Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

Zamani, Payman; Tan, Vern Hsen; Soto‐Calderon, Haideliza; Beraun, Melissa; Brandimarto, Jeffrey; Trieu, Lien; Varakantam, Swapna; Doulias, Paschalis‐Thomas; Townsend, Raymond R.; Chittams, Jesse; Margulies, Kenneth B.; Cappola, Thomas P.; Poole, David C.; Ischiropoulos, Harry; Chirinos, Julio A.

doi:10.1161/circresaha.116.309832

Cited by 53 publications

(49 citation statements)

References 38 publications

(47 reference statements)

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“…In both trials, organic nitrates were poorly tolerated. This is in sharp contrast with available studies which consistently suggest a favorable effect of inorganic nitrate/nitrite on exercise capacity or various hemodynamic parameters [100–102, 110 –114]. …”

Section: Therapeutic Implicationscontrasting

confidence: 84%

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

Chirinos

2017

J. of Cardiovasc. Trans. Res.

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Multiple phase III trials over the last few decades have failed to demonstrate a clear benefit of various pharmacologic interventions in heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF). Therefore, a better understanding of its pathophysiology is important. An accompanying review describes key technical and physiologic aspects regarding the deep phenotyping of arterial hemodynamics in HFpEF. This review deals with the potential of this approach to enhance our clinical, translational, and therapeutic approach to HFpEF. Specifically, the role of arterial hemodynamics is discussed in relation to (1) the pathophysiology of left ventricular diastolic dysfunction, remodeling, and fibrosis, (2) impaired oxygen delivery to peripheral skeletal muscle, which affects peripheral oxygen extraction, (3) the frequent presence of comorbidities, such as renal failure and dementia in this population, and (4) the potential to enhance precision medicine approaches. A therapeutic approach to target arterial hemodynamic abnormalities that are prevalent in this population (particularly, with inorganic nitrate/nitrite) is also discussed.

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Section: Therapeutic Implicationscontrasting

confidence: 84%

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

Chirinos

2017

J. of Cardiovasc. Trans. Res.

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“…53 Orally administered inorganic nitrate, which is converted to active molecule nitrite, has been shown to improve exercise duration and systemic vascular function when administered as a single dose or with repeated doses over 1-2 weeks in patients with HFpEF. 54-56 …”

Section: Pathophysiology Of Hfpefmentioning

confidence: 99%

INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)

Reddy

Lewis

Shah

et al. 2017

Circ: Heart Failure

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Approximately half of patients with heart failure (HF) have preserved ejection fraction (HFpEF). There is no proven treatment that improves outcome. The pathophysiology of HFpEF is complex and includes left ventricular (LV) systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide-cyclic guanosine monophosphate (NO-cGMP) bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidemic conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when LV filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF) trial, which is a multicenter, randomized, double-blind, placebo controlled crossover study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the NHLBI-sponsored Heart Failure Clinical Research Network. Clinical Trial Registration: clinicaltrials.gov; NCT02742129

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“…Future benefits of deciphering this relationship may include modifying existing treatments (Zamani et al 2017) to recover impaired exercise tolerance in microvascular disease. We therefore studied how muscle function and blood flow were affected by acute and chronic reductions in the number of functional (perfused) capillaries, and how the angiogenic response to mechanical overload (Degens et al 1992;Zhou et al 1998;Egginton et al 2011;Ballak et al 2016) was affected by an underlying constrained microcirculation in otherwise healthy tissue.…”

Section: Introductionmentioning

confidence: 99%

Impaired skeletal muscle performance as a consequence of random functional capillary rarefaction can be restored with overload‐dependent angiogenesis

Tickle

Hendrickse

Degens

et al. 2020

The Journal of Physiology

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Key points Loss of skeletal muscle capillaries is thought to contribute to a reduction in exercise tolerance, but the relative contribution of a compromised microcirculation with disease, in isolation of co‐morbidities, to impaired muscle function is unknown. We therefore developed a novel method to randomly occlude capillaries in the rat hindlimb to mimic the capillary rarefaction observed in many conditions. We demonstrate that muscle fatigue resistance is closely coupled with functional microvascular density, independent of arterial blood flow, while disturbance of the microcirculation leads to long‐term impairment of muscle function if left untreated. Mechanical stretch due to muscle overload causes a restoration of fatigue resistance via angiogenic remodelling. These observations highlight the importance of a healthy microcirculation and suggest that restoring impaired microvascular supply, regardless of disease co‐morbidities, will assist recovery of exercise tolerance in a variety of conditions that limit quality of life. Abstract To what extent microvascular rarefaction contributes to impaired skeletal muscle function remains unknown. Our understanding of whether pathological changes in the microcirculation can be reversed remains limited by a lack of basic physiological data in otherwise healthy tissue. The principal objectives here were to: (1) quantify the effect of random microvascular rarefaction on limb perfusion and muscle performance, and (2) determine if these changes could be reversed. We developed a novel protocol in rats whereby microspheres injected into the femoral artery allowed a unilateral reduction in functional capillary density in the extensor digitorum longus (EDL), and assessed acute and chronic effects on muscle function. Simultaneous bilateral EDL force and hindlimb blood flow measurements were made during electrical stimulation. Following functional capillary rarefaction there was an acute microsphere dose‐dependent reduction in muscle fatigue resistance (P < 0.001), despite preserved femoral artery perfusion. Histological analysis of EDL samples taken from injected animals confirmed a positive correlation between the proportion of functional capillaries and fatigue resistance (P = 0.002). Such impaired performance persisted for at least 2 weeks (P = 0.016). Concomitant mechanical overload improved both perfused capillary density and fatigue resistance (P<0.05), confirming that the capacity for muscle remodelling was retained following chronic distributed ischaemia, and that the impact of capillary rarefaction could be alleviated. These results demonstrate that loss of functional capillaries is detrimental to muscle function, even in otherwise healthy tissue, independent of arterial perfusion. Restoration of muscle performance following a mechanical overload stimulus indicates that angiogenic treatments to alleviate microvascular rarefaction may be key to restoring exercise tolerance.

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Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction

Cited by 53 publications

References 38 publications

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): Clinical and Therapeutic Considerations

INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)

Impaired skeletal muscle performance as a consequence of random functional capillary rarefaction can be restored with overload‐dependent angiogenesis

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