The Effect of Exercise and Alagebrium on the Diastolic Function of the Heart
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 65 - 80 |
| Updated: | 11/23/2017 |
| Start Date: | July 2008 |
| End Date: | December 2013 |
The purpose of this study is to determine whether an investigational drug (Alagebrium
(generic: ALT-711), a type of medication referred to as an advanced glycaton end-product
clever) can be combined with exercise training to reverse the stiffening of the heart that
takes place naturally with aging.
(generic: ALT-711), a type of medication referred to as an advanced glycaton end-product
clever) can be combined with exercise training to reverse the stiffening of the heart that
takes place naturally with aging.
Objectives: Chronic physical inactivity contributes to the deaths of nearly 1 in 10
Americans. In seniors, the single most common life-threatening disease is congestive heart
failure and for these patients, abnormalities of diastolic function play a critical role in
the pathophysiology of their disease. The sponsor's research has demonstrated that healthy
but sedentary aging leads to atrophy and stiffening of the heart with reduced myocardial and
chamber compliance. In contrast, highly competitive senior runners had cardiac compliance
that was indistinguishable from healthy young individuals suggesting that lifelong exercise
training prevented this stiffening. However, prolonged and intense exercise training (4-6
hrs/wk for 1 yr) failed to restore cardiac compliance in healthy seniors despite other health
benefits.
Why did this year of training fail to restore cardiac compliance? New evidence suggests that
the structural plasticity of myocardial cells in the elderly may be functionally constrained
by the accumulation of toxic metabolites called advanced glycation end-products (AGEs). AGEs
are arrays of protein which have been non-enzymatically cross-linked by sugars; these arrays
increase the stiffness of arterial walls and the myocardium. Investigators have recently
developed a drug capable of cleaving AGE cross-links. Termed ALT-711, this drug has been
shown to be safe in human studies with varying degrees of efficacy on endpoints such as blood
pressure and non-invasive indices of diastolic function. Based on animal studies, we
hypothesize that AGE cross-links must be broken before a meaningful improvement in cardiac
compliance can occur with exercise training in sedentary seniors.
Hypothesis: We hypothesize that AGE cross-links must be broken before a meaningful
improvement in cardiac compliance can occur with exercise training in previously sedentary
seniors; the combination of the AGE cross-link breaker, ALT-711, with exercise training will
be superior to either intervention alone in improving cardiac compliance in these subjects.
Specific Aim: To test this hypothesis, we will study four groups of previously sedentary
senior subjects for one year with the following interventions: A) sedentary controls taking
placebo; B) sedentary subjects taking ALT-711; C) subjects undergoing moderate intensity
exercise training while taking placebo and D) subjects undergoing moderate intensity exercise
training while taking ALT-711.
A comprehensive set of "Baseline Testing" (prior to the one year intervention) and "Follow-up
Testing" (after the one year intervention) will take place to assess the effects of the
intervention. This testing will include submaximal and maximal exercise testing as well as
comprehensive invasive (right heart catheterization) and non-invasive (ultrasound, MRI)
measures of cardiac mechanics, relaxation and morphology. From these data, the following
indices of diastolic and systolic function will be generated: Starling and pressure/volume
curves; calculations of LV wall stress and strain; and measurements of flow propagation
velocity, ejection fraction and relaxation velocity.
In assessing the risk benefit ratio for our study, the major benefits include: 1) obtaining
meaningful information for society regarding the effects of ALT-711 and moderate intensity
exercise training on the compliance of the left ventricular chamber; 2) obtaining important
information for the subject regarding ambulatory blood pressure, exercise performance,
cardiac morphology and cardiac function; and 3) providing the subject one year of supervised
moderate intensity exercise training or yoga training, each with associated health benefits.
The risks of the study are primarily imposed by the dosing of our investigational drug, which
has a favorable side effect profile, and the placement of a peripherally inserted right heart
catheter, which carries minimal risk when placed by an experienced cardiovascular specialist
in a catheterization lab. Hence, in the final analysis, we feel the benefits to both the
enrolled individual and to society far outweigh the risks of participation.
