Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure

2021 ◽  
Author(s):  
Scott K. Ferguson ◽  
Mary Nina Woessner ◽  
Michael J. Holmes ◽  
Michael D. Belbis ◽  
Mattias Carlström ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Tolerance ◽  
Vascular Dysfunction ◽  
Vital Role ◽  
Inorganic Nitrate ◽  
Clinical Investigations ◽  
Improve Exercise Tolerance ◽  
Complementary Role ◽  
No Bioavailability

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Central to these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2 delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. While many pre-clinical investigations have suggested that enhanced reduction of nitrite to NO in low PO2 and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in HFrEF and HFpEF patients. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.

scholarly journals Edward F. Adolph Distinguished Lecture. Contemporary model of muscle microcirculation: gateway to function and dysfunction

2019 ◽  
Vol 127 (4) ◽  
pp. 1012-1033 ◽  
Author(s):  
David C. Poole
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Exercise Tolerance ◽  
Contractile Function ◽  
Past Century ◽  
Capillary Recruitment ◽  
Improve Exercise Tolerance ◽  
Exercise Muscle ◽  
And Function ◽  
Exchange Surface

This review strikes at the very heart of how the microcirculation functions to facilitate blood-tissue oxygen, substrate, and metabolite fluxes in skeletal muscle. Contemporary evidence, marshalled from animals and humans using the latest techniques, challenges iconic perspectives that have changed little over the past century. Those perspectives include the following: the presence of contractile or collapsible capillaries in muscle, unitary control by precapillary sphincters, capillary recruitment at the onset of contractions, and the notion of capillary-to-mitochondrial diffusion distances as limiting O2 delivery. Today a wealth of physiological, morphological, and intravital microscopy evidence presents a completely different picture of microcirculatory control. Specifically, capillary red blood cell (RBC) and plasma flux is controlled primarily at the arteriolar level with most capillaries, in healthy muscle, supporting at least some flow at rest. In healthy skeletal muscle, this permits substrate access (whether carried in RBCs or plasma) to a prodigious total capillary surface area. Pathologies such as heart failure or diabetes decrease access to that exchange surface by reducing the proportion of flowing capillaries at rest and during exercise. Capillary morphology and function vary disparately among tissues. The contemporary model of capillary function explains how, following the onset of exercise, muscle O2 uptake kinetics can be extremely fast in health but slowed in heart failure and diabetes impairing contractile function and exercise tolerance. It is argued that adoption of this model is fundamental for understanding microvascular function and dysfunction and, as such, to the design and evaluation of effective therapeutic strategies to improve exercise tolerance and decrease morbidity and mortality in disease.

scholarly journals Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Patients With Heart Failure: Protocol for a Randomized, Placebo-Controlled, Cross-Over Trial (Preprint)

2017 ◽  
Author(s):  
Mary N. Woessner ◽  
Itamar Levinger ◽  
Christopher Neil ◽  
Cassandra Smith ◽  
Jason D Allen
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Exercise Test ◽  
Exercise Tolerance ◽  
Cardiopulmonary Exercise Test ◽  
Cardiopulmonary Exercise ◽  
Inorganic Nitrate ◽  
Patients With Heart Failure ◽  
Nitrate Supplementation ◽  
Nitric Oxide Bioavailability

BACKGROUND Chronic heart failure is characterized by an inability of the heart to pump enough blood to meet the demands of the body, resulting in the hallmark symptom of exercise intolerance. Chronic underperfusion of the peripheral tissues and impaired nitric oxide bioavailability have been implicated as contributors to the decrease in exercise capacity in these patients. nitric oxide bioavailability has been identified as an important mediator of exercise tolerance in healthy individuals, but there are limited studies examining the effects in patients with chronic heart failure. OBJECTIVE The proposed trial is designed to determine the effects of chronic inorganic nitrate supplementation on exercise tolerance in both patients with heart failure preserved ejection fraction (HFpEF) and heart failure reduced ejection fraction (HFrEF) and to determine whether there are any differential responses between the 2 cohorts. A secondary objective is to provide mechanistic insights into the 2 heart failure groups’ exercise responses to the nitrate supplementation. METHODS Patients with chronic heart failure (15=HFpEF and 15=HFrEF) aged 40 to 85 years will be recruited. Following an initial screen cardiopulmonary exercise test, participants will be randomly allocated in a double-blind fashion to consume either a nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo (for 5 days). Participants will continue daily dosing until the completion of the 4 testing visits (maximal cardiopulmonary exercise test, submaximal exercise test with echocardiography, vascular function assessment, and vastus lateralis muscle biopsy). There will then be a 2-week washout period after which the participants will cross over to the other treatment and complete the same 4 testing visits. RESULTS This study is funded by National Heart Foundation of Australia and Victoria University. Enrolment has commenced and the data collection is expected to be completed in mid 2018. The initial results are expected to be submitted for publication by the end of 2018. CONCLUSIONS If inorganic nitrate supplementation can improve exercise tolerance in patients with chronic heart failure, it has the potential to aid in further refining the treatment of patients in this population. CLINICALTRIAL Australian New Zealand Clinical Trials Registry ACTRN12615000906550; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368912 (Archived by WebCite at http://www.webcitation.org/6xymLMiFK)

scholarly journals Skeletal Muscle Microvascular Dysfunction Manifests Early in Diabetic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Sadi Loai ◽  
Yu-Qing Zhou ◽  
Kyle D. W. Vollett ◽  
Hai-Ling Margaret Cheng
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Myocardial Perfusion ◽  
Cardiac Dysfunction ◽  
Exercise Tolerance ◽  
Time Course ◽  
Microvascular Dysfunction ◽  
Diabetic Rats ◽  
Exercise Intolerance ◽  
Muscle Perfusion

