Stephen M Ratchford, Heather L Clifton, Jayson R Gifford, D Taylor LaSalle, Taylor S Thurston, Kanokwan Bunsawat, Jeremy K Alpenglow, Josephine B Wright, Markus Amann, John J Ryan, D Walter Wray
{"title":"急性抗氧化剂和四氢生物蝶呤（BH4）对心力衰竭患者运动肌肉微血管功能的影响。","authors":"Stephen M Ratchford, Heather L Clifton, Jayson R Gifford, D Taylor LaSalle, Taylor S Thurston, Kanokwan Bunsawat, Jeremy K Alpenglow, Josephine B Wright, Markus Amann, John J Ryan, D Walter Wray","doi":"10.1161/CIRCHEARTFAILURE.124.012446","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Peripheral microvascular dysfunction is a hallmark feature of both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) pathophysiology, due partly to impairments in nitric oxide signaling secondary to tetrahydrobiopterin (BH<sub>4</sub>) deficiency and oxidative stress.</p><p><strong>Methods: </strong>Using a randomized, double-blind, placebo-controlled crossover design, this study examined the impact of enteral BH<sub>4</sub> (10 mg/kg), an antioxidant cocktail (AOx), and coadministration of these 2 agents (BH<sub>4</sub>+AOx) on microvascular function in patients with HFrEF (n=14, 64±10 years) and HFpEF (n=19, 74±9 years). Passive limb movement was utilized to assess locomotor muscle microvascular function, and biomarkers of inflammation and oxidative damage were measured.</p><p><strong>Results: </strong>Compared with placebo, the peak change in leg blood flow was not statistically different after AOx administration (HFrEF, <i>P</i>=0.60; HFpEF, <i>P</i>=0.61), but improved following BH<sub>4</sub> (<i>P</i>=0.033) and BH<sub>4</sub>+AOx (<i>P</i>=0.019) in both HFrEF (placebo: 234±31; BH<sub>4</sub>: 357±45; BH<sub>4</sub>+AOx: 355±49 mL/min) and HFpEF (placebo: 269±33; BH<sub>4</sub>: 367±47; BH<sub>4</sub>+AOx: 394±65 mL/min). The total hyperemic response to passive limb movement (leg blood flow area under the curve) was not statistically different across treatments in patients with HFrEF (<i>P</i>=0.29), but increased following BH<sub>4</sub> (<i>P</i>=0.016) and BH<sub>4</sub>+AOx (<i>P</i>=0.040) in the HFpEF group. CRP (C-reactive protein) was lower following BH<sub>4</sub> (<i>P</i>=0.007) and BH<sub>4</sub>+AOx (<i>P</i>=0.007) in HFpEF (placebo: 4268±547; BH<sub>4</sub>: 2721±391; BH<sub>4</sub>+AOx: 2779±376 ng/mL), but was not statistically different in HFrEF (<i>P</i>=0.39).</p><p><strong>Conclusions: </strong>Together, these results provide new evidence for the efficacy of acute BH<sub>4</sub> administration to improve some aspects of locomotor muscle microvascular function in patients with HFrEF and HFpEF, with no apparent benefit of AOx administration, alone or in combination with BH<sub>4</sub>, in either group. These findings lend further conceptual support for the nitric oxide pathway as a modifiable target in the treatment of heart failure.</p>","PeriodicalId":10196,"journal":{"name":"Circulation: Heart Failure","volume":" ","pages":"e012446"},"PeriodicalIF":8.4000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173787/pdf/","citationCount":"0","resultStr":"{\"title\":\"Impact of Acute Antioxidant and Tetrahydrobiopterin (BH<sub>4</sub>) Administration on Locomotor Muscle Microvascular Function in Patients With Heart Failure.\",\"authors\":\"Stephen M Ratchford, Heather L Clifton, Jayson R Gifford, D Taylor LaSalle, Taylor S Thurston, Kanokwan Bunsawat, Jeremy K Alpenglow, Josephine B Wright, Markus Amann, John J Ryan, D Walter Wray\",\"doi\":\"10.1161/CIRCHEARTFAILURE.124.012446\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Peripheral microvascular dysfunction is a hallmark feature of both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) pathophysiology, due partly to impairments in nitric oxide signaling secondary to tetrahydrobiopterin (BH<sub>4</sub>) deficiency and oxidative stress.</p><p><strong>Methods: </strong>Using a randomized, double-blind, placebo-controlled crossover design, this study examined the impact of enteral BH<sub>4</sub> (10 mg/kg), an antioxidant cocktail (AOx), and coadministration of these 2 agents (BH<sub>4</sub>+AOx) on microvascular function in patients with HFrEF (n=14, 64±10 years) and HFpEF (n=19, 74±9 years). Passive limb movement was utilized to assess locomotor muscle microvascular function, and biomarkers of inflammation and oxidative damage were measured.