Americans. In seniors, the single most common life-threatening disease is congestive heart
failure and for these patients, abnormalities of diastolic function play a critical role in
the pathophysiology of their disease. The sponsor's research has demonstrated that healthy
but sedentary aging leads to atrophy and stiffening of the heart with reduced myocardial and
chamber compliance. In contrast, highly competitive senior runners had cardiac compliance
that was indistinguishable from healthy young individuals suggesting that lifelong exercise
training prevented this stiffening. However, prolonged and intense exercise training (4-6
hrs/wk for 1 yr) failed to restore cardiac compliance in healthy seniors despite other health
benefits.
Why did this year of training fail to restore cardiac compliance? New evidence suggests that
the structural plasticity of myocardial cells in the elderly may be functionally constrained
by the accumulation of toxic metabolites called advanced glycation end-products (AGEs). AGEs
are arrays of protein which have been non-enzymatically cross-linked by sugars; these arrays
increase the stiffness of arterial walls and the myocardium. Investigators have recently
developed a drug capable of cleaving AGE cross-links. Termed ALT-711, this drug has been
shown to be safe in human studies with varying degrees of efficacy on endpoints such as blood
pressure and non-invasive indices of diastolic function. Based on animal studies, we
hypothesize that AGE cross-links must be broken before a meaningful improvement in cardiac
compliance can occur with exercise training in sedentary seniors.
Hypothesis: We hypothesize that AGE cross-links must be broken before a meaningful
improvement in cardiac compliance can occur with exercise training in previously sedentary
seniors; the combination of the AGE cross-link breaker, ALT-711, with exercise training will
be superior to either intervention alone in improving cardiac compliance in these subjects.
Specific Aim: To test this hypothesis, we will study four groups of previously sedentary
senior subjects for one year with the following interventions: A) sedentary controls taking
placebo; B) sedentary subjects taking ALT-711; C) subjects undergoing moderate intensity
exercise training while taking placebo and D) subjects undergoing moderate intensity exercise
training while taking ALT-711.
A comprehensive set of "Baseline Testing" (prior to the one year intervention) and "Follow-up
Testing" (after the one year intervention) will take place to assess the effects of the
intervention. This testing will include submaximal and maximal exercise testing as well as
comprehensive invasive (right heart catheterization) and non-invasive (ultrasound, MRI)
measures of cardiac mechanics, relaxation and morphology. From these data, the following
indices of diastolic and systolic function will be generated: Starling and pressure/volume
curves; calculations of LV wall stress and strain; and measurements of flow propagation
velocity, ejection fraction and relaxation velocity.
In assessing the risk benefit ratio for our study, the major benefits include: 1) obtaining
meaningful information for society regarding the effects of ALT-711 and moderate intensity
exercise training on the compliance of the left ventricular chamber; 2) obtaining important
information for the subject regarding ambulatory blood pressure, exercise performance,
cardiac morphology and cardiac function; and 3) providing the subject one year of supervised
moderate intensity exercise training or yoga training, each with associated health benefits.
The risks of the study are primarily imposed by the dosing of our investigational drug, which
has a favorable side effect profile, and the placement of a peripherally inserted right heart
catheter, which carries minimal risk when placed by an experienced cardiovascular specialist
in a catheterization lab. Hence, in the final analysis, we feel the benefits to both the
enrolled individual and to society far outweigh the risks of participation.
Inclusion Criteria:
- Healthy senior status (age > 64)
- Body mass index < 30
- Sedentary status (not exercising > 2/wk)
Exclusion Criteria:
- Hypertension
- Diabetes
- Heart Failure
- Asthma
- Chronic obstructive pulmonary disease
- Coronary artery disease (as evidenced by angina or prior myocardial infarction)
- Cerebrovascular disease (as evidenced by prior transient ischemic attack or stroke)
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