While current medical practice has modestly improved the survival time in a patient that has developed heart failure, it has not done enough to address the underlying issue of an epidemic that as of 2013 plagues 5.8 million people in the United States and 23 million worldwide. Whether the 550,000 cases diagnosed or the 1 million hospitalizations each year in the United States are a matter of "increased incidence or increased survival leading to increased prevalence" (Roger, 2013 para.1), the fact of the matter is too little is being done too late for these patients when the AHA and American college of cardiology do not identify the syndrome of HF until the ejection fraction is at 50% (Roger, 2013 para. 9). Beta blockers, diuretics, and ACE inhibitors have ameliorated the consequences of HF, allowing the heart to not beat against high pressures, blocking the renin - angiotensin system, or simply getting worn out, but this has only prolonged the inevitable, which in numbers gives a 50% chance of survival at 5 years after diagnosis with heart failure and only a 10% survival rate after 10 years. This is not reassuring figuring that 33% of men and 29% of women have a lifetime risk of developing HF according to the Rotterdam Heart Study (Bleumink et al., 2004, p. 1614-1619). In nearly a decade the FDA has not approved a new treatment for heart failure until this year when Amgen plans to roll out a medication called Corlanor (Ivabradine), which reduces the heart rate by blocking channels that control the cardiac pacemaker. The SHIFT (systolic hear failure treatment with the If (funny current) inhibitor ivabaradine Trial) found increased resting HR among the strong predictors for outcomes of cardiovascular death, HF hospitalization, and all cause mortality (Ford et al., 2015, para. 14) .Although it has shown promise in Europe in reducing hospitalization in those suffering from HF, Ivabradine continues the trend of reducing mortality by prolonging the eventual exhaustion of the heart through eliminating external factors; in this case, reducing the heart rate, instead of fixing the actual problem that initially led to heart failure. Coenzyme Q 10 (CoQ10) is that very treatment that can correct the underlying issue, and thereby potentially not only treat HF, but prevent it from ever occurring. CoQ10 not only eliminate one predictor for hospitalization or mortality directly, but rather go to the source of the heart failure, not allowing these predictors to exist or even develop in the first place.
The interesting thing is Coenzyme Q 10 is not a novel treatment, yet it has not been given the proper attention. CoQ10 or quinone was first discovered in beef mitochondria in 1957 by Dr. Frederick Crane at the University of Wisconsin and was found to be synthesized by almost all tissues in the body from Tyrosine. Shortly after this discovery Japan recognized that there was a CoQ10 deficiency present in HF patients, which consequently led to the approval of CoQ10 as a treatment for HF in 1974 in Japan. In 1978, Peter Mitchell received the Nobel prize for demonstrating the vital role CoQ10 serves as a coenzyme in the electron transport chain and thus in ATP synthesis in the mitochondria. By acting as an electron and proton donor from one enzyme complex to another in the chain, with no other molecule being able to perform this function, high concentrations of CoQ10 translate into an increase in the total utilization of energy released by metabolic processes in the body (Langade, 2004, para. 6-20). This in turn allows an increase in energy available for Ca+2 uptake in the sarcoplasmic reticulum to undergo diastole and delivery of Ca+2 to the contractile apparatus to undergo systole. (Kayo & Carsten, 2005 p. 209) If there is a deficiency of CoQ10 however, energy is lost in the form of heat and not maximized to its fullest potential and systolic and diastolic function will suffer. In addition, because of its ability to improve the transport of electrons and protons it acts as an antioxidant by accepting the free electrons from free radicals, which then gets converted to the harmless compound ubiquinol. As a result, this prevents damage to cellular DNA, destruction of cell architecture, and interference with metabolic processes. There is also research that it takes part in optimizing blood viscosity by maintaining the cell membrane integrity of RBCs, it stabilizes the calcium channels, may promote apoptosis in malignant cells, and improve immune status of patients. These effects benefit body as a whole but CoQ10 is also targeted therapy for Congestive Heart Failure (Langade, 2004, para. 21).
Cardiac myocytes contain more mitochondria than any other cell in the body. The reason for such a heavy concentration of mitochondria is that these cells majorly rely on fat sources for ATP synthesis and thus require a higher oxygen concentration. With a greater requirement for O2, a deficiency of CoQ10 will inevitably impair mitochondrial function. Therefore, CoQ10 is vital in order to maximize cardiac function in contraction and relaxation, which both utilize the energy created by the mitochondria in the electron transport chain, and in fact more energy by is necessary for relaxation. By decreasing end diastolic ventricular pressure and improving the ejection fraction of the heart through sufficient concentrations of endogenous CoQ10, CHF can be both treated and prevented (Langade, 2004, para 25,26).
