Over the last decades, the pathophysiological understanding of CHF has developed from the rather simplistic model of mere pump failure to that of a multisystem disorder which affects not only the cardiovascular system but also the musculoskeletal, renal, neuroendocrine and immune systems. Members of the SICA-HF consortium have contributed significantly to broadening the views on CHF pathophysiology. Such findings have made novel therapeutic approaches possible. It is interesting to note, however, that large subgroups of patients with heart failure have not received systematic attention so far. For example, no treatment studies have focused on patients at the extreme ends of the body weight spectrum, i.e. patients with heart failure and obesity or patients with heart failure and cachexia. This fact is truly striking, because up to 50% of all patients with CHF might be considered obese (Curtis et al., 2005). Systematic large-scale studies on cachexia in CHF are not available, but one study found that up to 16% of out-patients with heart failure are cachectic (Anker et al., 1997). The incidence of diabetes mellitus ranges among patients with CHF between 24 and 47%, depending on the study population (e.g. in-patients vs. out-patients) (Cleland et al., 2003).
The European Commission identified co-morbidities of heart failure as an important area of research at a workshop jointly organized by DG Research (Health Directorate) and the Russian Federal Agency for Science and Innovations, held in St. Petersburg (Russia) in September 2007. The European Commission stated that the two selected topics represent areas of high importance, both scientifically and medically. Importantly, the European Commission acknowledged that the area of the co-morbidities type 2 diabetes, obesity, and cachexia in heart failure is an area in which both researchers in the European Union and in the Russian Federation have highly developed skills and knowledge. Thus, this area is deemed likely to benefit from mutual exchange of information and combination of efforts.
The SICA-HF consortium aims to study patients with CHF and type 2 diabetes, obesity, or cachexia. Areas to be addressed by the SICA-HF trial and their potential impact include:'Create awareness of physicians and the general public to the magnitude of the problem by providing data on incidence, prevalence, morbidity and mortality of type 2 diabetes, obesity, and cachexia in heart failure'
Retrospective analyses have highlighted the importance of the aforementioned co-morbidities in patients with heart failure. Prospective data are not available. It has not been prospectively investigated how the co-morbidities affect the clinical course of heart failure or whether their presence increases the incidence of the disease. The consortium aims to recruit and characterize 1100 consecutive patients with heart failure and to recruit and characterize 400 consecutive patients with suspected heart failure in whom no significant cardiac disease is established. We aim to study the incidence and prevalence of the co-morbidities. Due to its longitudinal nature and comprehensive follow-up, SICA-HF will answer many questions related to the prevalence, incidence and prognosis of diabetes, cachexia and obesity in patients with and without cardiovascular disease.'Improving the health of European citizens'
The assessment of incidence and prevalence of type 2 diabetes, obesity, and cachexia in patients with heart failure and in-depth pathophysiological studies will help to identify potential risk factors for the development of these co-morbidities. SICA-HF strives to help solve a major societal problem, which is related to the high level of morbidity and mortality arising from heart failure per se, particularly considering the importance of type 2 diabetes, obesity and cachexia. The impact of the SICA-HF project will be to overcome the roadblock in the awareness of heart failure in the general population, which is evidenced by recent surveys (Remme et al., 2005). Furthermore, SICA-HF aims to identify protective factors whose presence serves to improve the affected patients' prognosis.'Better understanding of pathophysiological processes in type 2 diabetes, obesity, and cachexia'
Close collaboration between clinical and preclinical procedures is paramount in SICA-HF. Tailored therapies for specified subgroups of patients require a thorough understanding of the pathophysiological changes that occur in patients with type 2 diabetes, obesity, or cachexia. A collaboration of clinical and preclinical researchers across Europe and the Russian Federation who have access to genetic, tissue, and blood samples from identical patients has not been performed so far. In fact, pathophysiological studies on a multicenter basis are very rare. The proposed studies on sleep disordered breathing may serve as one example. Its occurrence has little been investigated in patients with heart failure. Its prevalence in the subgroups of obese, cachectic, or diabetic patients is unclear. The same goes for the effect of sleep disordered breathing on morbidity and mortality of affected patients. In SICA-HF, researchers from experienced centers work hand-in-hand using biospecimens from the same patients to solve problems concerning fat or muscle metabolism, biomarkers in the blood or genetic markers. Thus, these data can be easily correlated with clinical data to understand pathophysiological links, and in case of sleep disordered breathing, to understand mechanisms that lead to its occurence. This approach applies likewise to all areas of pathophysiological research in SICA-HF. The members of the consortium are convinced that the trial will provide in-depth insight into the involved mechanisms, which allows to identify novel, potentially even causal therapeutic avenues.'Enable recommendations for European treatment guidelines on heart failure'