Aim: To perform a deep cardiac phenotyping of type II diabetes in a rat model, with the goal of gaining new insight into the temporality of microvascular dysfunction, cardiac dysfunction, and exercise intolerance at different stages of diabetes.Methods and Results: Diabetes was reproduced using a non-obese, diet-based, low-dose streptozotocin model in male rats (29 diabetic, 11 control). Time-course monitoring over 10 months was performed using echocardiography, treadmill exercise, photoacoustic perfusion imaging in myocardial and leg skeletal muscle, flow-mediated dilation, blood panel, and histology. Diabetic rats maintained a normal weight throughout. At early times (4 months), a non-significant reduction (30%) emerged in skeletal muscle perfusion and in exercise tolerance. At the same time, diabetic rats had a normal, slightly lower ejection fraction (63 vs. 71% control, p < 0.01), grade 1 diastolic dysfunction (E/A = 1.1 vs. 1.5, isovolumetric relaxation time = 34 vs. 27 ms; p < 0.01), mild systolic dysfunction (ejection time = 69 vs. 57 ms, isovolumetric contraction time = 21 vs. 17 ms; p < 0.01), and slightly enlarged left ventricle (8.3 vs. 7.6 mm diastole; p < 0.01). Diastolic dysfunction entered grade 3 at Month 8 (E/A = 1.7 vs. 1.3, p < 0.05). Exercise tolerance remained low in diabetic rats, with running distance declining by 60%; in contrast, control rats ran 60% farther by Month 5 (p < 0.05) and always remained above baseline. Leg muscle perfusion remained low in diabetic rats, becoming significantly lower than control by Month 10 (33% SO2 vs. 57% SO2, p < 0.01). Myocardial perfusion remained normal throughout. Femoral arterial reactivity was normal, but baseline velocity was 25% lower than control (p < 0.05). High blood pressure appeared late in diabetes (8 months). Histology confirmed absence of interstitial fibrosis, cardiomyocyte hypertrophy, or microvascular rarefaction in the diabetic heart. Rarefaction was also absent in leg skeletal muscle.Conclusion: Reduced skeletal muscle perfusion from microvascular dysfunction emerged early in diabetic rats, but myocardial perfusion remained normal throughout the study. At the same time, diabetic rats exhibited exercise intolerance and early cardiac dysfunction, in which changes related to heart failure with preserved ejection fraction (HFpEF) were seen. Importantly, skeletal muscle microvascular constrictionadvanced significantly before the late appearance of hypertension. HFpEF phenotypes such as cardiac hypertrophy, fibrosis, and rarefaction, which are typically associated with hypertension, were absent over the 10 month time-course of diabetes-related heart failure.

scholarly journals Dietary Inorganic Nitrate Supplementation And Exercise Tolerance In Patients With Reduced Ejection Fraction Heart Failure

2020 ◽  
Vol 52 (7S) ◽  
pp. 341-341
Author(s):  
Jason D. Allen ◽  
Christopher Neil ◽  
Luke C. McIlvenna ◽  
Joaquin Ortiz de Zevallos ◽  
Itamar Levinger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Exercise Tolerance ◽  
Reduced Ejection Fraction ◽  
Inorganic Nitrate ◽  
Nitrate Supplementation

scholarly journals Targeting the DPP-4-GLP-1 pathway improves exercise tolerance in heart failure patients: a systematic review and meta-analysis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chengcong Chen ◽  
Ying Huang ◽  
Yongmei Zeng ◽  
Xiyan Lu ◽  
Guoqing Dong
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Systematic Review ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Exercise Tolerance ◽  
Meta Analysis ◽  
Heart Failure Patients ◽  
Improve Exercise Tolerance