Although the mechanism is clear by which CoQ10 can have a favorable response in HF patients, and it has even been found that the severity of the deficiency correlates with the severity of symptoms i.e. NYHA class IV having significantly lower CoQ10 in endomyocardial biopsy samples than those with NYHA class I (Folkers, 1985, 901- 904), there are studies which refute the efficacy of CoQ10 in HF. Langsjoen (2000, para. 1-5) explained the fallacy in a few of these studies. In the article, he referenced a placebo-controlled double-blind randomized crossover trial of coenzyme Q performed by Watson et al. (1999, p. 1549 - 1552) in which 30 patients with chronic heart failure (duration 41 ± 35 months) and left ventricular dysfunction (ejection fraction <35% on echocardiography) for at least three months with their heart failure stabilized on conventional vasodilator therapy. They were given 33.3 mg dose of CoQ10 (ubiquinone), 3 times per day for three months. The study found that "despite the levels of plasma CoQ10 levels being increased by more than double, it failed to improve resting left ventricular systolic function or quality of life". He quoted 2 studies which utilized the same 100 mg dose with one such study, the Hofman-Bang et al. (1995, p. 101 - 107) study which demonstrated that in a 3-month period 79 patients with an ejection fraction at rest of 22% ± 10% , the ejection fraction only slightly improved, although significantly from 23% ± 12% to 24% ± 12% (p < 0.05). Langsjoen explained that this is a "case of too little for too short a time" (Langsjoen, 2000, para. 1). He expounds this idea in the finding of Watson et al. (1999, p. 1549 - 1552) in which CoQ10 plasma levels increased from 903 ± 345 to 2029 ± 856 nmol/liter which converts to a baseline value of 0.8 mcg/mL to a treatment value of 1.7 mcg/mL. by attesting to the fact that "optimal improvement of myocardial function in our patient did not occur until the average blood level of 2.9 mcg/mL was reached which is only achievable on an average dose of 240 mg of CoQ10 per day" (Langsjoen, 2000 para 4). He also clarifies that it is "too late in the course of CHF before the development of irreversible myocyte loss and fibrosis"(Langsjoen, 2000 para 4). He contrasts this with his own study (Langsjoen et al., 1985, 4240 - 4244) in which 19 patients with idiopathic dilated cardiomyopathy showed an improvement from 44 ± 3% to 56 ± 10% with 3 months of the same 100 mg dose, simply because "these patients were much earlier in the course of their disease" (Langsjoen 2000, para. 3) It is worth noting in reference to adequate doses to reach specific concentrations and earlier therapy being more successful, that Watson et al. in their own study admit that "we did not perform myocardial biopsies and we cannot be sure that myocardial stores were replenished nor can we comment on whether beginning coenzyme Q therapy earlier in the natural history of the disease might have improved left ventricular function". (Watson et al. 1999 pg. 1552)
However, the question that lingers is how does one reconcile the fact that in NYHA class IV patients significantly lower CoQ10 was found in the endomyocardial biopsy samples than those with NYHA class I with Langsjoen's assumption from his contrast of his own study to Watson's that CoQ10 is effective in prevention of HF progressing in those earlier in the course of the disease, but not reversing HF in the later stages? The position that CoQ10 levels are directly related to death in CHF patients is further bolstered by Molyneux et al. (2008, p. 1435 - 1441), a study which found that found a plasma concentration of CoQ10 of 0.73 umol/l was the optimal value in predicting mortality among 236 CHF patients ( a majority being in NYHA class II ), with those above the curve having a decreased risk of mortality in CHF 22% died vs. 39% who died below the 0.73 umol/L cut off point.
The idea that CoQ10 concentration may possibly only be a prognosis for severity of CHF and predictor mortality, but only an actual treatment earlier in the course of the syndrome is further reinforced by Ivanov et al. (2014 p. 1-5), a study which induced a Myocardial Infarction in 80 healthy rats by occluding the LAD using an atraumatic needle and prolene suture. A bolus injection of 30 mg/kg solubilized CoQ10 was injected in some rats at 60 minutes after the onset of the MI and in others at 180 minutes, along with saline and sham procedure control groups. In both the 60 min. and 180 min. groups administered IV CoQ10 high levels of CoQ10 were sustained in the plasma, left ventricle, and especially in the liver 21 days later; however, only in the 60 min. group was there seen significantly improved cardiac systolic and diastolic function with limited LV damage and dilatation. This study displays the level of CoQ10 after 21 days was not a factor if the heart muscle had reached a certain stage of myocardial damage like in the 180 min. group. The limitation of the study was that it did not analyze CoQ10 concentrations shortly after administration to compare the levels after 21 days , but instead compared it to values that were calculated relative to sham - operated animals. This is important as the question then becomes that if this study had maintained the levels of CoQ10 to a consistently higher level than what they found after 21 days, would the outcome be any different.
