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Nitric Oxide (NO) Enhancement: New Strategy to Treat Heart Failure
The National Heart, Lung, and Blood Institute convened a workshop of experts on July 29-30, 2009 in Bethesda, Maryland to address knowledge gaps, challenges and opportunities related to the strategy that promotes nitric oxide (NO) enhancement as a treatment for heart failure. The need for new effective strategies to improve outcomes for patients with heart failure is underscored by persistently high health care utilization and costs associated with heart failure, with over 1.1 million U.S. heart failure hospitalizations in 2006 and an estimated direct and indirect cost in the U.S. of $39.2 billion in 2010. Workshop participants were charged to recommend the logical next step(s) in clinical investigation to evaluate and translate the potential role of NO enhancement in the treatment of heart failure. Workshop objectives were to:
The workshop is responsive to NHLBI Strategic Plan Goals 2 & 3.
NO plays an active role in the preservation of the structural and functional integrity of the vasculature and myocardium. NO dysregulation and high oxidative stress occur in the presence of atherosclerosis, heart failure and cardiovascular risk factors. Thus targeting NO availability and/or reducing oxidative stress might be expected to improve a broad range of vascular and myocardial outcomes. This would constitute a new strategy for CVD treatment and prevention and, in fact, has already demonstrated efficacy in patients with advanced heart failure.
The African American Heart Failure Trial (A-HeFT), a multicenter randomized, placebo-controlled trial, demonstrated a large positive impact on mortality and other heart failure outcomes by adding the drug combination of fixed-dose isosorbide dinitrate plus hydralazine (I/H) to guideline-driven medical treatment in patients with advanced heart failure. The positive treatment effect was consistent across subgroups of age, gender, blood pressure, diabetes and renal insufficiency. Despite these findings, few patients are receiving I/H therapy, including less than 2% of eligible African Americans, the sole group included in A-HeFT.
Workshop participants reviewed epidemiologic, fundamental and clinical studies addressing NO enhancement in heart failure. Why strong evidence that I/H improves outcomes in patients with advanced heart failure failed to result in its consistent use in eligible patients was a key focus of the workshop. Race-specific labeling for I/H pills may have served as an obstacle for prescribing to non-African American patients with advanced heart failure. Additionally, the cost of the combination pill is excessive compared to generic pills. The initial treatment guideline review and recommendation following the presentation of the A-HeFT findings (but pre-dating published results) did not strongly endorse treatment with I/H in the African American population. Despite a revised guideline which endorsed its use, both fixed-dose I/H and its generic substitution remain under-prescribed for eligible patients.
Since A-HeFT, the understanding and evidence for mechanisms of benefit of NO enhancement and reduction of oxidative stress in the treatment of heart failure have improved and include animal and clinical evidence to further support myocardial and vascular protection. Current phase II trials investigating alternate pathways for NO donors, such as phosphodiesterase-5 (PDE-5) inhibition with sildenafil or tadalafil and soluble guanylate cyclase (sGC) stimulators and activation with riociguat or cinaciguat, were reviewed. Additionally, phase II trials of xanthine oxidase inhibition with allopurinol or oxypurinol, both of which target reduction of oxidative stress in heart failure, were also identified and reviewed. Renal interactions of NO and reactive oxygen species suggest that NO enhancement would promote cardiorenal protection. If proven, this effect would be especially important for heart failure therapy since renal pathophysiology can be both a complication of treatment and a cause of increased risk for adverse outcomes.
Workshop experts also identified numerous opportunities for investigating mechanisms of NO enhancement that are appropriate for clinical evaluation. Specifically, substudies in a large trial of NO enhancement should include blood samples for biomarkers of oxidative stress, inflammation, renal function, genetics, genomics and pharmacogenetics as well as traditional markers of heart failure. Other important substudies identified included: 1) measuring circulating myocardial and endothelial progenitor cells to provide insight into vascular and myocardial repair and reverse remodeling; 2) applying MRI to non-invasively assess cardiac structure, function and reverse remodeling; 3) monitoring serial measure(s) to assess vascular remodeling; and 4) collecting markers to elucidate gender and race differences.
The workshop participants will develop a meeting proceedings report for publication in a peer-reviewed cardiovascular journal.
Division of Cardiovascular Sciences
Patrice Desvigne-Nickens, MD
Robin Boineau, MD
Stephen Goldman, PhD
Lisa Schwartz Longacre, PhD
Monica Shah, MD
George Sopko, MD, MPH
Myron Waclawiw, PhD
Etai Gamliel (summer student)
Last Updated: April 2010