Taking NO for an Answer
Exploring the Therapeutic Potential of Nitrite in HFpEF
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Heart failure with preserved ejection fraction (HFpEF) accounts for at least half of the heart failure (HF) hospitalizations in North America.1 The symptoms of HFpEF generally center around 2 main features: (1) dyspnea, likely reflective of pulmonary congestion, and (2) exertional intolerance, consistent with inefficient oxygen delivery or utilization. After an HF hospitalization, survival is poor.2 Despite the scope and seriousness of this problem, no targeted therapeutic intervention has been clearly identified to decrease the morbidity or mortality from this syndrome. Treatment has, therefore, largely focused on the management of comorbidities and volume status. The reasons for failing to identify effective therapeutic interventions in HFpEF are varied but primarily revolve around the clinical heterogeneity of the condition with significant difficulties in providing a unifying pathophysiology for this syndrome and consequent challenges in clinical trial design.
Article, see p 880
Yet, patients with HFpEF have distinct identifiable abnormalities in vascular and endothelial function, which may help tie together the varied systemic and cardiac manifestations of this condition with its associated comorbidities. Endothelial dysfunction is indicative of impaired endothelium-mediated nitric oxide (NO) bioavailability and can be assessed clinically by demonstrating a deficient vasodilatory response to various stimuli. NO, through stimulation of guanylate cyclase, leads to the generation of the second-messenger molecule cyclic guanosine monophosphate, which depending on the cell type, results in multiple fundamental downstream processes, such as contraction, relaxation, cell growth, apoptosis, and specific gene expression.3 Paulus and Tschöpe4 described coronary microvascular endothelial inflammation in HFpEF resulting in decreased NO bioavailability, low cyclic guanosine monophosphate content, and reduced protein kinase G activity in cardiomyocytes. This decreased protein kinase G activity favors the development of cardiac hypertrophy and, because of hypophosphorylation of titin, increases resting tension in cardiomyocytes. In fact, it has been proposed that correction of myocardial …