Clinical Evidence for Q10 Coenzyme Supplementation in Heart Failure: From Energetics to Functional Improvement

Oxidative stress and mitochondrial dysfunction are hallmarks of heart failure (HF). Coenzyme Q10 (CoQ10) is a vitamin-like organic compound widely expressed in humans as ubiquinol (reduced form) and ubiquinone (oxidized form). CoQ10 plays a key role in electron transport in oxidative phosphorylation of mitochondria. CoQ10 acts as a potent antioxidant, membrane stabilizer and cofactor in the production of adenosine triphosphate by oxidative phosphorylation, inhibiting the oxidation of proteins and DNA. Patients with HF showed CoQ10 deficiency; therefore, a number of clinical trials investigating the effects of CoQ10 supplementation in HF have been conducted. CoQ10 supplementation may confer potential prognostic advantages in HF patients with no adverse hemodynamic profile or safety issues. The latest evidence on the clinical effects of CoQ10 supplementation in HF was reviewed.


Introduction
Despite brilliant research development in medical and device therapies, heart failure (HF) still remains a complex multifaceted syndrome with poor outcomes [1][2][3]. Mitochondrial dysfunction is a hallmark of HF syndrome, predominantly characterized by a deficit in the production of myocardial adenosine triphosphate, derailment of calcium exchange and increased production of reactive oxygen species leading to endothelial dysfunction [4][5][6] (Figure 1).
Since Coenzyme Q10 (CoQ10) plays a key role in cell energetics acting as an effective anti-inflammatory agent exerting endothelial function improvement, it may represent a plausible therapeutic option for HF patients [30][31][32][33][34]. Interestingly, lower CoQ10 levels have been found in more compromised HF patients presenting with high New York Heart Association (NYHA) class and reduced left ventricular ejection fraction (HFrEF). CoQ10 supplementation may potentially confer prognostic advantages in HFrEF [35] neutrally impacting on hemodynamic profile and without safety issues [36].
The present review summarizes the latest evidence of the clinical effects of CoQ10 supplementation in HF.
Since Coenzyme Q10 (CoQ10) plays a key role in cell energetics acting as an effective antiinflammatory agent exerting endothelial function improvement, it may represent a plausible therapeutic option for HF patients [30][31][32][33][34]. Interestingly, lower CoQ10 levels have been found in more compromised HF patients presenting with high New York Heart Association (NYHA) class and reduced left ventricular ejection fraction (HFrEF). CoQ10 supplementation may potentially confer prognostic advantages in HFrEF [35] neutrally impacting on hemodynamic profile and without safety issues [36].
The present review summarizes the latest evidence of the clinical effects of CoQ10 supplementation in HF.

Mitochondria Dysfunction and Energy Depletion in HF
Chronic HF inexorably progresses intermittently, with relatively steady phases alternated with acute decompensation needing therapy upgrading or hospitalization. Furthermore, although conventional drugs may ameliorate morbidity and mortality rates, specific HF symptoms (i.e., fatigue and exercise intolerance) remain a major challenge for physicians [37].
Modulating cardiac energetics might represent an intriguing therapeutic option [38,39]. It has been postulated that energy depletion is the main constant of the failing and decompensated heart, which requires more energy to maintain homeostasis [40,41]. Abnormal calcium handling, ATP depletion and mitochondrial dysfunction derailing cardiac metabolic pathways are all common findings in HF patients [39][40][41]. These alterations lead to energy depletion that negatively affects cardiac contractile function. Therapies counteracting cardiac energy exhaustion may play a role in HF management increasing the duration of compensation phases [38].
Mitochondrial dysfunction, led by activation of immune-inflammatory pathways and overproduction of reactive oxygen species (ROS), overwhelms the antioxidant cell enzyme defense and is associated with the initiation and progression of atherosclerosis [42]. Therefore, new approaches to support standard therapies of atherosclerosis are needed. CoQ10 has been shown to enhance ATP production as a carrier in the mitochondrial respiratory chain; furthermore, CoQ10 can improve endothelial function and mediate epigenetic regulation in genes involved in cell signaling [43].

