Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction

Zamani, Payman; Proto, Elizabeth A.; Mazurek, Jeremy A.; Prenner, Stuart B.; Margulies, Kenneth B.; Townsend, Raymond R.; Kelly, Daniel P.; Arany, Zoltàn; Poole, David C.; Wagner, Peter D.; Chirinos, Julio A.

doi:10.1016/j.jacbts.2020.01.003

Cited by 33 publications

(39 citation statements)

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“…The effect of coexisting sarcopenia and obesity on HFpEF related exercise intolerance is yet to be delineated. However, an elegant study by Zamani et al has recently demonstrated that adiposity is inversely associated with local skeletal muscle oxygen consumption in HFpEF patients (47). In addition, in the previously mentioned retrospective analysis of "healthy" Koreans without overt cardiovascular disease, individuals with SO reported significantly lower VO 2 peak compared with those who only had sarcopenia or obesity (42).…”

Section: Exercise Intolerancementioning

confidence: 97%

“…However, a paradigm shift toward the periphery implicates skeletal muscle abnormalities that are synonymous with sarcopenia as the predominant limitation of exercise capacity in these patients ( 46 ). In this regard, aberrant skeletal muscle structure and function reported in HFpEF patients hamper oxygen extraction and utilization during exercise with deleterious consequences on exercise capacity ( 46 , 47 ). Readers are referred to in-depth reviews detailing skeletal muscle dysfunctions and their role in exercise intolerance in HF ( 25 , 48 ).…”

Section: Clinical Consequences Of Sarcopenic Obesity In Hfpefmentioning

confidence: 99%

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Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction

et al. 2020

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Heart failure with preserved ejection fraction (HFpEF) is a public health epidemic that is projected to double over the next two decades. Despite the high prevalence of HFpEF, there are currently no FDA approved therapies for health-related outcomes in this clinical syndrome making it one the greatest unmet needs in cardiovascular medicine. Aging and obesity are hallmarks of HFpEF and therefore there is a high incidence of sarcopenic obesity (SO) associated with this syndrome. The presence of SO in HFpEF patients is noteworthy as it is associated with co-morbidities, worsened cardiovascular health, hospitalizations, quality of life, and mortality. Furthermore, SO plays a central role in exercise intolerance, the most commonly reported clinical symptom of this condition. The aim of this review is to provide insights into the current knowledge pertaining to the contributing pathophysiological mechanisms and clinical outcomes associated with HFpEF-related SO. Current and prospective therapies to address SO in HFpEF, including lifestyle and pharmaceutical approaches, are discussed. The urgent need for future research aimed at better understanding the multifaceted physiological contributions to SO in HFpEF and implementing interventional strategies to specifically target SO is highlighted.

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Section: Exercise Intolerancementioning

confidence: 97%

Section: Clinical Consequences Of Sarcopenic Obesity In Hfpefmentioning

confidence: 99%

Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction

et al. 2020

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“…In this regard, data collected from patients with HFpEF have identified clear impairments in the ability to widen arterial-venous O 2 content ( AVO 2 ) and augment peripheral oxygen extraction during exercise compared with HFrEF or controls (Haykowsky et al 2011;Bhella et al 2011a;Dhakal et al 2015;Houstis et al 2018;Zamani et al 2020). It remains unclear whether the capillary loss we observed contributes to abnormal skeletal muscle O 2 extraction at peak exercise in HFpEF, with a peripheral O 2 diffusive limitation postulated as a major mechanism underpinning exercise intolerance in HFpEF (Dhakal et al 2015;Houstis et al 2018).…”

Section: Impact Of Hfpef On Limb Skeletal Muscle Morphologymentioning

confidence: 99%

“…While the primary pathology of HFpEF is of cardiac origin, there is a poor correlation between heart dysfunction and the main symptom of exercise intolerance , and many clinical trials have shown cardiac-orientated drugs are not associated with beneficial outcomes (Shah et al 2016). Recent investigations, therefore, have suggested non-cardiac 'peripheral' factors as major mechanisms limiting functional capacity and quality of life in patients with HFpEF, with skeletal muscle abnormalities receiving much attention (Adams et al 2017;Poole et al 2018;Zamani et al 2020). For example, animal and human studies have shown that HFpEF is associated with various skeletal muscle impairments that are closely associated with exercise intolerance and lower quality of life, including lower skeletal muscle mass and strength (Bekfani et al 2016), generalised fibre atrophy (Bowen et al 2018), fat infiltration Zamani et al 2020), reduced global capillary-to-fibre ratio (Kitzman et al 2014;Bowen et al 2018), reduced mitochondrial function and content (Bowen et al 2015;Molina et al 2016;Bowen et al 2017b), disrupted high-energy phosphate metabolism (Bhella et al 2011b;Weiss et al 2017), and impaired O 2 extraction (Dhakal et al 2015;Houstis et al 2018;Zamani et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…For example, it remains controversial whether leg muscle arterial blood flow (i.e. perfusive O 2 transport) is impaired during exercise in HFpEF due to a lack of direct measurements (Hundley et al 2007;Haykowsky et al 2013;Lee et al 2016a;Weavil et al 2020), with key studies dependent upon systemic blood sampling reporting contrasting findings regarding whether a perfusive or diffusive O 2 transport limitation impairs muscle O 2 extraction and thus exercise intolerance in HFpEF (Dhakal et al 2015;Houstis et al 2018;Zamani et al 2020). As such, there remains a lack of clarity on whether functional indices related to leg blood flow and perfusive O 2 delivery are constrained in HFpEF.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese‐HFpEF

Espino-González

Tickle

Benson

et al. 2021

The Journal of Physiology

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Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. r Here we report that obese-HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. r We also demonstrate that obese-HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation-atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. r These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches.

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Potassium Nitrate in Heart Failure With Preserved Ejection Fraction

Zamani,

Shah,

Cohen

et al. 2024

JAMA Cardiol

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ImportanceNitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration.ObjectiveTo assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF.Design, Setting, and ParticipantsThis multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024.InterventionPotassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between.MAIN OUTCOMES AND MEASURESThe coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire.ResultsEighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P &lt; .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated.Conclusions and RelevanceIn this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT02840799

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Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction

Cited by 33 publications

References 50 publications

Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction

Sarcopenic Obesity in Heart Failure With Preserved Ejection Fraction

Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese‐HFpEF

Potassium Nitrate in Heart Failure With Preserved Ejection Fraction

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