The same question could be asked of de Frutos et al. (2014 para. 35,36), in which a meta-analysis found that the outcome that is reported by the majority of the various studies which used CoQ10 in the days and/or hours before and after cardiac surgery, and/or during the surgery itself is the significant reduction of the proportion of patients who required inotropic drugs and the incidence of ventricular arrhythmias after surgery. However, there was no evidence to conclude that CoQ10 improved the cardiac index 24 hours after surgery or reduced the hospital stay or the incidence of atrial fibrillation. However, the limitation again was that none of these studies tracked improvement after surgery in a scenario where high dosages of CoQ10 were administered several months before and/or after the surgery which may have improved the items which were inconclusive.
The idea behind both these studies is that CoQ10 prevented cardiac remodeling by not allowing the buildup of free radicals and limiting the inflammatory cytokine response thereby hindering the progress to HF. Is it a possibility that due to the myocardial necrosis, fibrosis, and apoptosis resulting from cell damage and rupture of mitochondria that not only a higher dose, for a longer period of time is necessary to reverse heart failure like Langsjoen (2000) stated above, but a different form of CoQ10 is essential to accomplish this.
This was exactly what Langsjoen himself, who stated that CoQ10 was not effective on the late stages of heart failure since they had "irreversible myocyte loss and fibrosis" (Langsjoen, 2000, para. 4), postulated in (Langsjoen and Langsjoen, 2008 119-128), a study involving 7 patients with advanced CHF with a mean EF of 22%. Even on an average dose of 450 mg of ubiquinone, the oxidized form of CoQ10, these patients only reached sub - therapeutic plasma CoQ10 levels with a mean level of 1.6 mcg/mL due to the intestinal edema, which impaired their ability to absorb CoQ10. However when supplemented with an average dose of 580 mg/day of ubiquinol, the reduced form of CoQ 10, plasma levels of CoQ10 increased up to 6.5 mcg/mL and consequently improved mean EF from 22% up to an astounding 39% and NYHA class improving from a mean of IV to a mean of II. Similar results were found in comparing the bioavailability of ubiquinone versus ubiquinol in a study of 12 healthy volunteers in a study by (Langsjoen and Langsjoen, 2014, para. 1). The reasoning for the difference in bioavailability explains (Failla, Chitchumroonchokchai & Aoki, 2014) is that the reduced form of CoQ10, ubiquinol is "more efficiently incorporated into mixed micelles during digestion in the small intestine and having a greater uptake and basolateral secretion in a glutahione- dependant mechanism" . (Failla, Chitchumroonchokchai & Aoki, 2014 Para. 1) These previously mentioned studies were a tremendous breakthrough in the utilization of CoQ10 to not only prevent HF in its early stages, but to improve the quality of life even in those with severely symptomatic HF. However, the limitations of these studies are the small number of participants. In order to lend credibility to these studies a larger scale study was necessary.
After a 2-year prospective clinical trial with 420 patients from 9 different countries enrolled in what is called the Q-Symbio study, (Mortensen et al., 2014, 641-649) demonstrated the remarkable effectiveness of long term CoQ10 supplementation. In the study patients with moderate to severe HF were either given 300 mg ubiquinone, the less absorbable form, as was mentioned earlier, or a placebo. After 16 weeks, the short term end point, no meaningful changes were seen. However, after following the patients for two years, the risk of a major adverse cardiovascular event (which included "unplanned hospitalization due to worsening of heart failure, cardiovascular death, urgent cardiac transplantation, and mechanical circulatory support) was cut in half in the CoQ10 group with only 14% of the CoQ10 group reaching that end point while 25% of the placebo group reaching that end point. In addition, only 9% of the CoQ10 group died a cardiovascular death within the time period versus 16% of the placebo group. All cause mortality was 10% versus 18%. Incidence of hospital stays and significant improvement of NYHA class was also found. This study demonstrated that even CoQ10 in the form of ubiquinone, when given in high enough doses (300 mg) over a long period of time can have dramatic effects on the lives of HF patients.
These studies of CoQ10's benefits in the last few decades have laid the groundwork to encourage further studies preferably with a large group size using high doses of CoQ10 in its most absorbable form of ubiquinol over a long period of time in patients with severe HF. This would combine all the qualities and successes of all the aforementioned studies. In addition, more studies of CoQ10 with adjunctive therapies to enhance the effect of CoQ10 in improving the quality of life by diminishing the dyspnea and fatigue brought on by HF, need to be done. This can be accomplished by reducing pro - inflammatory cytokines as is seen by combining CoQ10 with L-carnitine (Kumar et al., 2007, 349 - 354) or reducing pro-BNP levels by adding selenium to a CoQ10 regimen (Alehagen et al., 2013, 1860-1866). Although the material presented here about CoQ10 was only in regard to protecting the heart against muscle damage, it also aids in preventing worsening of heart failure by protecting against arterial occlusion by atherosclerosis and improving endothelial dysfunction which was not mentioned here. With all this ground-breaking research and the fact that CoQ10 provides energy for a starved heart, not just controlling the symptoms of HF like other medications, and with the bonus that it is virtually without side effects, there is no reason that numerous studies should not be funded to prove the efficacy of CoQ10 that Japan had recognized 40 years ago.
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