Study protocol, randomized controlled trial: reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D-ribose

Abstract

BackgroundHeart failure (HF), the leading cause of morbidity and mortality in the US, affects 6.6 million adults with an estimated additional 3 million people by 2030. More than 50% of HF patients have heart failure with preserved left ventricular ejection fraction (HFpEF). These patients have impaired cardiac muscle relaxation and diastolic filling, which investigators have associated with cellular energetic impairment. Patients with HFpEF experience symptoms of: (1) fatigue; (2) shortness of breath; and (3) swelling (edema) of the lower extremities. However, current HF guidelines offer no effective treatment to address these underlying pathophysiologic mechanisms. Thus, we propose a biobehavioral symptom science study using ubiquinol and D-ribose (therapeutic interventions) to target mitochondrial bioenergetics to reduce the complex symptoms experienced by patients with HFpEF.MethodsUsing a randomized, double-blind, placebo-controlled design, the overall objective is to determine if administering ubiquinol and/or D-ribose to HFpEF patients for 12 weeks would decrease the severity of their complex symptoms and improve their cardiac function. The measures used to assess patients’ perceptions of their health status and level of vigor (energy) will be the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Vigor subscale of the Profile of Mood States. The 6-min walk test will be used to test exercise tolerance. Left ventricular diastolic function will be assessed using innovative advanced echocardiography software called speckle tracking. We will measure B-type natriuretic peptides (secreted from ventricles in HF) and lactate/ATP ratio (measure of cellular energetics).DiscussionsUbiquinol (active form of Coenzyme Q10) and D-ribose are two potential treatments that can positively affect cellular energetic impairment, the major underlying mechanism of HFpEF. Ubiquinol, the reduced form of CoQ10, is more effective in adults over the age of 50. In patients with HFpEF, mitochondrial deficiency of ubiquinol results in decreased adenosine triphosphate (ATP) synthesis and reduced scavenging of reactive oxygen species. D-ribose is a substrate required for ATP synthesis and when administered has been shown to improve impaired myocardial bioenergetics. Therefore, if the biological underpinning of deficient mitochondrial ATP in HFpEF is not addressed, patients will suffer major symptoms including lack of energy, fatigue, exertional dyspnea, and exercise intolerance.Trial registrationClinicalTrials.gov Identifier: NCT03133793; Data of Registration: April 28, 2017.

Effect of Metformin on Cardiac Metabolism and Longevity in Aged Female Mice

“…Indeed decreased ATP with preserved ejection fraction is found in patients of HFpEF. Mitochondrial deficiency of ubiquinol resulting in decreased ATP synthesis has been documented as a possible mechanism for the lowered ATP in HFpEF patients (Pierce et al, 2018 ). Moreover, cardiac cell types, extracellular matrix (ECM) composition, and detection methods may also affect the EF and ATP readouts.…”

Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities

“…Despite its limitations, the study reported promising results, such as reduction in major adverse cardiovascular events and lower rates of hospitalization and mortality among the patients treated with CoQ10 [126]. Another ongoing randomized, double-blind and placebo-controlled design clinical trial currently tests whether ubiquinol treatment (active form of Coenzyme Q10) improves the outcome of heart failure patients with preserved ejection fraction (HFpEF) (estimated enrollment of 250 participants) [127]. In the same direction, short-chain synthetic CoQ analogues have also been developed (e.g.…”

Using the NIH symptom science model to understand fatigue and mitochondrial bioenergetics

“…Thus, researchers are investigating whether supplemental oral ubiquinol could stimulate production of additional ATP to assist older patients with heart failure. More ATP will perhaps improve myocardial function, and the patient will experience less fatigue [57].…”