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J Am Coll Cardiol, 2005; 45:1425-1427, doi:10.1016/j.jacc.2005.02.021 © 2005 by the American College of Cardiology Foundation |
Section of Heart Failure and Cardiac Transplant Medicine, Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Cleveland Clinic Foundation Lerner College of Medicine, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. Randall C. Starling, Head, Section of Heart Failure and Cardiac Transplant Medicine, Cleveland Clinic Foundation, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk F-25, Cleveland, Ohio 44195. (Email: starlir{at}ccf.org).
Nitric oxide (NO) remains the topic of considerable debate in the pathogenesis of human and experimental heart failure (2,3). Nitric oxide can exert negative inotropic effects and apoptotic effects on cardiac myocytes (4,5). Previous investigations have suggested that elevated local levels of NO in cardiac myocytes explain important pathophysiologic observations. Three distinct nitric oxide synthase (NOS) isoforms can be expressed in the heart.
Triggers for iNOS expression include inflammatory cytokines (interleukin-6, tumor necrosis factor-alpha, interferon-gamma) and lipopolysaccharides; hence, catecholamine-resistant hypotension associated with septic shock has been attributed to enhanced iNOS activity. Known triggers of the iNOS isoform include acute ischemia, sepsis, myocarditis, cardiac allograft rejection, and mechanical stress. The interaction between NO and superoxide is delicate because deficiencies of NO and an overabundance of superoxide can impair the balance between physiologic and pathologic pathways. Cellular damage that occurs in the setting of elevated iNOS is a consequence of common stimuli that result in the formation of NOS and that also up-regulate oxidase, hence resulting in tissue elevations in both NO and superoxide, which leads to the formation of peroxynitrite (8). Peroxynitrite and superoxide are toxic species capable of causing cellular damage (9). Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation associated with fibrosis, hypertrophy, and chamber dilation, a cardiomyopathic phenotype (10). Hence, a scenario evolves in which the overexpression of iNOS can ironically lead to pathologic consequences, presumably by the simultaneous up-regulation of oxidase and, therefore, upsetting the balance between NO and superoxide production. Hence, the observation of elevated iNOS in human heart failure that is attenuated by mechanical unloading with a VAD provides additional insight into the deleterious consequences of elevated wall stress in perpetuating progressive left ventricular dysfunction and myocardial failure.
The role of iNOS in heart failure pathogenesis is contentious. The complexity of this topic has been attributed to the differing physiologic effects of leukocyte-derived iNOS versus myocyte-derived iNOS and the impact of the cellular microenvironment (2). Previous work in humans has shown an elevation of iNOS gene expression in humans with heart failure, but the extent was greater in New York Heart Association functional class II versus class IV patients (11). However, as noted earlier, common stimuli that increase iNOS/NO can be deleterious by facilitating superoxide and peroxynitrite production. It appears unclear whether indeed wall stress or cytokine activation is the predominant stimulus for iNOS. Mechanical strain suppresses iNOS in cardiac myocytes in contrast to NOS III, which is up-regulated, hence the concept that NOS in the failing human heart is a "double-edged sword" (12). The hemodynamics in these New York Heart Association functional class IV patients were very abnormal at the time of VAD implantation and improved with VAD unloading, suggesting that iNOS expression is correlated positively with an increasing severity of heart failure. A reduction in wall stress is inferred based on LaPlace’s law because both a pressure and radius decrease after VAD unloading and a concomitant reduction in iNOS expression were observed. Perhaps this theory explains why better outcomes have been observed with unloading therapies versus inotropic therapies in human studies (13)?
The etiology of heart failure did not appear to influence the results; however, the limited samples were confined to ischemic and nonischemic myocardial failure and did not include inflammatory heart disease. The results in previous human studies have differed with respect to the relationship between etiology of heart failure and iNOS expression (7,14). The authors did not attempt to determine whether iNOS expression was related to myocyte or leukocyte production, but this distinction does not seem relevant to their observations, albeit mechanistically of interest (2,14). Similarly, an examination of inflammatory cytokines and the relationship to iNOS expression may have yielded further mechanistic insights (15).
The major conclusions of this study provide new insights and unanswered questions. Inducible nitric oxide synthase protein expression was increased in the hearts of patients with refractory heart failure before heart transplantation. Mechanical unloading with VAD therapy decreases iNOS protein abundance in association with a decrease in the rate of cardiomyocyte apoptosis. A significant correlation between iNOS protein abundance and cardiomyocyte apoptosis was demonstrated. These observations suggest that severe heart failure is associated with up-regulation of iNOS, which correlates with the extent of cell damage and is attenuated by unloading with VAD therapy. It is intriguing to speculate that medical unloading with vasodilators and, specifically, NO enhancers might lead to analogous salutary effects in less severe heart failure.
This work adds to the wealth of information that has amassed in humans supported with VADs showing that the cardiac phenotype can change with mechanical unloading. The authors speculate that nuclear factor kappa B, the ubiquitous and putative regulator of genes associated with apoptosis, may be the mediator of "reverse remodeling." Perhaps iNOS is a marker of the dynamic myocardial events that take place as mechanical stress develops and is alleviated? Many steps in the pathway to failed myocardium have been described by other investigators, including atrial natriuretic peptide, brain natriuretic peptide, interleukin-6, tumor necrosis factor-alpha, and transforming growth factor-beta, to name a few, and shown to "reverse" with mechanical unloading. However, despite the restoration of health with VAD therapies, rarely does the native heart recover to sustain long-term and event-free survival, except in an extremely small percentage of patients and especially those with relatively acute onset of heart failure (16). Future studies using paired tissue samples are important to elucidate the mechanisms of human heart failure. Consortiums that pool resources of clinical information and tissue banks will facilitate and enable future discoveries to unravel the complex and vexing process of myocardial failure.
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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