Effects of Exercise Training and AGE-crosslink Breaker on Cardiovascular Structure and Function

Study Overview
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Brief Summary
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Healthy but sedentary aging leads to increased morbidity and mortality of cardiovascular disease. This is partly due to the accumulation of Advanced Glycation Endproducts (AGEs) and the stiffening of the myocardium and arteries. New medication has been developed to break these AGE-crosslinks to improve cardiovascular compliance. The positive influence of regular physical activity is well known for cardiovascular disease and aging. Therefore, what is the most effective intervention, physical exercise and/or new medication AGE-crosslink breakers, in improving the cardiovascular and cerebrovascular compliance and improving the endothelial function in healthy sedentary elderly.

Official Title
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Combining Exercise Training With a Drug to Break AGE-crosslinks; Effects on Cardiovascular Structure and Function and Related Mechanisms

Conditions
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Cardiovascular Disease, Aging, Endothelial Dysfunction, Physical Activity

Intervention / Treatment
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* Drug: Alt-711
* Behavioral: Physical exercise training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy sedentary elderly Age 65 yrs and older Exclusion Criteria: Cardiovascular disease Cerebrovascular disease Changes on ECG indicating cardiomyopathy or ischemia No cardiovascular medication Diabetes Mellitus Hypercholesterolemia BMI > 33 kg/m2 Intensive exercise > 1 hour a week

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

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: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Alagebrium<br>In this study there will be four different groups: One Alagebrium 100 mg twice daily and exercise training 3x/week Two Placebo twice daily and exercise training 3x/week Three Alagebrium 100 mg twice daily and no exercise training Four Placebo twice daily and no exercise training | Drug: Alt-711<br>* Alt-711, also known as Alagebrium, an AGE-crosslink breaker, will be given twice daily 100mg<br>* Other names: 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride;Behavioral: Physical exercise training<br>* Exercise training will be given three times a week for 45 minutes per training session. The heart rate reserve will be slowly increased from 70% to 85%.<br>* Other names: Cycloergometer;|
| Other: Exercise training<br>In this study there will be four different groups: One Alagebrium 100 mg twice daily and exercise training 3x/week Two Placebo twice daily and exercise training 3x/week Three Alagebrium 100 mg twice daily and no exercise training Four Placebo twice daily and no exercise training | Drug: Alt-711<br>* Alt-711, also known as Alagebrium, an AGE-crosslink breaker, will be given twice daily 100mg<br>* Other names: 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride;Behavioral: Physical exercise training<br>* Exercise training will be given three times a week for 45 minutes per training session. The heart rate reserve will be slowly increased from 70% to 85%.<br>* Other names: Cycloergometer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the combined effects of one year exercise training and the AGE-crosslink breaker Alagebrium on vascular endothelial function. | At baseline and 12 months the endothelial function will be measured with an invasive vascular function measurement using the leg model. Via an arterial line in the common femoral artery acethylcholine, sodium nitroprusside and LNMMA will be infused at different dosages. Vascular response will be measured using venous occlusion plethysmography. Non-invasive vascular measurements, e.g.flow mediated dilation and pulse wave velocity, using ultrasound techniques will be performed at 0, 6 and 12 months. Also, cardiopulmonary fitness level will be tested at 0, 3, 6 and 12 months with an ergometer. | 0 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the individual effects of one year exercise training and the AGE-crosslink breaker Alagebrium on vascular endothelial function. | At baseline and 12 months the endothelial function will be measured with an invasive vascular function measurement using the leg model. Via an arterial line in the common femoral artery acethylcholine, sodium nitroprusside and LNMMA will be infused at different dosages. Vascular response will be measured using venous occlusion plethysmography. Non-invasive vascular measurements, e.g.flow mediated dilation and pulse wave velocity, using ultrasound techniques will be performed at 0, 6 and 12 months. Also, cardiopulmonary fitness level will be tested at 0, 3, 6 and 12 months with an ergometer. | 0 and 12 months | 
| Examine the combined effects of one year exercise training and the AGE-crosslink breaker Alagebrium on cardiac function. | An echocardiogram will be performed at baseline, 6 and 12 months. Measures such as strain, strain rate and myocardial velocity, together with the diastolic function parameters (e.g. E/A, S/D, and E/E' ratio) will be specifically evaluated. Also, the common measures such as wall thickness, volumes, etc, will be examined. | 0, 6 and 12 months | 
| Examine the individual effects of one year exercise training and the AGE-crosslink breaker Alagebrium on cardiac function. | An echocardiogram will be performed at baseline, 6 and 12 months. Measures such as strain, strain rate and myocardial velocity, together with the diastolic function parameters (e.g. E/A, S/D, and E/E' ratio) will be specifically evaluated. Also, the common measures such as wall thickness, volumes, etc, will be examined. | 0, 6 and 12 months | 
| Examine the combined effects of one year exercise training and the AGE-crosslink breaker Alagebrium on cerebral perfusion and cognitive function. | A cerebral perfusion measurement will be performed at baseline and after 12 months with transcranial doppler, near infra-red spectroscopy and continuous beat to beat blood pressure monitoring using the Finameter during different posture maneuvers and hypo- and hypercapnia. Dynamic cerebral autoregulation and vasoreactivity will be examined. Cognitive function will be measured at baseline, 6 and 12 months using the CANTAB. | 0 and 12 months | 
| Examine the individual effects of one year exercise training and the AGE-crosslink breaker Alagebrium on cerebral perfusion and cognitive function. | A cerebral perfusion measurement will be performed at baseline and after 12 months with transcranial doppler, near infra-red spectroscopy and continuous beat to beat blood pressure monitoring using the Finameter during different posture maneuvers and hypo- and hypercapnia. Dynamic cerebral autoregulation and vasoreactivity will be examined. Cognitive function will be measured at baseline, 6 and 12 months using the CANTAB. | 0 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aging, Cardiovascular disease, Endothelial function, Physical activity, Advanced Glycation Endproducts, AGE crosslink breakers