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Cardiac aging and the fountain of youth

2016; Elsevier BV; Volume: 18; Issue: 6 Linguagem: Inglês

10.1002/ejhf.525

1879-0844

Barry A. Borlaug,

Nitric Oxide and Endothelin Effects

This article refers to 'Impact of dietary nitrate on age-related diastolic dysfunction'† by C. Rammos et al. published in this issue on pages….. Aging is one of the dominant forces driving the development of heart failure with preserved ejection fraction (HFpEF).1, 2 Components of cardiovascular function that become impaired in people with HFpEF also deteriorate with normal aging, including left ventricular (LV) diastolic function.1 For example, LV diastolic chamber stiffness increases by 8% over durations as short as 4 years, even in people free of cardiovascular disease.3 The magnitude of this age-related stiffening is correlated with obesity, weight gain, and pulsatile vascular loading, suggesting that adiposity and arterial stiffening importantly accelerate cardiovascular senescence.3-5 Impairments in nitric oxide (NO) signalling are implicated in the pathogenesis of both HFpEF and its attendant comorbidities including obesity, hypertension, metabolic syndrome, and aging.1, 6 Lifestyle habits such as regular exercise, which may improve NO signalling, seem to deter age-related LV stiffening.7 However, it remains unknown whether pharmacological or nutritional interventions to restore NO bioavailability might retard or even reverse cardiac aging, like the mythical fountain of youth. In this issue of the Journal, Rammos and colleagues8 report the results of an impressive array of experiments suggesting that this dream of reversing cardiac aging might not be as mythical as we had once believed. The authors treated young and old wild-type mice with inorganic nitrate for 8 weeks. Cardiovascular function was assessed non-invasively using echocardiography and invasively using gold standard conductance catheter-based techniques, along with ex vivo preparations. Compared with young mice, old mice displayed LV diastolic dysfunction, evident by prolonged relaxation and increased LV stiffness (assessed by the linearized slope of the LV diastolic pressure–volume relationship during transient caval occlusion). Nitrate supplementation enhanced relaxation and reduced LV stiffness in old mice, but not young mice, and this benefit was observed consistently across the non-invasive and invasive functional indices examined. Coronary endothelium-dependent vasodilation assessed in Langendorff preparations was impaired in old animals compared with young, and similarly was improved with nitrate despite no effect in the young animals. Arterial stiffness increases as part of normal aging, and nitrate supplementation reduced blood pressure and aortic stiffness in old but not young animals, suggesting that vascular aging might also be targeted by this approach.8, 9 To explore the mechanisms underlying these benefits from nitrate, the authors then evaluated in vivo calcium handling using an elegant manganese-enhanced magnetic resonance imaging (MRI) technique.8 This revealed diminished entry of calcium through the L-type calcium channel in the hearts of old animals compared with young animals, which was improved with nitrate supplementation. Myocardial activation of the NO-cyclic guanosine monophosphate–protein kinase G pathway (NO-cGMP-PKG) was assessed by evaluating myocardial cGMP content and PKG activity, both of which are known to be depleted in human HFpEF.10 Mirroring the other results, nitrate supplementation was associated with increases in myocardial cGMP content and PKG activity in old but not young animals. The authors conclude that nitrate supplementation reverses age-related LV diastolic dysfunction and improves vascular function in older mice through improvements in NO signalling and myocardial calcium handling.8 Activation of NO signalling has been a therapeutic target for years in cardiovascular medicine, but the traditional thinking has been that the principal source of NO is from the oxygen-dependent activity of NO synthase. However, recent studies have shown that the inorganic anions nitrate (NO3) and nitrite (NO2) function as an important in vivo reservoir to recycle NO.11 Under conditions of hypoxia and acidosis, nitrite is reduced to NO through the action of a variety of haem- and non-haem-containing proteins. Nitrate itself is inert, and mammals lack the ability to reduce nitrate to nitrite, so absorbed nitrate must be secreted in the mouth where it can be reduced to nitrite by commensal oral bacteria. Nitrite swallowed in the saliva is then absorbed in the gut allowing for reduction to NO and secondary biological