Mitochondria Dysfunction and Energy Depletion in HF
Chronic HF inexorably progresses intermittently, with relatively steady phases alternated with acute decompensation needing therapy upgrading or hospitalization. Furthermore, although conventional drugs may ameliorate morbidity and mortality rates, specific HF symptoms (i.e., fatigue and exercise intolerance) remain a major challenge for physicians [37].
Modulating cardiac energetics might represent an intriguing therapeutic option [38,39]. It has been postulated that energy depletion is the main constant of the failing and decompensated heart, which requires more energy to maintain homeostasis [40,41]. Abnormal calcium handling, ATP depletion and mitochondrial dysfunction derailing cardiac metabolic pathways are all common findings in HF patients [39][40][41]. These alterations lead to energy depletion that negatively affects cardiac contractile function. Therapies counteracting cardiac energy exhaustion may play a role in HF management increasing the duration of compensation phases [38].
Mitochondrial dysfunction, led by activation of immune-inflammatory pathways and overproduction of reactive oxygen species (ROS), overwhelms the antioxidant cell enzyme defense and is associated with the initiation and progression of atherosclerosis [42]. Therefore, new approaches to support standard therapies of atherosclerosis are needed. CoQ10 has been shown to enhance ATP production as a carrier in the mitochondrial respiratory chain; furthermore, CoQ10 can improve endothelial function and mediate epigenetic regulation in genes involved in cell signaling [43].
In patients with HF, CoQ10 levels are inversely associated with functional status and with a severity of HF symptoms such as fatigue, exercise tolerance and dyspnea. In a sample of 43 HF patients with heterogeneous etiology, endomyocardial biopsies showed that myocardial CoQ10 levels are inversely related to NYHA functional class: higher CoQ10 levels were observed in less compromised patients (NYHA class I and II patients); conversely, more compromised HF patients (NYHA class III and IV) had significantly lower myocardial CoQ10 levels [49]. CoQ10 supplementation efficiently restored CoQ10 levels both in the myocardium and sera [49]. The associations between CoQ10 levels and HF symptoms have been observed in other cohorts [35,50]. In the CORONA (Controlled Rosuvastatin Multinational Study in HF) trial (n = 1191), the lowest CoQ10 levels were significantly associated either to the lowest left ventricular ejection fraction (LVEF) or to the highest natriuretic peptide levels [51].
Finally, Soongswang et al. [58] showed significant improvement in the NYHA class in 15 pediatric patients (median age 4.4 years) with idiopathic chronic dilated cardiomyopathy (DCM) undergoing CoQ10 supplementation (3.1 ± 0.6 mg/kg/d for nine months, four patients had improved by one functional class and one patient had improved by two classes at nine months with CoQ10, p = 0.005, Table 1).

Effects of CoQ10 Supplementation on Echocardiographic Parameters
In 79 stable HFrEF patients, Hofman-Bang et al. [59] reported that patients undergoing CoQ10 supplement (50 mg orally TID vs. placebo for three months) showed a slight improvement in LVEF (Table 1). In 22 patients with HFrEF, Munkholm et al. [60] observed that CoQ10 supplementation (100 mg orally twice a day vs. placebo for one year) exerted a significant improvement in echo parameters of great clinical relevance (i.e., an increase in stroke index, mean pulmonary artery pressure and a reduction in pulmonary capillary wedge pressure); however, no significant changes were observed in the placebo group (Table 1). No effects were reported on LVEF [60] (Table 1). Similarly, CoQ10 supplementation (200 mg orally daily vs. placebo for six months) exerted neutral results on LVEF in 55 patients with HFrEF [61] (Table 1).

Effects of CoQ10 Supplementation on Functional Capacity
CoQ10 supplementation showed a significant increase in maximal exercise capacity [60] (Table 1). Although some authors reported no significant improvement in exercise duration or peak oxygen consumption (peak VO2) [62], Belardinelli et al. [63], in a small cohort of 23 patients (NYHA class II/III with stable HF of ischemic etiology supplemented with 100 mg orally of CoQ10 four times per day vs. placebo), reported a significant improvement in functional capacity (as measured by peak VO2) and in endothelial function (as expressed by endothelium-dependent dilation of the brachial artery). Notably, CoQ10 supplementation exerted a +9% increase in peak VO2, a +38% increase of endothelium-dependent dilation of the brachial artery and a significant decrease (−D12%) in systolic wall thickening score index [63]. Interestingly, exercise training (ET) exerted comparable effects to CoQ10 administration, thus reinforcing the need for performing training programs in HF patients [7,11,37,62,63,77,[80][81][82]. CoQ10 supplementation induced a four-fold increase in baseline CoQ10 levels; notably, the combination strategy CoQ10 plus ET further increased levels with no reported side effects. In the randomized controlled trial conducted in 35 HF patients after three-month CoQ10 supplementation (150 mg/d), Rosenfeldt et al. [56] reported a significant increase in exercise capacity assessed by the Specific Activity Scale, treadmill exercise time and 6-min walking test distance (Table 1). A significant improvement of exercise capacity (measured as exercise duration, walking distance or both) have been reported in group undergoing CoQ10 supplementation (150 to 800 mg/d vs. placebo) in a recent meta-analysis including four clinical trial in 234 HF patients (SMD = 0.62; 95% CI = 0.02-1.12; p = 0.04) [57] (Table 1).

