitroglycerin 0.25 mg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a single dose of sublingual nitroglycerin was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Nitro resoriblet, Orion Pharma, Espoo, Finland; Drug: Salbutamol 400 µg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a 400 µg dose of inhaled salbutamol was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Ventoline, GlaxoSmithKline, Uxbridge, Middlesex, UK
Liquorice (recordings completed); Normotensive subjects, daily liquorice ingestion (daily glycyrrhizin dose 290-370 mg) for 2 weeks, haemodynamic measurements before and after the intervention.	Drug: Nitroglycerin 0.25 mg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a single dose of sublingual nitroglycerin was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Nitro resoriblet, Orion Pharma, Espoo, Finland; Drug: Salbutamol 400 µg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a 400 µg dose of inhaled salbutamol was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Ventoline, GlaxoSmithKline, Uxbridge, Middlesex, UK; Dietary supplement: Liquorice (2 weeks, glycyrrhizin 290-370 mg daily, no longer given since 2012); Daily liquorice intake (daily glycyrrhizin dose 290-370 mg) for two weeks, measurements before and after intervention (recordings completed).; Other Names: Halva liquorice (TM), Kouvola liquorice (TM)
Milk polypeptides (recordings completed); Daily ingestion of yoghurt containing small milk casein-derived polypeptides for 12 weeks versus placebo yoghurt.	Dietary supplement: Small milk casein-derived polypeptides (12 weeks daily, recordings completed 2011); Daily intake of yoghurt containing small milk casein-derived polypeptides (12 weeks) and placebo yoghurt (12 weeks), measurements before and after intervention (recordings completed 2011).; Other Names: Valio (TM) evolus yoghurt
Bisoprolol (recordings completed); Hypertensive subjects, bisoprolol 5 mg once daily versus placebo in a double-blind, cross-over protocol.	Drug: Nitroglycerin 0.25 mg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a single dose of sublingual nitroglycerin was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Nitro resoriblet, Orion Pharma, Espoo, Finland; Drug: Salbutamol 400 µg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a 400 µg dose of inhaled salbutamol was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Ventoline, GlaxoSmithKline, Uxbridge, Middlesex, UK; Drug: Bisoprolol (5 mg daily for 3 weeks, recordings completed 2011); Bisoprolol 5 mg daily for 3 weeks and placebo tablet daily for 3 weeks, double-blind, randomized, placebo-controlled cross-over protocol. Measurements before and after interventions (recordings completed 2011).; Other Names: Emconcor 5 mg, Merck KGaA, Darmstadt, Germany
Aortic stenosis (ongoing); Subjects with aortic stenosis confirmed by echocardiography
Methodological (recordings completed); 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	Drug: Nitroglycerin 0.25 mg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a single dose of sublingual nitroglycerin was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Nitro resoriblet, Orion Pharma, Espoo, Finland; Drug: Salbutamol 400 µg (single dose, no longer given since January 2017); From the beginning of the study until the end of year 2016 a 400 µg dose of inhaled salbutamol was given to examine the associated acute haemodynamic effects (recordings completed).; Other Names: Ventoline, GlaxoSmithKline, Uxbridge, Middlesex, UK; Drug: L-arginine (10 min infusion, no longer given since January 2017); From the beginning of the study until the end of year 2016 L-arginine infusion 10 mg/kg/min could be given for 10 minutes to examine acute haemodynamic effects (recordings completed).; Other Names: L-arginine HCl 20 mg ml/l, B. Braun Ag, Melsungen, Germany
Participants of Ironman Triathlon; Altogether 80 athletes participating in a full length Ironman competition. Non-invasive recordingds are performed under normal conditions during the training period and after completion of a full-length Ironman competition.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Haemodynamic response to head-up tilt and research drugs	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)	0, 5, 10, 15, 20, 25 and 30 minutes
Haemodynamic response to bisoprolol or dietary supplements (liquorice, milk casein-derived polypeptides)	The change in haemodynamic variables after daily consumption of liquorice (2 weeks); bisoprolol (3 weeks); small milk casein-derived polypeptides (12 weeks)	baseline and after 2 weeks (liquorice); 3 weeks (bisoprolol), or 12 weeks (polypeptides)
Haemodynamic changes induced by Ironman competition	Recordings are performed during normal conditions (training peroid) and after completion of a full-length 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

Collaborators and Investigators

• Sponsor: Tampere University
• Collaborators: Finnish Cultural Foundation; Sigrid Jusélius Foundation; Päivikki and Sakari Sohlberg Foundation, Finland; Medical Research Fund of the Tampere University Hospital, Finland; Finnish Medical Foundation; Finnish Foundation for Cardiovascular Research; Paavo Nurmi Foundation; Tampere Tuberculosis Foundation; Aarne Koskelo Foundation; Finnish Kidney Foundation

