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SEVENTH FRAMEWORK PROGRAMME

About SICA-HF - Objectives

Objectives

CHF is still not curable, and all available therapies are aimed at limiting its progression. Important subgroups of patients have only received limited systemic research. This is particularly true for patients with heart failure and type 2 diabetes mellitus, obesity, and (cardiac) cachexia. Since conclusive data are not available, current guidelines for heart failure fail to mention specific (treatment) guidance for these patient subgroups. The aim of the research proposed by the SICA-HF consortium is to provide detailed characteristics of the patients with heart failure and the aforementioned co-morbidities in order to provide a basis for improving the outcomes of the affected patients. We are confident that our innovative and collaborative approaches that tie preclinical and clinical research, as well as third parties such as the industry will contribute to overcoming the translational roadblock in this field.

The areas of particular interest and key topics that will be the focus of the proposed research therefore include:

1. Deterioration of heart failure is the result of co-morbidity action: CHF is a multisystem disorder developing as a consequence of various vicious cycles. Co-morbidities including type 2 diabetes, obesity, and cachexia affect key regulators causing these vicious cycles to be highly active.

2. Diabetes mellitus is a factor contributing to morbidity and mortality in heart failure: Increasing evidence suggests a relationship between impaired glucose metabolism and CHF. Diabetes mellitus has been shown to be a predisposing factor for development of CHF. In large heart failure trials, diabetes mellitus has a prevalence of more than 25%. CHF can be viewed as a state of insulin resistance developing independently of disease aetiology. Insulin resistance may occur prior to type 2 diabetes, which makes the fact likely that the prevalence of insulin resistance is much higher.

3. The role of obesity in heart failure is controversial: Several retrospective studies have shown that there is a relation between increasing body mass index (BMI) and improved survival in patients with heart failure, but these studies did not exclude patients with cachexia and did not adjust for the presence of type 2 diabetes. Patients with moderate obesity may represent a group of patients with a higher metabolic reserve, who are better (and longer) able to tolerate the metabolic stress of heart failure than those with more "ideal" body weights. The complex relationships require prospective studies.

4. The clinical significance of cachexia in heart failure: Cardiac cachexia is a relatively common complication of heart failure, which is associated with a very poor prognosis. If we were to make a conservative estimate that cardiac cachexia occurs in 8-10% of the heart failure population then at least 1,400,000 patients suffer from this condition in Europe alone. No data from large prospective studies are available. The availability of reliable epidemiological data is vital to the appropriate planning of limited healthcare resources.

5. The relationship between body composition changes and mortality in heart failure is unknown: Early evidence buttresses the view that a higher fat mass is associated with better survival in patients with heart failure. Prospective data are lacking.

6. The complexity of heart failure biology: Neuroendocrine activation, overactivity of the immune system, and the dysregulation of the catabolic/anabolic balance make the pathophysiology of heart failure exceedingly complex. Several tissues interact with each other via nervous or endocrine connections. Among these tissues primary research endeavours should include the myocardium, skeletal muscle, fat tissue, and progenitor cells from the bone marrow.

7. To link preclinical (pathophysiological) and clinical findings in order to improve the patients' quality of life: Large-scale studies linking clinical and preclinical research in heart failure are not available. The preclinical identification of pathways involved in the clinical deterioration of the affected patients is likely to show novel possibilities for future therapeutic interventions.

8. Gender aspects are underinvestigated in heart failure research: Regulatory neuroendocrine pathways and general body composition are significantly different in healthy as well as diseased men and women. Women are generally underrepresented in clinical studies investigating disease mechanisms as well as novel therapies in heart failure. This implies that the gender-specific impact is largely unknown.

9. Better understanding of vascular, cellular, and molecular pathways in the context of body weight alterations and changes of glucose metabolism: Clear data on the mechanisms involved in the development of cachexia in patients with heart failure are not available. The mechanisms and the interactions between different types of tissues in heart failure aggravated by type 2 diabetes, obesity, or cachexia are not clear. Multidisciplinary research is required to elucidate the pathophysiological pathways that are involved in the deterioration of the clinical status of the patients and thus in decreasing quality of life.

