Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction

Borlaug, Barry A.; Anstrom, Kevin J.; Lewis, Gregory D.; Shah, Sanjiv J.; Levine, James A.; Koepp, Gabe A.; Givertz, Michael M.; Felker, G. Michael; LeWinter, Martin M.; Mann, Douglas L.; Margulies, Kenneth B.; Smith, Andrew L.; Tang, W.H. Wilson; Whellan, David J.; Chen, Horng H.; Dávila‐Román, Víctor G.; McNulty, Steven E.; Desvigne‐Nickens, Patrice; Hernandez, Adrian F.; Braunwald, Eugene; Redfield, Margaret M.

doi:10.1001/jama.2018.14852

Cited by 194 publications

(136 citation statements)

References 31 publications

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“…Borderline significance toward enhanced production or cellular responses to NO was detected in our pathway analysis, which could suggest that NO biology may still be a promising therapeutic target for age‐related HFpEF. However, given the neutral results in randomized controlled trials with organic nitrate and inorganic nitrite therapies (Borlaug et al., 2018; Redfield et al., 2015), alternative approaches to targeting this biology need to explored. Second, in contrast to its lack of effect on the transcriptional profile of neurohormonal pathways, ExT induced a marked reversal in the global downregulation of cell cycle‐related pathways seen in the aged heart (Figure 5c).…”

Section: Discussionmentioning

confidence: 99%

“…HF remains the leading cause of hospitalization amongst persons over 65 years old, and nearly 1/3 of all older adults hospitalized for HF are either readmitted or dead within 90 days of discharge (Upadhya et al., 2015). Notably, no pharmacological agent, including neurohormonal antagonists and nitrate derivatives (Borlaug et al., 2018; Massie et al., 2008; Pitt et al., 2014; Redfield et al., 2015), has improved survival in HFpEF, making it one of the largest unmet needs in geriatric and cardiovascular medicine (Parikh et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

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Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Roh

Houstis

et al. 2020

Aging Cell

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Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Roh

Houstis

et al. 2020

Aging Cell

View full text Add to dashboard Cite

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“…A randomized, placebo-controlled pilot trial examining the effect of dietary nitrates, in addition to aerobic ET, in subjects with HFpEF showed no benefit when compared to placebo on peak VO 2 [92]. The authors suggested that this may have been related to inadequate dosing; however, a recent trial of inhaled nitrates without ET also failed to increase peak VO 2 in subjects with HFpEF [93]. Dietary nitrate supplementation has also resulted in mixed effects on CRF in small pilot trials of subjects with HFrEF without ET [85,86].…”

Section: Dietary Nitrate Supplementation In Hfpefmentioning

confidence: 99%

Lifestyle Interventions with a Focus on Nutritional Strategies to Increase Cardiorespiratory Fitness in Chronic Obstructive Pulmonary Disease, Heart Failure, Obesity, Sarcopenia, and Frailty

et al. 2019

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Cardiorespiratory fitness (CRF) is an independent predictor for all-cause and disease-specific morbidity and mortality. CRF is a modifiable risk factor, and exercise training and increased physical activity, as well as targeted medical therapies, can improve CRF. Although nutrition is a modifiable risk factor for chronic noncommunicable diseases, little is known about the effect of dietary patterns and specific nutrients on modifying CRF. This review focuses specifically on trials that implemented dietary supplementation, modified dietary pattern, or enacted caloric restriction, with and without exercise training interventions, and subsequently measured the effect on peak oxygen consumption (VO 2 ) or surrogate measures of CRF and functional capacity. Populations selected for this review are those recognized to have a reduced CRF, such as chronic obstructive pulmonary disease, heart failure, obesity, sarcopenia, and frailty. We then summarize the state of existing knowledge and explore future directions of study in disease states recently recognized to have an abnormal CRF.

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“…A recent animal study using a rodent HFpEF model demonstrated that genetic inhibition of inducible nitric oxide synthase improved ventricular relaxation and exercise performance [59]. Unfortunately, human clinical trials targeting the nitric oxide pathway including use of isosorbide mononitrate [60] and inorganic nitrites [61] have so far not demonstrated clinical improvement for HFpEF subjects.…”

Section: Inflammation and Endothelial Dysfunctionmentioning

confidence: 99%

Biomarkers in Heart Failure With Preserved Ejection Fraction: An Update on Progress and Future Challenges

Carnes

Gordon

2020

Heart, Lung and Circulation

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Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction

Cited by 194 publications

References 31 publications

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Lifestyle Interventions with a Focus on Nutritional Strategies to Increase Cardiorespiratory Fitness in Chronic Obstructive Pulmonary Disease, Heart Failure, Obesity, Sarcopenia, and Frailty

Biomarkers in Heart Failure With Preserved Ejection Fraction: An Update on Progress and Future Challenges

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