Effects of CoQ10 Supplementation on Mortality
Despite the association between worse clinical status and lower CoQ10 levels in HF patients, the prognostic role of CoQ10 levels is still debated. In 236 HF patients hospitalized for acute decompensating, increased CoQ10 levels improved survival (independent of clinical risk factors such as natriuretic peptides and renal function, hazard ratio (HR), 2.0; 95% CI = 91.2-3.3) [35]. However, in the CORONA trial (n = 1191), no association between CoQ10 levels and mortality has been reported [35] ( Table 1). Although CoQ10 levels reduction is induced by rosuvastatin use, no interaction between these two factors for any outcome was reported [50]. These results suggest that CoQ10 levels might be likely useful to stratify HF severity instead of the prognostic indicator.
In 1985, Langsjoen et al. [64] orally supplemented two groups of HF patients with NYHA class III or IV with CoQ10 versus a matched placebo. In this study, Group A patients received CoQ10 first and then placebo; conversely, Group B received placebo first and then CoQ10. Cardiac function indexes and CoQ10 levels were evaluated at 0 and 4 weeks (control stabilization period) and at 16 and 28 weeks (after the 12-week CoQ10/placebo-treatment periods). Group A showed significant improvement of cardiac function with an increase in CoQ10 levels during the CoQ10 supplementation phase which decreased during crossover to placebo. Specular findings were observed for Group B patients. All patients generally showed a brilliant clinical response to CoQ10 supplementation, with an increased survival in this cohort of patients usually experiencing a higher mortality rate at two years under conventional therapy [78] ( Table 1).
The These limitations could be ascribed to the researcher or site-related limitations, patient acceptance of drug administration, competing ongoing trials and other causes. The significant treatment effect consisting of about halved reduction in both primary composite end-point and all-cause mortality is quite unexpected and enthusiastic; however, it is plausible that either small number of events (mortality rate of 7% per year for the overall population) or the relatively small sample size might interfere with major findings; therefore results should be interpreted with caution. More recently, post-hoc analysis of baseline characteristics for short-term (three months) and long-term (two years) endpoints on the efficacy of CoQ10 in HF was investigated in a European cohort of 231 patients of the Q-SYMBIO trial (n = 420) [55]. After two years, all-cause mortality was lower in the CoQ10 group compared to placebo (10 (9%) vs. 24 (20%) patients, respectively), corresponding to a relative reduction of 53% (p = 0.04). Data also showed a significant reduction in hospitalization due to worsening HF in the CoQ10 group (3%) compared to placebo (13%, p = 0.007) [55].

CoQ10 Supplementation in HFpEF
Reduced ventricular compliance during the diastolic phase is a hallmark of clinically relevant HFpEF. In this case, the increase of left ventricular end-diastolic pressure occurs with normal left ventricular systolic function. Since the diastolic phase is sustained by ATP hydrolysis for disjoining myofilaments and consensual ventricular relaxation to occur, HFpEF can be viewed as energetic mismatch disorder [83]. In addition, inflammatory status and increased ROS production may lead to endothelial dysfunction driving to adverse cardiac remodeling and subsequent impaired ventricular relaxation [84][85][86][87] (Figure 1).
Analogously, only one trial investigated the effects of CoQ10 supplementation in patients with hypertrophic cardiomyopathy and diastolic dysfunction [64]. Compared to conventional therapy, patients with hypertrophic cardiomyopathy (n = 46) supplemented with CoQ10 showed a significant improvement in functional status (NYHA class ≥ 1), quality of life, 6-min walking test, and diastolic dysfunction (as evaluated by ≥1 parameter and in mitral regurgitation ≥1 grade). Post-treatment echocardiogram showed a significant reduction in the left ventricular outflow tract (LVOT) gradient of ≥15 mm Hg in obstructive cases (12 out of 46) in the treatment group. The mean interventricular septal thickness showed a 22.4% reduction (p < 0.005); and the mean posterior wall thickness showed a 23.1% reduction (p < 0.005) [64].
However, the small sample size strongly limits the conclusions in this cohort. Due to the evidence that current therapies may improve survival in patients with HFpEF, the research agenda should include trials testing the hypothesis that CoQ10 supplementation may improve survival.