effects. Nitrate is found in high levels in green leafy vegetables, and this has been proposed as a key mediator of the blood pressure-lowering effects of certain diets.12 As nitrate supplementation improved cardiovascular function in old but not young animals, the authors next sought to examine the oral microbiome to see if there might have been differences in mouth flora that could plausibly explain the greater effects from nitrate in the older animals, and there were indeed a large number of age-related differences in oral bacteria.8 These differences were coupled with higher plasma nitrite levels in old animals, despite similar plasma nitrate levels, consistent with enhanced nitrate conversion to nitrite with aging, although heart nitrite levels were not elevated in older animals, despite the greater cGMP/PKG observed. The authors are to be congratulated on an elegant and comprehensive suite of experiments that advance our understanding,8 and their results importantly extend upon recent studies evaluating the potential benefits of the nitrate–nitrite–NO pathway in humans suffering with age-related cardiovascular diseases such as HFpEF.13, 14 In a double-blind, placebo-controlled trial, we recently demonstrated that sodium nitrite modestly reduces LV filling pressures at rest, while substantially reducing filling pressures during exercise in patients with HFpEF.13 The preferential haemodynamic improvement during exercise compared with rest is likely explained by the venous hypoxia and acidosis that develop during stress, which facilitate reduction of nitrite to NO. This hypothesis was supported by tenfold greater than expected decreases in plasma nitrite levels during exercise, reflecting increased consumption, presumably related to greater conversion to active NO.13 Improvements in LV stroke work during exercise were observed in tandem with lower filling pressures with nitrite, suggesting acute improvements in LV diastolic compliance, similar to what was observed with chronic nitrate supplementation in the present study.8 In a separate acute trial, Zamani et al.14 found that a single dose of nitrate supplementation with beetroot juice improved aerobic capacity and cardiac output reserve in patients with HFpEF, mediated in part by salutary peripheral vascular effects. Larger scale clinical trials are currently in the planning stages to test whether chronic administration of nitrite or nitrate can improve exercise capacity and clinical status in people with HFpEF. A number of limitations in the study of Rammos et al.8 merit further discussion. All animals received nitrate supplementation, so there was no placebo group. Improvements in calcium flux and cGMP/PKG are demonstrated, but there is no proof that these changes account for the improvements in diastolic function observed, and other effects of nitrate on coronary vasodilation, mitochondrial function, inflammation or extracellular matrix composition may also contribute.11 The importance of abnormal calcium handling in determining diastolic dysfunction might have been overestimated by the authors, as changes in viscoelastic stiffness and ventricular interdependence probably play a greater role in elevating diastolic filling pressures in human HFpEF.15 Interventions that are effective in rodents frequently do not apply to humans, and the model studied was not even a heart failure model, as shown by the normal LV filling pressures. However, the results are consistent with beneficial effects from nitrate–nitrite–NO intervention studies in human HFpEF, which is encouraging.13, 14 It is unclear how the differences in the oral microbiome in young vs. old mice might relate to human aging and alternative explanations for higher nitrite availability in older animals, such as greater tissue hypoxia, were not explored. The dose of nitrate administered was fairly high, but plasma nitrite levels achieved were not far from levels associated with improved LV filling pressures in human HFpEF patients.13 Aging is not a modifiable risk factor, and as we continue to enjoy greater longevity in the developed world, age-associated cardiac diseases such as HFpEF will continue to increase in prevalence. While there may be no true fountain of youth, the elegant experiments of Rammos and colleagues8 provide new hope that therapies aimed at restoring NO signalling such as the nitrate–nitrite pathway may at least help slow down the clock regarding the inexorable effects of aging on the heart and vasculature. The author has received research support from Mast Therapeutics to support investigator-initiated trials examining the use of inhaled nitrite in patients with HFpEF. Conflict of interest: none declared.