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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01045512
Recruitment Status : Terminated (unsufficient recruitment)
First Posted : January 11, 2010
Last Update Posted : January 28, 2015
Information provided by (Responsible Party):
Martin-Luther-Universität Halle-Wittenberg

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".


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".

Condition or disease Intervention/treatment Phase
Aging Inflammation Drug: fluvastatin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 96 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing
Study Start Date : October 2009
Actual Primary Completion Date : September 2014
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Fluvastatin

Arm Intervention/treatment
Active Comparator: statins, standardised physical training Drug: fluvastatin
40-80mg once daily

No Intervention: to continue with current lifestyle

Primary Outcome Measures :
  1. 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 Measures :
  1. quality of life [ Time Frame: 24 months ]
  2. inflammatory parameters [ Time Frame: 24 months ]
  3. major adverse cardiac events (MACE)including death, non lethal myocardial infarction and hospitalisation for cardiovascular reason [ Time Frame: 24 month ]
  4. inflammatory parameters in vaccinated and unvaccinated probands [ Time Frame: 24 months ]
  5. heart rate variability in vaccinated and unvaccinated probands [ Time Frame: 24 month ]
  6. 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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01045512

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Martin-Luther-Universität Halle-Wittenberg, Medizinische Fakultät, Klinik und Poliklinik für Innere Medizin III, Universitätsklinikum Halle (Saale), Ernst-Grube-Strasse 40
Halle (Saale), Sachsen-Anhalt, Germany, 06097
Sponsors and Collaborators
Martin-Luther-Universität Halle-Wittenberg
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Study Chair: Ursula Müller-Werdan, Martin-Luther-University Halle-Wittenberg, Medical Faculty

Additional Information:
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Responsible Party: Martin-Luther-Universität Halle-Wittenberg Identifier: NCT01045512     History of Changes
Other Study ID Numbers: KKSH-38
2007-003003-12 ( Registry Identifier: EudraCT )
First Posted: January 11, 2010    Key Record Dates
Last Update Posted: January 28, 2015
Last Verified: January 2015

Keywords provided by Martin-Luther-Universität Halle-Wittenberg:
heart rate variability
autonomic nervous system
inflammatory/pathogen burden
physical activity

Additional relevant MeSH terms:
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Pathologic Processes