10. Tailored therapies for heart failure are the future: Recent data buttress the view that not all patients with heart failure benefit from the same therapies. Patients with anaemia aggravating heart failure have recently received increasing attention, and the first phase II studies of anaemia treatment were recently published. Type 2 diabetes, obesity, and cachexia aggravating heart failure appear to be such subgroup that may benefit from tailored therapies, but these therapies need to be based on a thorough pathophysiological understanding.
These ten areas are linked on all levels and therefore need to be tackled by an integrative approach. CHF pathophysiology, as well as cardiac reorganisation and repair, are highly complex. Developing successful strategies for cardiac and tissue protection and repair therefore require a joint effort of experts on basic science on a vascular, molecular, and cellular, but also on clinical level. We will work on a common model and methods platforms, in which for the first time relevant co-morbidities (particularly type 2 diabetes, obesity and cachexia), gender, age, and long-term outcomes will be investigated. The training of young researchers will lead to a standardisation and harmonisation of laboratory practices within the SICA-HF consortium, and implement standard operating procedures (SOPs) generated by the consortium. Importantly, the SICA-HF consortium combines expertise in clinical as well as preclinical research in CHF. Our clinical platform, consisting of outstanding European heart failure clinicians, will provide advice to the basic researchers of the consortium on clinically relevant questions and modelling, and will periodically review the ongoing development of innovative therapies to ultimately take the most promising preclinical strategy developed by our consortium into a multicenter randomized clinical trial.

Based on the above analysis of basic research and medical needs, bottlenecks, and opportunities, the SICA-HF consortium has formulated the following, highly interconnected objectives:

Objective 1: To characterise the prevalence, incidence, persistence, and phenotype of obesity, cachexia, and type 2 diabetes in patients with heart failure
There is a clear need to better characterise the subgroups of patients with these co-morbidities in heart failure. SICA-HF aims to recruit 1600+ patients with CHF, 300+ patients with type 2 diabetes without heart failure, and 150+ healthy control subjects. These patients will allow insight into the incidence and prevalence of type 2 diabetes, obesity, and cachexia in patients with heart failure. Moreover, we will gain insight into the morbidity and mortality of these patients.

Objective 2: To describe patterns of exercise capacity and cardiorespiratory reflex control
SICA-HF will develop standardised protocols for cardiopulmonary exercise testing and for cardiopulmonary reflex testing. Patients with assessments of these parameters will be followed-up for 28-30 months and re-assessed after 4-6 months, 16-18 months, and at annual intervals thereafter. The aim is to establish exercise capacity, data on heart rate and blood pressure control and baroreflex and chemoreflex sensitivity. These data will be integrated with other clinical and preclinical analyses and help in prognosis estimation.

Objective 3: To analyse body composition and its changes over time in patients with heart failure and type 2 diabetes, obesity, or cachexia
We aim to investigate body composition and body composition alterations in patients with CHF in the context of assessments of the presence of type 2 diabetes, obesity, and cachexia. The planned analyses include assessments of the whole body and of its regions (limbs vs. trunk), and we aim to relate them to several pathophysiological changes with particular focus on the assessment of vascular and cellular status. Better understanding of the regulation of body composition may contribute to develop therapeutic strategies to delay or prevent weight loss and development of cachexia, may help to better understand the obesity paradox of heart failure as well as the importance of diabetes as co-morbidity of CHF.

Objective 4: To investigate the incidence and prevalence of sleep disordered breathing and its impact on the clinical severity in patients with heart failure
Patients will be screened for autonomic dysfunction and pro-arrhythmias, and sleep disordered breathing will be assessed in an ambulatory setting. The combination of a preclinical and a clinical approach in SICA-HF allows that the analysis of the final dataset will take into account alterations in body composition, in insulin resistance, peripheral blood flow, and several other parameters including the endocrine functions of, for example, adipose tissue.

Objective 5: To establish the impact of impaired vascular reactivity on impaired skeletal muscle metabolic and functional capacity including its underlying mechanisms.

We aim to establish the pathophysiologic characteristics of impaired metabolic balance of the peripheral tissues in patients with heart failure. The emphasis is put on impaired insulin signalling for its pivotal role in the regulation of energy and anabolic stimulation including an assessment of peripheral blood flow.

Objective 6: To describe the interplay and metabolic signaling pathways between adipose tissue, skeletal muscle, the bone marrow and the heart in patients with heart failure and type 2 diabetes, obesity, and cachexia.

We will examine the cross-talk between muscle, adipose tissue and the immune system "ex vivo" by co-cultures of primary human myoblasts with mature adipocytes, as well as with peripheral blood mononuclear cells extracted from the same patients (autologous system), in order to better understand the pathophysiology of peripheral metabolic abnormalities in CHF. We will further assess circulating adipokine levels and adipokine mRNA and aim to define the role of lipolytic stimuli in isolated adipocytes from heart failure patients. We will investigate intracellular signalling pathways in endothelial progenitor cells and adipose stromal cells and their response to physical, chemical, and biological "stressors". Using these data, we aim to establish a system of criteria that allows estimating the regenerative potential of any given patient. Data obtained in these ex vivo models will be integrated with clinical data.

Objectives