The current guidelines for the treatment of heart failure, issued by the European Society of Cardiology, do not provide evidence-based recommendations for the treatment of patients with heart failure and type 2 diabetes, obesity, or cachexia. For obesity, the guidelines simply state that obesity should be avoided, although retrospective data suggest otherwise. The guidelines further conclude that weight reduction should be considered in patients with a BMI >30 kg/m2 "in order to prevent the progression of heart failure, decrease symptoms, and improve well-being" (class of recommendation I, level of evidence C) (Dickstein et al., 2008). This statement is not supported by retrospective or prospective data, but can be called merely intuitive. Therefore, the statement "In moderate to severe heart failure, weight reduction should not be routinely recommended since unintentional weight loss and anorexia are common problems" (class of recommendation IIa, level of evidence C) is likewise not based on large-scale prospective data (Dickstein et al., 2008). The guidelines acknowledge that "body wasting is a serious complication of heart failure ... during the natural course of the disease." However, the guidelines also state that oral antidiabetic therapy should be individualized" (class of recommendation IIa, level of evidence A) and that metformin should be considered as a first-line agent in overweight patients ... without significant renal dysfunction" (class of recommendation I, level of evidence B). The SICA-HF consortium aims to enable recommendations for these guidelines with regards to (i) weight gain and weight loss, particularly in defining cut-off points, (ii) the influence of type 2 diabetes, obesity, or cachexia on biomarkers of heart failure such as BNP or NT-proBNP, (iii) the provision of data on prevalence and incidence to buttress the magnitude of the co-morbidities.'Translation of basic discoveries into clinical applications including scientific validation of experimental results'
As stressed earlier, an important advantage of the SICA-HF approach is the close collaboration of basic researchers and clinicians who work with samples from identical patients across several countries. Additionally, SICA-HF provides a multidisciplinary approach, because not only cardiologists but also haematologists are involved. Bench to beside translation remains a major bottleneck of heart failure research. SICA-HF researchers as leaders in clinical as well as in experimental heart failure research, have demonstrated in a number of investigator initiated clinical trials that they can successfully obtain proof of principle for their findings. SICA-HF research aims at improving translation by
'Define standards for pathophysiological multicenter research'
- exploring clinically relevant issues (bedside to bench);
- fostering very close interaction between leading basic and clinical heart failure researchers;
- exploiting databases from several promising clinical trials which have been recently completed and whose full database are available to or from members of the consortium;
- developing a clinical platform geared at overseeing the translational process.
SICA-HF uses a multicenter approach to study pathophysiological aspects of the co-morbidites type 2 diabetes, obesity, and cachexia in patients with CHF. Such an approach is rare in medicine, which may set standards for pathophysiological studies in other areas. The methods used in SICA-HF will achieve a high level of standardisation validated in European and Russian centers creating standard operating procedures that can serve as a model for future research in other areas. The sustainability of these methods will be achieved by distribution via the SICA-HF website.'Increasing European competitiveness'
Heart failure research in the EU is highly competitive at the international level. Multidisciplinary institutional and academic and industrial collaborations are very rare in the United States. However, due to the magnitude and complexity of the problem, such collaborations are clearly warranted to substantially improve the situation of heart failure patients and their families. SICA-HF research, due to its innovative approaches, its focus on translation, and, importantly, strong interaction between clinicians and researchers will have a strong impact on European competitiveness in the heart failure field.
Copyright (c) by SICA-HF, e-mail: info(at)sica-hf.com