Cardiovascular Effects of Selective I(f)-Channel Blockade

Study Overview
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Brief Summary
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The study compares three treatment modalities in a human model of Postural orthostatic tachycardia syndrome (POTS): beta-blockers, I(f)-blockers, and placebo.

Detailed Description
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Elevated heart rate may lead to cardiac disease in the long-term. Therefore, drugs lowering heart rate are useful. Beta-blockers are an established treatment modality. They not only lower heart rate but also contractility, which might be undesirable in certain tachycardic disorders. Postural orthostatic tachycardia syndrome (POTS) patients complain about dizziness, weakness, headache, lightheadedness, fatigue, nausea, and presyncope. In some patients there is elevated heart rate even during supine rest. In POTS patients it is preferable to lower heart rate without reducing cardiac contractility which can be achieved by using so-called I(f)-blockers. Thus, they might be superior to beta-blockers in POTS. In our study, we artificially generate POTS in healthy male subjects for about 48 hours. We want to compare the cardiovascular effects and orthostatic tolerance of the following treatments: beta-blocker, I(f)-blocker, and placebo. Moreover, we will quantify changes in cardiovascular autonomic regulation brought about by I(f)-blockade versus placebo.

Official Title
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Einfluss Selektiver I(f)-Blockade Auf Orthostase-Toleranz Und Sympathikusaktivität Bei Gesunden

Conditions
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Postural Orthostatic Tachycardia Syndrome

Intervention / Treatment
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* Drug: beta-blocker (Metoprolol)
* Drug: I(f)-blocker (ivabradine)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy male age 18-40 years BMI: 18-30 kg/m² arterial blood pressure <=160/100 mm Hg co-operativity voluntariness Exclusion Criteria: conditions in which treatment might be ineffective or insecure co-medication within the last 4 weeks participation in another clinical trial within the last 4 weeks unability to understand the study's aim drug or alcohol abuse secondary hypertension creatinine > 130 μM (1.47 mg/dl) GOT/GPT > 2 times normal GGT > 3 times normal contraindications against reboxetine, beta-blocker, ivabradine asthma, psoriasis diabetes heart failure (NYHA III or IV) coronary artery disease peripheral occlusive disease cerebrovascular disease ventricular extrasystoles (Lown III-V) atrial fibrillation resting heart rate <60/min neurologic/psychiatric disorder pulmonary hypertension dysthyroid metabolism

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>beta-blocker | Drug: beta-blocker (Metoprolol)<br>* Metoprolol 95 mg once per day<br>|
| Experimental: 2<br>I(f)-blocker | Drug: I(f)-blocker (ivabradine)<br>* ivabradine 7.5 mg once per day<br>|
| Placebo Comparator: 3<br>Placebo | Drug: Placebo<br>* matching appearance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sub-study 'Orthostatic tolerance': Change in heart rate after 20 mins of passive orthostasis. Sub-study 'Sympathetic system': arterial pressure related heart rate |  | 12-18 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 'Orthostatic tolerance': Hemodynamics during head-up tilt. Time to presyncope. |  | 12-18 hours | 
| 'Sympathetic system': Muscle sympathetic nerve activity (MSNA). |  | 12-18 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POTS