Immunological and Molecular Mechanisms in Myocardial Remodeling and Heart Failure

Arne Yndestad
Group Leader

Heart failure (HF) is defined as a clinical syndrome characterized by dyspnea and fatigue, at rest or with exertion due to impaired structure and/or function of the heart. HF represents a major cause of cardiovascular and also total morbidity and mortality in the western hemisphere. The incidence and prevalence of this disorder is rising and it is estimated that HF affects 1-3% of the population. Moreover, the prognosis is poor. In fact, in its advanced stages, the 5 year survival rate is comparable with that of severe malignancies. Due to the high prevalence and morbidity, HF also represent a major and increasing socioeconomic burden. Thus, there is an obvious need for new treatment options for this patient group.

The development of HF is characterized by several cellular and molecular processes, referred to as remodelling, leading to important changes in myocardial structure and function. These changes include cardiomyocyte hypertrophy, increased ventricular volume due to dilation of the ventricular cavity, regression to a fetal phenotype characterized by expression of fetal genes and proteins, enhanced apoptosis, as well as the development of fibrosis involving changes in the quantity and quality of the extracellular matrix. Initially the ventricular remodelling is thought to be adaptive and accommodates the increased myocardial wall stress. However, over time, this process turns maladaptive, leading to a progressive decrease in myocardial function.

The progression of myocardial remodeling to heart failure. Myocardial stress including hemodynamic overload, myocardial infarction and neurohormonal stimulation may induce a remodeling process that over time cause functional and structural deterioration of the heart, increased myocardial dysfunction and heart failure.

A range of factors have been suggested as mediators of myocardial remodelling, including angiotensin II, endothelin-1, nitric oxide and other reactive oxygen species. However, the exact mechanism as well as the relative importance of the various actors is far from clear, and this represents an important area of HF research. 

Inflammation - pathogenic factor in the development of heart failure
Patients with HF have raised plasma/serum levels of inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1β and IL-6, with increasing levels according to disease severity. Such an inflammatory pattern has also been found in leukocyte subsets. Importantly, the rise in inflammatory mediators seems not to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10, resulting in an inflammatory imbalance. Moreover, enhanced expression of inflammatory mediators has also been found within the failing myocardium (e.g., TNFα, IL-6-related cytokines and chemokine receptors), suggesting a potential role for cytokine-related interactions in the pathogenesis of myocardial failure. Although, the inflammatory cytokines initially may have cardioprotective effects, a series of experimental studies have revealed that the biological effects of cytokines may explain several aspects of chronic HF through mechanisms such as induction of cardiomyocyte apoptosis, enhanced matrix degradation, direct effects on Ca2+-dependent processes and impaired β-adrenergic signal transduction. 

However, even though studies in experimental models indicate a pathogenic role of inflammatory cytokines in the development of myocardial failure, the role of cytokine dysregulation in the development of human HF needs to be further elucidated. In particular, the mechanisms for the inflammatory activation as well as the balance between cardioprotective and pathogenic effects needs to be better understood.

Research Aim

Our hypothesis is that immunological and inflammatory mechanisms play an important role in the development and progression of HF. This hypothesis is based on several studies, including our own original observations. The main aim of the project is to characterize potential pathogenic effects of innate immune mechanisms in HF with the objective to form the basis for new treatment modalities as well as for the identification of new biomarkers in this disorder.

Our experimental approaches include clinical studies in well characterized patients with heart failure, examining samples from peripheral blood as well as tissue samples from the failing myocardium, in vitro studies in cardiac myocytes and fibroblasts, experimental studies in animal models of HF including studies in gene modified mice and therapeutic intervention studies in heart failure patients.

Sources of systemic inflammation in chronic heart failure. The elevated circulating levels of inflammatory mediators [e.g., tumor necrosis factor (TNF)α, interleukin (IL)-1, -6, and -8, and monocyte chemoattractant peptide (MCP)-1] during heart failure may be due to release from the failing heart itself, but also from circulating leukocytes, blood platelets, endothelial cells, as well as the lungs and the liver.


Induction of systemic inflammation in chronic heart failure. While several stimuli may be operating such as autoantibodies, heat shock proteins, microbial antigens, endotoxins, shear and oxidative stress, hypoxia, oxidized (Ox)-LDL, hemodynamic overload and neurohormones, it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in HF regardless of the initial event. LDL, low-density lipoprotein; TLR, toll-like receptor.


Photo Øystein H. Horgmo, University of Oslo

From left: Kuan Yang, Øystein Sandanger, Arne Yndestad, Maria Belland Olsen, Marina Sokolova, Mieke Louwe, Linn Fosshaug, Katrine Alfsnes, Trine Ranheim, Knut Husø Lauritzen, Negar Shahini, Jonas Øgaard, Alexandra Finsen, Margrethe Holt, Azita Rashidi