Abstract Background The most significant manifestation of heart failure is exercise intolerance. This systematic review and meta-analysis was performed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RAs), widely used anti-diabetic drugs, could improve exercise tolerance in heart failure patients with or without type 2 diabetes mellitus. Methods An electronic search of PubMed, EMBASE and the Cochrane Library was carried out through March 8th, 2019, for eligible trials. Only randomized controlled studies were included. The primary outcome was exercise tolerance [6-min walk test (6MWT) and peak O2 consumption], and the secondary outcomes included quality of life (QoL), adverse events (AEs) and all-cause death. Result After the literature was screened by two reviewers independently, four trials (659 patients) conducted with heart failure patients with or without type 2 diabetes met the eligibility criteria. The results suggested that targeting the DPP-4-GLP-1 pathway can improve exercise tolerance in heart failure patients [MD 24.88 (95% CI 5.45, 44.31), P = 0.01] without decreasing QoL [SMD -0.51 (95% CI -1.13, 0.10), P = 0.10]; additionally, targeting the DPP-4-GLP-1 pathway did not show signs of increasing the incidence of serious AEs or mortality. Conclusion Our results suggest that DPP-4 inhibitors or GLP-1 RAs improve exercise tolerance in heart failure patients. Although the use of these drugs for heart failure has not been approved by any organization, they may be a better choice for type 2 diabetes mellitus patients with heart failure. Furthermore, as this pathway contributes to the improvement of exercise tolerance, it may be worth further investigation in exercise-intolerant patients with other diseases.

Abstract 15025: Visceral Adiposity and Muscle Composition in Heart Failure With Preserved Ejection Fraction and Association With Exercise Tolerance

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Wendy Ying ◽  
Kavita Sharma ◽  
Lisa R Yanek ◽  
Dhananjay Vaidya ◽  
Michael Schar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Ejection Fraction ◽  
Exercise Tolerance ◽  
Nyha Class ◽  
Well Being ◽  
Liver Fat ◽  
Exercise Intolerance ◽  
Preserved Ejection Fraction ◽  
Intermuscular Fat

Introduction: Visceral adipose tissue (AT) promotes inflammation and adverse metabolic changes that mediate disease progression in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but little is known about its relation to the extent and distribution of AT. We characterized regional AT distribution in HFpEF patients and controls and analyzed associations with comorbidities and exercise tolerance. Methods: MRI was performed to quantify epicardial, liver, abdominal and thigh skeletal muscle AT. We assessed NYHA class, 6-minute walk distance (6MWD), and global well-being score (GWBS). Multivariable linear and logistic regression models were used, adjusted for age, sex, and body surface area. Results: We studied 55 HFpEF patients (41 women, mean age 67) and 33 controls (21 women, mean age 57). Epicardial AT (4.6 vs 3.2mm, p = 0.03), thigh intermuscular fat (11.0 vs 5.0cm 2 , p < 0.01) and liver fat fraction (FF) (6.4% vs 4.1%, p = 0.04) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal (443.9 vs 297.3 cm 2 , p = 0.03) and thigh (228.6 vs 112.3 cm 2 , p < 0.001) subcutaneous AT than men. Higher thigh intermuscular fat was associated with higher blood pressure (β [SE] 14.1 [3.3], p < 0.001) and diabetes (β [SE] 2.6 [1.1], p = 0.02), and liver FF was associated with chronic kidney disease (β [SE] 1.6 [0.6], p = 0.01). Higher thigh intramuscular fat was associated with both higher NYHA class and shorter 6MWD, and higher thigh intermuscular AT FF was associated with higher NYHA class ( Table ). Higher epicardial AT and liver FF were associated with lower GWBS. Conclusions: HFpEF patients have increased epicardial, liver, and skeletal muscle fat compared to controls out of proportion to their body size, and adiposity was associated with worse exercise intolerance in HFpEF. These results provide the basis for further investigation into regional AT distribution in relation to HFpEF symptoms and pathophysiology.

Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure

2012 ◽  
Vol 303 (12) ◽  
pp. H1474-H1480 ◽  
Author(s):  
Priscila A. Sperandio ◽  
Mayron F. Oliveira ◽  
Miguel K. Rodrigues ◽  
Danilo C. Berton ◽  
Erika Treptow ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Exercise Tolerance ◽  
Near Infrared ◽  
Vastus Lateralis ◽  
Beneficial Effects ◽  
Subsequent Response ◽  
Constant Work Rate ◽  
No Bioavailability ◽  
O2 Delivery

Nitric oxide (NO) can temporally and spatially match microvascular oxygen (O2) delivery (Q̇o2mv) to O2 uptake (V̇o2) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Q̇o2mv-to-O2 utilization matching and V̇o2 kinetics, 10 males with CHF (ejection fraction = 27 ± 6%) undertook constant work-rate exercise (70–80% peak). Breath-by-breath V̇o2, fractional O2 extraction in the vastus lateralis {∼deoxygenated hemoglobin + myoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ∼20%, an effect that was related to faster on- and off-exercise V̇o2 kinetics ( P < 0.05). Active treatment, however, failed to accelerate CO dynamics ( P > 0.05). On-exercise [deoxy-Hb + Mb] kinetics were slowed by sildenafil (∼25%), and a subsequent response “overshoot” ( n = 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb + Mb] recovery was faster with sildenafil (∼15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise V̇o2 kinetics, blunted oscillations in ventilation ( n = 9), and greater exercise capacity ( P < 0.05). Sildenafil intake enhanced intramuscular Q̇o2mv-to-V̇o2 matching with beneficial effects on V̇o2 kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects.

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