Effects of CoQ10 Supplementation on Quality of Life (QoL)
In HF patients, common symptoms such as fatigue, exercise intolerance, inability in daily activities are linked to mitochondrial dysfunction and energy depletion. These symptoms have a strong impact on quality of life (QoL). In a double-blind placebo-controlled trial including 79 HF patients undergoing CoQ10 supplementation (100 mg/d for three months), Hofman-Bang et al. [59] reported a significant improvement in QoL score (Table 1). Conversely, Watson et al. [68] found no differences in the QoL score as evaluated by the Minnesota "Living with Heart Failure" questionnaire in the CoQ10 supplementation group (33 mg TID for three months) vs. placebo (Table 1).

CoQ10 Dosing, Duration of Supplementation and Drug Interactions in HF Trials
In all examined trials, CoQ10 doses ranging from 60 to 300 mg/d were orally administered. In 143 HF patients (NYHA class III/IV), CoQ10 supplementation (100 mg/d) resulted in an increase in CoQ10 levels from 0.85 to 2 mg/L associated to an increase in LVEF and to functional status improvement, with no reported adverse events [88]. Consequently, the highest CoQ10 level obtained in other studies was selected as the target in the Q-SYMBIO trial (2 mg/L), which used CoQ10 at 300 mg/d orally administered. Keogh et al. [52] reported a significant reduction in stroke index, pulmonary artery pressure and pulmonary capillary pressure in the cohort that reached CoQ10 levels of 3.25 ± 1.57 mg/L compared to placebo. Only one RCT has been conducted in patients with ischemic heart disease, which used CoQ10 at 300 mg/d for three months vs. placebo showing a significant reduction of inflammatory markers (i.e., tumor necrosis factor-α and interleukin-6) [89].
In a small sample size study (n = 7), Langsjoen et al. [90] focused on advanced HF patients (average LVEF = 22%), NYHA class IV, in which CoQ10 supplementation with CoQ10 (ubiquinone) 900 mg/d often did not attain therapeutic plasma CoQ10 levels (less than 2.5 mcg/mL); instead, therapeutic plasma levels (up to 6.5 mcg/mL) and significant improvement of EF (average up to 39%) and NYHA class (mean of IV to mean of II) were achieved supplementing these patients with reduced form of CoQ10 (ubiquinol) average 450 mg/d (therapeutic plasma level = >3.5 µg/mL).
Three months was the duration for the majority of examined trials, whereas the longest administration of CoQ10 was performed in the Q-SYMBIO trial (two years of CoQ10 supplementation) [61].

Conclusions
Overall, the relatively small sample size with sparse events reported, heterogeneous populations and study outcomes, different trial design and follow-up duration, different administered doses of CoQ10 and lack of use of novel HF drugs contribute to the uncertainty in evaluating and pooling data. Changes in the antioxidant systems in HF support the idea that CoQ10 may improve the outcome, quality of life and decrease morbidity and mortality. In recent years, the beneficial effects of CoQ10 supplementation in HF prevention and treatment have been consistently observed in many trials suggesting that CoQ10 may be considered as an adjunct to conventional treatment.
Several important issues on CoQ10 should be prioritized in the research agenda. The optimal dose of CoQ10 supplementation for HF patients should be defined. In this view, high-performance liquid chromatography may help to establish the plasma concentration, which is optimal for clinical effect. It also allows determining the normal levels of CoQ10, as well as adjusting the dose of administered CoQ10. The duration of CoQ10 supplementation in order to achieve clinical benefit in HF patients should be clearly defined. Better-powered studies are needed to assess the CoQ10 supplementation effect on survival in HF patients. Statins have been shown to decrease CoQ10 levels by inhibiting the mevalonate pathway. Statins can reduce blood serum levels of CoQ10 by almost much as 40%. It has been suggested that fatigue, muscle pain and weakness with statin use are related to a deficiency in CoQ10. Therefore, properly powered studies are needed in order to understand the role of CoQ10 supplementation in restoring CoQ10 levels in HF patients undergoing statin therapy. Furthermore, whether CoQ10 supplementation in HF on statin therapy may exert beneficial effects on the outcome by improving drug adherence remains to be elucidated.