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

NCT01045512 | Terminated Phase 2 DMC

• 2 other identifiers: KKSH-382007-003003-12
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

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".

Conditions

Aging; Inflammation

Keywords

immunosenescence; heart rate variability; autonomic nervous system; ageing; inflammatory/pathogen burden; physical activity

Outcome Measures

Primary Outcomes (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)

  24 months

Secondary Outcomes (6)

• quality of life

  24 months

• inflammatory parameters

  24 months

• major adverse cardiac events (MACE)including death, non lethal myocardial infarction and hospitalisation for cardiovascular reason

  24 month

• inflammatory parameters in vaccinated and unvaccinated probands

  24 months

• heart rate variability in vaccinated and unvaccinated probands

  24 month

Study Arms (2)

statins, standardised physical training

ACTIVE COMPARATOR

Drug: fluvastatin

to continue with current lifestyle

NO INTERVENTION

Interventions

fluvastatin DRUG

40-80mg once daily

statins, standardised physical training

Eligibility Criteria

• Age: 60 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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
• known cataract

Sponsors & Collaborators

• Martin-Luther-Universität Halle-Wittenberg: lead
• Novartis: collaborator

Study Sites (1)

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

Halle, Saxony-Anhalt, 06097, Germany

Location

MeSH Terms

Conditions

Inflammation; Motor Activity

Interventions

Fluvastatin

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Ursula Müller-Werdan, Prof.Dr.med.

  Martin-Luther-University Halle-Wittenberg, Medical Faculty

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2010
• First Posted: January 11, 2010
• Study Start: October 1, 2009
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: January 28, 2015

Record last verified: 2015-01

Locations

DE (1)