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The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing (AntiCardAgeing)

Primary Purpose

Aging, Inflammation

Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
fluvastatin
Sponsored by
Martin-Luther-Universität Halle-Wittenberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Aging focused on measuring immunosenescence, heart rate variability, autonomic nervous system, ageing, inflammatory/pathogen burden, physical activity

Eligibility Criteria

60 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • age 60-75
  • physical activity less than 3 times a week
  • written informed consent

Exclusion Criteria:

  • heart disease requiring treatment
  • treatment with beta-receptor-antagonists
  • treatment with statins
  • treatment with immunosuppressive drugs
  • treatment with anti- inflammatory drugs
  • underlying hematological disease
  • alcohol abuse, drug abuse
  • diabetes mellitus
  • study participation within past 30 days
  • known intolerance to active agent or any other component of the drug
  • active liver disease or unexplained persistent elevation of serum levels of transaminases or cholestasis
  • existing myopathy
  • pregnancy or nursing period
  • absence of an ophthalmological examination within 12 month prior inclusion
  • known cataract

Sites / Locations

  • Martin-Luther-Universität Halle-Wittenberg, Medizinische Fakultät, Klinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Ernst-Grube-Strasse 40

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

statins, standardised physical training

to continue with current lifestyle

Arm Description

Outcomes

Primary Outcome Measures

reduced narrowing of heart rate variability (measured by SDNN of a standardised 20 minute- resting-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration)

Secondary Outcome Measures

quality of life
inflammatory parameters
major adverse cardiac events (MACE)including death, non lethal myocardial infarction and hospitalisation for cardiovascular reason
inflammatory parameters in vaccinated and unvaccinated probands
heart rate variability in vaccinated and unvaccinated probands
evidence of reduced narrowing of heart rate variability (measured by SDNN of a 24-hours-holter-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration)

Full Information

First Posted
January 8, 2010
Last Updated
January 27, 2015
Sponsor
Martin-Luther-Universität Halle-Wittenberg
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT01045512
Brief Title
The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing
Acronym
AntiCardAgeing
Official Title
The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing
Study Type
Interventional

2. Study Status

Record Verification Date
January 2015
Overall Recruitment Status
Terminated
Why Stopped
unsufficient recruitment
Study Start Date
October 2009 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Martin-Luther-Universität Halle-Wittenberg
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In the elderly a chronic basal systemic inflammation prevails - which is evident by enhanced CRP or IL-6 plasma concentrations - and by compromised defense mechanisms against invading microbes. These alterations belong to the physiological ageing process of the immune system (immunosenescence) and are regarded as an inflammatory response towards lifelong antigen stress ("inflammatory/pathogen burden"). This lifelong antigen stress evokes an age-dependent basal inflammatory activation of innate immunity as well as a wasting of specific immunity: it is supposed that in the course of life-time due to a multitude of infectious/inflammatory events ("multiple hits") an inflammatory stress prevails or "inflammatory/pathogen burden" accumulates, which substantially contributes to an enhancement of the inflammatory parameters of natural immune response. Such enhanced inflammatory parameters characterize persons at increased risk of degenerative diseases like atherosclerosis or coronary heart disease. The risk is the higher, the higher the "pathogen burden". An impact of the inflammatory load on cardiac ageing has not yet been described. "CARDIAC AGEING", REFLECTED BY A NARROWING OF HEART RATE VARIABILITY: The physiological ageing process of the heart goes along with a narrowing of heart rate variability as shown by various groups, including our own. Arguments in favour of a causal relationship between inflammation and cardiac ageing come from an experimental study with healthy human volunteers who had received a low dose of endotoxin: such a proinflammatory stimulus leads to a reversible narrowing of heart rate variability (7). Also in senescence heart rate variability steadily declines, paralleled by a steady increase of basal inflammatory activity. The reduction of heart rate variability also is regarded as a sensitive parameter of autonomic dysfunction, which contributes to the compromise of cardiac reserve in old age. Apart from typical morphological features and functional deterioration, e.g. diastolic dysfunction, the senescent heart is typically characterized by a narrowed heart rate variability. Efforts have been made to estimate the cardiac age of an individual by this compromised heart rate variability, which may be divergent to the biological age. In recent years diverse approaches were proposed to measure cardiac age on the basis of heart rate variability. The published mathematical formulae were mostly validated with small patient groups and have presently not entered clinical practice. Still heart rate variability is an accepted surrogate parameter of cardiac ageing and is amenable by therapeutic measures, e.g. beta-blockade. The interaction between autonomic nervous system and inflammation is bilateral: thus vagal stimulation can improve heart rate variability and at the same time evoke anti-inflammatory action: this "cholinergic anti-inflammatory" reflex could make the basis for pharmacological interventions to confine overwhelming inflammatory response syndromes. The afferent vagal nerve, on the other hand, can be stimulated by inflammatory mediators and toxins (endotoxin, Interleukin-1), thus activating the efferent vagus to release acetylcholine, which can bind to a nicotinergic acetylcholine receptor on macrophages and thus interrupt cytokine release and limit the rise in the blood levels of proinflammatory cytokines (TNF, IL-6). The biological meaning of this reflex is to localise inflammatory reactions in the organism and prevent a spill of cytokines to the circulation. A functioning autonomic nervous system is thus mandatory to prevent overshooting of inflammatory response to infection and non-infectious stimuli. The link between cardiac ageing and autonomic dysfunction gives another argument in favour of the notion that autonomic dysfunction and pathogen/inflammatory load could be factors promoting cardiac ageing. This, on the other hand, implies the chance of slowing down the cardiac ageing process by successfully modulating the extent of autonomic dysfunction and the scope of "pathogen/inflammatory burden". THE NEED FOR A TRIAL: A possible causal relationship between basal inflammatory activation and cardiac ageing has not been established. This is the issue of the project proposal. In this trial the investigators strive to lower the "pathogen/ inflammatory load" by simple and safe measures. The investigators therefore chose treatment with statins, standardised physical training (both parameters of heart function and heart rate variability could thus be improved) and vaccinations against influenza and pneumococci to prevent a further enhanced "pathogen/ inflammatory burden".

