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Mitochondrial dysfunction in pathophysiology of heart failure.

ABSTRACT: Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial Ca2+ homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy.

SUBMITTER: Zhou B

PROVIDER: S-EPMC6118589 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction in pathophysiology of heart failure.

Zhou Bo B Tian Rong R

The Journal of clinical investigation 20180820 9

Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating ...[more]

PMID: 30124471

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Project description:Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin-angiotensin-aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio-ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio-ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non-neutralizing ADM-binding antibody with a half-life of 15 days. Adrecizumab binds at the N-terminal epitope of ADM, leaving the C-terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM-binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

Dataset Information

Mitochondrial dysfunction in pathophysiology of heart failure.

Publications

Mitochondrial dysfunction in pathophysiology of heart failure.

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