Novel Pathophysiological Insight and Treatment Strategies for Heart Failure

Hiroyuki Tsutsui
2004 Circulation Journal  
ongestive heart failure (HF) is a leading cause of morbidity and mortality in industrialized countries, 1 and is also a growing public health problem, mainly because of the aging of the population and the increased prevalence of HF in the elderly. Previous basic, clinical, and population studies have advanced the modern treatment of HF, but efficacy is still limited in the 'real world'. There are 2 approaches to solve this crucial issue. First is the further development of therapeutic
more » ... erapeutic strategies based on a novel insight into the pathophysiology of myocardial remodeling and failure. Second is the improvement of quality of care in routine clinical practice. Reactive oxygen species (ROS) such as superoxide anions (·O2 -) and hydroxy radicals (·OH) cause the oxidation of membrane phospholipids, proteins, and DNAs 2 and have been implicated in a wide range of pathological conditions including ischemia -reperfusion injury, neurode- Increased ROS Production Within the Failing Myocardium Recent experimental and clinical investigations have suggested that the generation of ROS increases in chronic HF. 3-6 Lipid peroxides and 8-iso-prostaglandin F2 , which are the major biochemical consequences of ROS generation, are elevated in the plasma and pericardial fluid of patients with HF and also positively correlate with the severity of HF. 3,4 However, these findings provide only indirect evidence of ROS generation in the failing hearts and it is difficult to quantify the amount of ROS in the intact biological system because they are unstable and rapidly react with unoxidized adjacent molecules, thus having a very short half life. The only method of directly quantifying ROS in biological tissue is electron spin resonance (ESR) spectroscopy. Using ESR combined with the nitroxide radical, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), as a spin probe, a definitive and direct demonstration of enhanced generation of ROS in the The ultimate goal of heart failure (HF) treatment is to improve the prognosis of patients. Previous basic, clinical, and population studies have advanced the modern treatment of HF, but efficacy is still limited especially in 'real world' patients. There are 2 approaches to solve this crucial issue. First is the further development of novel therapeutic strategies based on new insight into the pathophysiology of myocardial remodeling and failure. Second is the improvement of the quality of care in routine clinical practice. The basic approach is to develop the treatment of myocardial remodeling by regulating mitochondrial oxidative stress. In the failing heart, oxygen radicals are the result of defects of mitochondrial electron transport, causing mitochondrial DNA damage and functional decline, and further production of oxygen radicals. Oxidative stress causes myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases, all of which result in myocardial remodeling and failure. Therefore, mitochondrial oxidative stress and DNA damage are good therapeutic targets. The clinical approach is to develop effective strategies of HF management for the 'real world' patients. Readmission because of exacerbation is common in HF patients and further impairs their quality of life. Noncompliance with treatment is the most common precipitating factor for readmission. Regular medical follow-up and social support are important components that should be included in the disease management program of HF patients. These basic and clinical approaches are needed to establish new and effective treatment strategies for Japanese patients with HF. (Circ J 2004; 68: 1095 -1103
doi:10.1253/circj.68.1095 pmid:15564690 fatcat:zdcrnbovznbjpmjtmvuixsxbgq