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aging, Inflammation
Keywords
immunosenescence, heart rate variability, autonomic nervous system, ageing, inflammatory/pathogen burden, physical activity

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
96 (Actual)

8. Arms, Groups, and Interventions

Arm Title
statins, standardised physical training
Arm Type
Active Comparator
Arm Title
to continue with current lifestyle
Arm Type
No Intervention
Intervention Type
Drug
Intervention Name(s)
fluvastatin
Intervention Description
40-80mg once daily
Primary Outcome Measure Information:
Title
reduced narrowing of heart rate variability (measured by SDNN of a standardised 20 minute- resting-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration)
Time Frame
24 months
Secondary Outcome Measure Information:
Title
quality of life
Time Frame
24 months
Title
inflammatory parameters
Time Frame
24 months
Title
major adverse cardiac events (MACE)including death, non lethal myocardial infarction and hospitalisation for cardiovascular reason
Time Frame
24 month
Title
inflammatory parameters in vaccinated and unvaccinated probands
Time Frame
24 months
Title
heart rate variability in vaccinated and unvaccinated probands
Time Frame
24 month
Title
evidence of reduced narrowing of heart rate variability (measured by SDNN of a 24-hours-holter-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration)
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: age 60-75 physical activity less than 3 times a week written informed consent Exclusion Criteria: heart disease requiring treatment treatment with beta-receptor-antagonists treatment with statins treatment with immunosuppressive drugs treatment with anti- inflammatory drugs underlying hematological disease alcohol abuse, drug abuse diabetes mellitus study participation within past 30 days known intolerance to active agent or any other component of the drug active liver disease or unexplained persistent elevation of serum levels of transaminases or cholestasis existing myopathy pregnancy or nursing period absence of an ophthalmological examination within 12 month prior inclusion known cataract
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ursula Müller-Werdan, Prof.Dr.med.
Organizational Affiliation
Martin-Luther-University Halle-Wittenberg, Medical Faculty
Official's Role
Study Chair
Facility Information:
Facility Name
Martin-Luther-Universität Halle-Wittenberg, Medizinische Fakultät, Klinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Ernst-Grube-Strasse 40
City
Halle (Saale)
State/Province
Sachsen-Anhalt
ZIP/Postal Code
06097
Country
Germany

12. IPD Sharing Statement

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The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing

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