Publications and helpful links

General Publications

• Koskela JK, Tahvanainen A, Tikkakoski AJ, Kangas P, Uitto M, Viik J, Kahonen M, Mustonen J, Porsti I. Resting heart rate predicts cardiac autonomic modulation during passive head-up tilt in subjects without cardiovascular diseases. Scand Cardiovasc J. 2022 Dec;56(1):138-147. doi: 10.1080/14017431.2022.2079713.
• Hamid H, Kurra V, Choudhary MK, Bouquin H, Niemela O, Kahonen MAP, Mustonen JT, Porsti IH, Koskela JK. Plasma uric acid is related to large arterial stiffness but not to other hemodynamic variables: a study in 606 normotensive and never-medicated hypertensive subjects. BMC Cardiovasc Disord. 2021 May 26;21(1):257. doi: 10.1186/s12872-021-02072-9.
• Kokko E, Nevalainen PI, Choudhary MK, Koskela J, Tikkakoski A, Huhtala H, Niemela O, Viukari M, Mustonen J, Matikainen N, Porsti I. Aldosterone-to-renin ratio is related to arterial stiffness when the screening criteria of primary aldosteronism are not met. Sci Rep. 2020 Nov 13;10(1):19804. doi: 10.1038/s41598-020-76718-7.
• Hautaniemi EJ, Tikkakoski AJ, Eraranta A, Kahonen M, Hamalainen E, Turpeinen U, Huhtala H, Mustonen J, Porsti IH. Liquorice ingestion attenuates vasodilatation via exogenous nitric oxide donor but not via beta2-adrenoceptor stimulation. PLoS One. 2019 Oct 18;14(10):e0223654. doi: 10.1371/journal.pone.0223654. eCollection 2019.
• Kangas P, Tahvanainen A, Tikkakoski A, Koskela J, Uitto M, Viik J, Kahonen M, Koobi T, Mustonen J, Porsti I. Increased Cardiac Workload in the Upright Posture in Men: Noninvasive Hemodynamics in Men Versus Women. J Am Heart Assoc. 2016 Jun 21;5(6):e002883. doi: 10.1161/JAHA.115.002883.
• Wilenius M, Tikkakoski AJ, Tahvanainen AM, Haring A, Koskela J, Huhtala H, Kahonen M, Koobi T, Mustonen JT, Porsti IH. Central wave reflection is associated with peripheral arterial resistance in addition to arterial stiffness in subjects without antihypertensive medication. BMC Cardiovasc Disord. 2016 Jun 7;16:131. doi: 10.1186/s12872-016-0303-6.
• Tahvanainen AM, Tikkakoski AJ, Koskela JK, Nordhausen K, Viitala JM, Leskinen MH, Kahonen MA, Koobi T, Uitto MT, Viik J, Mustonen JT, Porsti IH. The type of the functional cardiovascular response to upright posture is associated with arterial stiffness: a cross-sectional study in 470 volunteers. BMC Cardiovasc Disord. 2016 May 23;16:101. doi: 10.1186/s12872-016-0281-8.
• Leskinen MH, Hautaniemi EJ, Tahvanainen AM, Koskela JK, Paallysaho M, Tikkakoski AJ, Kahonen M, Koobi T, Niemela O, Mustonen J, Porsti IH. Daily liquorice consumption for two weeks increases augmentation index and central systolic and diastolic blood pressure. PLoS One. 2014 Aug 25;9(8):e105607. doi: 10.1371/journal.pone.0105607. eCollection 2014.
• Koskela JK, Tahvanainen A, Haring A, Tikkakoski AJ, Ilveskoski E, Viitala J, Leskinen MH, Lehtimaki T, Kahonen MA, Koobi T, Niemela O, Mustonen JT, Porsti IH. Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects. BMC Cardiovasc Disord. 2013 Nov 15;13:102. doi: 10.1186/1471-2261-13-102.

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2006
• Primary Completion (Anticipated): December 31, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: November 29, 2012
• First Submitted That Met QC Criteria: December 3, 2012
• First Posted (Estimate): December 5, 2012

Study Record Updates

• Last Update Posted (Actual): August 19, 2021
• Last Update Submitted That Met QC Criteria: August 12, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Hypertension; Cardiac output; Arterial stiffness; Blood pressure; Head-up tilt; Vascular resistance; Pulse wave reflection
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Neoplasms; Kidney Diseases; Urologic Diseases; Neoplastic Processes; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Hypertension; Neoplasm Metastasis; Aortic Valve Stenosis; Renal Insufficiency; Essential Hypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Chelating Agents; Sequestering Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Albuterol; Bisoprolol; Nitroglycerin; Caseins; Glycyrrhizic Acid
• Other Study ID Numbers: R06086M (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); 2006-002065-39 (EudraCT Number); 2009-014542-29 (EudraCT Number); R07110M (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); R07053M (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); R08012 (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); R09103M (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); R10056 (Other Identifier: Ethics Committee of Pirkanmaa Hospital District); R21094 (Other Identifier: Ethics Committee of Pirkanmaa Hospital District)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No