Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction

Udelson, James E.; Lewis, Gregory D.; Shah, Sanjiv J.; Zile, Michael R.; Redfield, Margaret M.; Burnett, John C.; Parker, John D.; Seferović, Jelena P.; Wilson, Phebe; Mittleman, Robert S.; Profy, Albert T.; Konstam, Marvin A.

doi:10.1001/jama.2020.16641

Cited by 92 publications

(66 citation statements)

References 32 publications

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“…More optimal blood flow redistribution may represent an improvement in the heterogeneity of skeletal myofiber–perfusion matching, as previously demonstrated for nitrite therapy, 34,35 and this too may partially explain the improvement in O 2 kinetics and Dm during acute exercise with nitrite. Despite the evidence for impaired NO–cGMP signalling in HFpEF, clinical trials evaluating the nitrate–NO–cGMP axis in patients with HFpEF have failed to improve exercise capacity and quality of life, including organic nitrates, 36 soluble guanylate cyclase stimulators, 37–39 and phosphodiesterase inhibitors 40,41 . A key distinguishing feature of inorganic nitrite is the fact that haemodynamic and peripheral improvements at rest are less than what is observed with exercise.…”

Section: Discussionmentioning

confidence: 99%

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

Reddy

Stewart

Obokata

et al. 2021

European J of Heart Fail

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Aims To determine whether inorganic nitrite improves peripheral and pulmonary oxygen (O2) transport during exercise in heart failure with preserved ejection fraction (HFpEF). Methods and results Data from two invasive, randomized, double‐blind, placebo‐controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis (n = 51). Directly measured O2 consumption (VO2) and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O2 conductance (Dm), VO2 kinetics, alveolar capillary membrane O2 conductance (DL), and O2 utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9 ± 6.5 vs. −0.9 ± 4.3 mL/mmHg*min, P = 0.0008) as well as VO2 kinetics measured by mean response time (−5.0 ± 6.9 vs. −0.6 ± 6.0 s, P = 0.03), with preserved O2 utilization despite increased convective O2 delivery through cardiac output (+0.4 ± 0.7 vs. −0.3 ± 0.9 L/min, P = 0.02). Nitrite improved DL (+2.5 ± 6.3 vs. −2.0 ± 9.0 mL/mmHg*min, P = 0.05) with exercise, which was associated with lower pulmonary capillary pressures (r = −0.34, P = 0.02), and reduced pulmonary dead space ventilation fraction (−0.01 ± 0.05 vs. +0.02 ± 0.05, P = 0.02). Conclusion Sodium nitrite enhances skeletal muscle Dm during exercise as well as pulmonary O2 diffusion, optimizing O2 kinetics in tandem with increased convective O2 delivery through cardiac output augmentation. The favourable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation. Clinical Trial Registration: ClinicalTrials.gov ID NCT01932606 and NCT02262078.

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Section: Discussionmentioning

confidence: 99%

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

Reddy

Stewart

Obokata

et al. 2021

European J of Heart Fail

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“…Recent data from the VITALITY-HFpEF randomized placebo-controlled trial showed that 24-week treatment with Vericiguat compared with placebo did not improve the physical limitation score (67). Similarly, Praliciguat did not improve significantly the Peak Rate of Oxygen Consumption, thus not supporting its use in patients with HFpEF (CAPACITY HFpEF trial) (68).…”

Section: Treatment Of Hfpef: Knowledge Gaps and Future Perspectivesmentioning

confidence: 99%

Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

Graziani

Lillo

Crea

2021

Front. Cardiovasc. Med.

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Heart failure with preserved ejection fraction (HFpEF) is a major public health problem with growing prevalence and poor outcomes, mainly due to the lack of an effective treatment. HFpEF pathophysiology is heterogeneous and complex. Recently a “new paradigm” has been proposed, suggesting that cardiovascular and non-cardiovascular coexisting comorbidities lead to a systemic inflammatory state, perturbing the physiology of the endothelium and the perivascular environment and engaging molecular pathways that ultimately converge to myocardial fibrosis. If inflammation and fibrosis are the “fil rouge” in the heterogeneous spectrum of HFpEF, anti-fibrotic and anti-inflammatory drugs may have a role in its treatment. Pirfenidone is an orally bioavailable drug with antifibrotic and anti-inflammatory properties already approved for the treatment of idiopathic pulmonary fibrosis. Pirfenidone has been recently tested in animal models of myocardial fibrosis with promising results. Here we will review the rationale underlying the potential therapeutic effect of Pirfenidone in HFpEF.

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“…Finally, as randomized trials in nephrology with hard endpoints (i.e., death or cardiovascular events) are difficult to perform and scarce, several studies, including elegant randomized research efforts in patients with CKD include intermediate cardiac end points, such as left-ventricular mass index and left-ventricular ejection fraction [76, 77]. As of this writing, trials in other patient populations (i.e., individuals with heart failure) have used CPET parameters as intermediate cardiovascular endpoints [78, 79]. On this basis, using comprehensive CPET end points could be a valid option also for cardiorenal outcome trials [69]; for this to happen, long-term and optimally designed studies should first evaluate the association of key CPET parameters, such as VO 2 peak, with key outcomes such as cardiovascular and all-cause mortality specifically in patients with CKD.…”

Section: Potential Clinical Applications Of Cpet In Patients With Ckdmentioning

confidence: 99%

Assessment of Exercise Intolerance in Patients with Pre-Dialysis CKD with Cardiopulmonary Function Testing: Translation to Everyday Practice

et al. 2021

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Background: Chronic kidney disease (CKD) is often characterized by increased prevalence of cardiovascular risk factors and increased incidence of cardiovascular events and death. Reduced cardiovascular reserve and exercise intolerance are common in patients with CKD and are associated with adverse outcomes. Summary: The gold standard for identifying exercise limitation is cardiopulmonary exercise testing (CPET). CPET provides an integrative evaluation of cardiovascular, pulmonary, hematopoietic, neuropsychological, and metabolic function during maximal or submaximal exercise. It is useful in clinical setting for differentiation of the causes of exercise intolerance, risk stratification, and assessment of response to relevant treatments. A number of recent studies have used CPET in patients with pre-dialysis CKD, aiming to assess the cardiovascular reserve of these individuals, as well as the effect of interventions such as exercise training programs on their functional capacity. This review provides an in-depth description of CPET methodology and an overview of studies that utilized CPET technology to assess cardiovascular reserve in patients with pre-dialysis CKD. Key Messages: CPET can delineate multisystem changes and offer comprehensive phenotyping of factors determining overall cardiovascular risk. Potential clinical applications of CPET in CKD patients range from objective diagnosis of exercise intolerance to preoperative and long-term risk stratification and providing intermediate endpoints for clinical trials. Future studies should delineate the association of CPET indexes, with cardiovascular and respiratory alterations and hard outcomes in CKD patients, to enhance its diagnostic and prognostic utility in this population.

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Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction

Cited by 92 publications

References 32 publications

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction

Rationale for the Use of Pirfenidone in Heart Failure With Preserved Ejection Fraction

Assessment of Exercise Intolerance in Patients with Pre-Dialysis CKD with Cardiopulmonary Function Testing: Translation to Everyday Practice

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