The overall objective of this work package is to establish the pathophysiologic characteristic of impaired metabolic balance of the peripheral tissues in patients with chronic heart failure. The emphasis is put on impaired insulin signalling for its pivotal role in the regulation of energy and anabolic stimulation.
This research will provide novel data on the metabolic aspect within CHF pathophysiology that is currently only incompletely understood. The findings from the planned research will support the development of potential novel therapeutic targets in patients with CHF. Current therapeutic options in CHF with prognostic implications are limited to targeting the neurohormonal activation. A better understanding of the metabolic impairment occurring in CHF may provide the basis for significant advances in therapeutic strategies.
The study population for this project will be enrolled at all participating clinical SICA centres according to pre-specified common inclusion and exclusion criteria and standardized assessment methods will be implemented in all contributing centres. In order to maximise the overall profit from the joint efforts, a two level co-operations will be pursuit:
(a) Highly specialized centres will contribute to the specific and more demanding methodologies (biopsies, intravenous glucose tolerance testing, assessment of peripheral blood flow and vascular reactivity - method description see below).
(b) All SICA partners involved in recruitment of patients, however, will contribute to accumulation of a common standard of metabolic data and body composition characteristics to obtain a larger study population than from any single centre possible.
Assessment plan for baseline and follow-up assessments: All assessments outlined below are clinical pathophysiological tests involving various specialised test procedures to be used in these patients. The Patients will be assessed cross-sectionally at baseline (enrolment). All patients will further be followed up for survival and clinical status (longitudinal assessment) and repeated assessment are planned according to the follow-up schedule as specified from WP 3.
Task 1: Whole body insulin sensitivity
Detailed pathophysiological studies will be performed in several specialised clinical research centres of the SICA consortium (HULL, CHAR, SCCS) on both systemic level and tissue specific cellular level (biopsy studies) to assess specific aspects of impaired insulin sensitivity of the skeletal muscle in association to clinical and functional characterisation of the patients. (objective 1). The following tests will be performed:
Task 2: Metabolic characterisation of CHF patients
In a larger study population including all co-operation centres of the SICA consortium with patient recruitment (HULL, WROC, CHAR, SCCS, Moscow, Bolnisnica Golnik) a common standard of metabolic characterisation will be performed in association to clinical functional status and follow-up for disease progression and mortality. (objective 1). In detail, the following assessments will be performed:
Task 3: Impaired peripheral blood flow and vascular reactivity
Impaired peripheral blood flow and vascular reactivity will be assessed in the setting of CHF and the association specifically to insulin sensitivity and metabolic and hormonal regulation. Using venous occlusion plethysmography we will measure peripheral blood flow of the leg and of the forearm at rest, at post-ischemic peak blood flow and as flow dependent flow (HULL, SCCS, CHAR). Using this method we will obtain data on vasodilator capacity and particular on endothelium dependent vasodilation in these patients. The co-ordination of this project in several participating centres of the SICA consortium will allow for the first time a prospective multicenter approach of a pathophysiologic study on peripheral abnormalities in CHF. (objective 2)
Task 4: Muscle and fat tissue metabolic abnormalities
Tissue specific characteristics will be studied from biopsy assessments from skeletal muscle and fat tissue biopsies. This objective will be conducted in co-operation within the SICA consortium of several clinical centres for both biopsy collection (HULL, WROC, Moscow) and biopsy assessment (CHAR, ROME, MHH). Biopsies from muscle tissue will be obtained using the Bergstrom needle technique and from fat tissue using liposuction. Both procedures are widely employed as routine clinical research techniques under sterile conditions. Muscle tissue and fat tissue will then be analysed in specialized laboratories (CHAR, ROME, MHH) to assess on a cellular level the activity of the insulin signalling cascade (IRS-1 and IRS-1- phosphorylation, GLUT4 transport protein, PPAR gamma activation) and proteasome activation and in CHF. In adipose tissue adipokines such as TNFa, Leptin, Adiponectin will be assessed as the activation of PPAR gamma. Finally the results from tissue analyses will be evaluated in relation to clinical variables and to body composition changes in long term follow up. (objective 3)
Work description for the Researcher (0.5 clinical research fellow in WP7)
The researcher (full medical license as physician required) will be responsible for patient screening and enrolment. He will perform all clinical patients related assessments and tests. In particular insulin sensitivity assessments by ivGTT and minimal modelling, clinical evaluation, blood sampling, body composition analysis (bioimpedance) muscle strength testing, blood flow assessment by plethysmography and biopsy procedures. He is responsible for the clinical evaluation at baseline as well as at follow-up visits. Serum samples and tissue samples obtained will be sent to specialized laboratories for the assessments outlined above. The research is further responsible for the overall data collection of the WP and under supervision for evaluation and statistical analysis and the publication of the results.