</p><p><strong>Results: </strong>Compared with placebo, the peak change in leg blood flow was not statistically different after AOx administration (HFrEF, <i>P</i>=0.60; HFpEF, <i>P</i>=0.61), but improved following BH<sub>4</sub> (<i>P</i>=0.033) and BH<sub>4</sub>+AOx (<i>P</i>=0.019) in both HFrEF (placebo: 234±31; BH<sub>4</sub>: 357±45; BH<sub>4</sub>+AOx: 355±49 mL/min) and HFpEF (placebo: 269±33; BH<sub>4</sub>: 367±47; BH<sub>4</sub>+AOx: 394±65 mL/min). The total hyperemic response to passive limb movement (leg blood flow area under the curve) was not statistically different across treatments in patients with HFrEF (<i>P</i>=0.29), but increased following BH<sub>4</sub> (<i>P</i>=0.016) and BH<sub>4</sub>+AOx (<i>P</i>=0.040) in the HFpEF group. CRP (C-reactive protein) was lower following BH<sub>4</sub> (<i>P</i>=0.007) and BH<sub>4</sub>+AOx (<i>P</i>=0.007) in HFpEF (placebo: 4268±547; BH<sub>4</sub>: 2721±391; BH<sub>4</sub>+AOx: 2779±376 ng/mL), but was not statistically different in HFrEF (<i>P</i>=0.39).</p><p><strong>Conclusions: </strong>Together, these results provide new evidence for the efficacy of acute BH<sub>4</sub> administration to improve some aspects of locomotor muscle microvascular function in patients with HFrEF and HFpEF, with no apparent benefit of AOx administration, alone or in combination with BH<sub>4</sub>, in either group. These findings lend further conceptual support for the nitric oxide pathway as a modifiable target in the treatment of heart failure.</p>\",\"PeriodicalId\":10196,\"journal\":{\"name\":\"Circulation: Heart Failure\",\"volume\":\" \",\"pages\":\"e012446\"},\"PeriodicalIF\":8.4000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173787/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Heart Failure\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCHEARTFAILURE.124.012446\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/24 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Heart Failure","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCHEARTFAILURE.124.012446","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/24 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Impact of Acute Antioxidant and Tetrahydrobiopterin (BH4) Administration on Locomotor Muscle Microvascular Function in Patients With Heart Failure.
Background: Peripheral microvascular dysfunction is a hallmark feature of both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) pathophysiology, due partly to impairments in nitric oxide signaling secondary to tetrahydrobiopterin (BH4) deficiency and oxidative stress.
Methods: Using a randomized, double-blind, placebo-controlled crossover design, this study examined the impact of enteral BH4 (10 mg/kg), an antioxidant cocktail (AOx), and coadministration of these 2 agents (BH4+AOx) on microvascular function in patients with HFrEF (n=14, 64±10 years) and HFpEF (n=19, 74±9 years). Passive limb movement was utilized to assess locomotor muscle microvascular function, and biomarkers of inflammation and oxidative damage were measured.
Results: Compared with placebo, the peak change in leg blood flow was not statistically different after AOx administration (HFrEF, P=0.60; HFpEF, P=0.61), but improved following BH4 (P=0.033) and BH4+AOx (P=0.019) in both HFrEF (placebo: 234±31; BH4: 357±45; BH4+AOx: 355±49 mL/min) and HFpEF (placebo: 269±33; BH4: 367±47; BH4+AOx: 394±65 mL/min). The total hyperemic response to passive limb movement (leg blood flow area under the curve) was not statistically different across treatments in patients with HFrEF (P=0.29), but increased following BH4 (P=0.016) and BH4+AOx (P=0.040) in the HFpEF group. CRP (C-reactive protein) was lower following BH4 (P=0.007) and BH4+AOx (P=0.007) in HFpEF (placebo: 4268±547; BH4: 2721±391; BH4+AOx: 2779±376 ng/mL), but was not statistically different in HFrEF (P=0.39).
Conclusions: Together, these results provide new evidence for the efficacy of acute BH4 administration to improve some aspects of locomotor muscle microvascular function in patients with HFrEF and HFpEF, with no apparent benefit of AOx administration, alone or in combination with BH4, in either group. These findings lend further conceptual support for the nitric oxide pathway as a modifiable target in the treatment of heart failure.
期刊介绍：
Circulation: Heart Failure focuses on content related to heart failure, mechanical circulatory support, and heart transplant science and medicine. It considers studies conducted in humans or analyses of human data, as well as preclinical studies with direct clinical correlation or relevance. While primarily a clinical journal, it may publish novel basic and preclinical studies that significantly advance the field of heart failure.
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