Randomized, Double-Blind, Placebo-Controlled Trial of Coenzyme Q10 in Isolated Systolic Hypertension.

ABSTRACT

Background. Increasing numbers of the adult population are using alternative or complementary health resources in the treatment of chronic medical conditions. Systemic hypertension affects more than 50 million adults and is one of the most common risk factors for cardiovascular morbidity and mortality. This study evaluates the antihypertensive effectiveness of oral coenzyme Q10 (CoQ), an over-the-counter nutritional supplement, in a cohort of 46 men and 37 women with isolated systolic hypertension.

Methods. We conducted a 12-week randomized, double-blind, placebo-controlled trial with twice daily administration of 60 mg of oral CoQ and determination of plasma CoQ levels before and after the 12 weeks of treatment.

Results. The mean reduction in systolic blood pressure of the CoQ-treated group was 17.8 [+ or -] 7.3 mm Hg (mean n SEM). None of the patients exhibited orthostatic blood pressure changes.

Conclusions. Our results suggest CoQ may be safely offered to hypertensive patients as an alternative treatment option.

SYSTEMIC HYPERTENSION is the most prevalent cardiovascular disorder in the United States, affecting more than 50 million adults. (1) It remains one of the most common risk factors for cardiovascular morbidity and mortality, (1) affecting a disproportionate number of the elderly. Two thirds of hypertensive patients over age 65 have isolated systolic hypertension (ISH), (2) defined as systolic blood pressure (SBP) >140 with diastolic blood pressure (DBP) <90. Two large clinical trials confirmed that reducing SBP 20 mm Hg in patients over age 60 with ISH reduced the incidence of stroke, heart failure, and mortality. (3,4) Using antihypertensive agents to treat elderly patients, however, can be problematic because of the increased incidence of postural hypotension in this group of patients, with consequent risk of falls and associated morbidity. (5)

Coenzyme Q10 (2,3 dimethoxy-5 methyl-6-decaprenyl benzoquinone), also known as ubiquinone, is a naturally occurring fat soluble quinone ubiquitous in eukaryotic cells (6) and is available in the United States as an over-the-counter nutritional supplement. It has been used for 35 years as adjunctive therapy for various cardiovascular disorders. (7-9) Several studies have reported oral CoQ to be an effective antihypertensive agent. (10-14) However, previous studies have had methodologic problems, including small sample size, lack of controls, unblinded protocols, and the presence of comorbid conditions that may confound interpretation of results. In addition, oral CoQ is poorly absorbed, and few previous studies included determination of plasma levels. (15) We undertook this study to assess the clinical usefulness of oral CoQ in the treatment of ISH in patients without comorbid conditions.

METHODS

In this randomized, double-blind, placebo-controlled study, 41 men and 35 women with ISH (SBP 150 to 170 mm Hg; DBP <90 mm Hg) and 5 normotensive men and 4 normotensive women were enrolled from outpatient medical clinics in Boise, Idaho, between January 17, 1999, and July 25, 1999. Exclusion criteria are shown in Table 1. After a 10-day "washout" period during which any existing antihypertensive therapy was discontinued, patients were randomized to receive twice daily dosing of 60 mg of emulsified CoQ (Hydrosoluble Q-Gel, Tishcon, New York, NY) containing 150 IU of vitamin E or a similar-appearing placebo containing vitamin E alone. The dose of vitamin E contained in the capsules has been shown to have no effect on blood pressure. (16) The emulsified formulation of CoQ chosen exhibited enhanced bioavailability in previous studies. (15) Randomization was accomplished by having each patient select a numbered token from a basket; even numbers were assigned to placebo and odd numbers to CoQ. The treatment key, he ld by a participating pharmacist, was broken upon termination of the study. Access to the key was also possible in case of any emergency that might necessitate knowledge of what an individual patient was taking. Treatment lasted 12 weeks. Patients whose SBP without medication was >170 mm Hg were excluded and placed back on their previous antihypertensive regimen. Eighty-seven percent of patients enrolled had the diagnosis of essential hypertension established for a year or more.

Blood pressure readings during the study were measured with a standard mercury sphygmomanometer with the patient in the sitting postion. First and fifth Karotkoff sounds were used for pressure determinations. The patient rested sitting for 10 minutes before pressure measurement. Repeat readings were taken at 2-minute intervals for a total of 3 sitting measurements at each visit. Orthostatic readings were then made with the patient supine for 5 minutes, then standing for 60 seconds. This was repeated once. Averages of repeated measurements at a given visit were recorded. Nine healthy normotensive patients (5 male, 4 female) were enrolled, treated with CoQ and subject to identical blood pressure measurements. Normotensive patients were free from cardiovascular disease and were screened with the same exclusion criteria as hypertensive patients. All female patients had ceased menstruation.

Blood pressures were monitored twice weekly between the hours of 8 AM and 11 AM by the same nurse, and both physicians and nurses were blinded to treatment. Monthly pill counts by a member of the clerical staff blinded to the study protocol were used to monitor compliance. Of the total of 85 enrolled, 44 men and 36 women completed the study: 5 men and 4 women in the normotensive group, 21 men and 18 women in the ISH CoQ group, and 18 men and 14 women in the ISH placebo group. Reasons for presentation to the clinic in the normotensive cohort were gastrointestinal (3), respiratory (4), and musculoskeletal (2). There were no differences between control and treatment groups with regard to baseline parameters (Table 2). A SBP [greater than or equal to]175 mm Hg at any time during the study or a systolic pressure >170 mm Hg on 3 consecutive visits resulted in patient withdrawal from the study and institution of alternate treatment (likewise for diastolic pressures >115 mm Hg). The project was reviewed and approved by the Institutional Review Board of St. Luke's Regional Medical Center, Boise, Idaho, and all subjects provided written informed consent in compliance with National Institutes of Health guidelines on the use of human subjects. Plasma levels of CoQ before and after treatment were available in 23 CoQ-treated hypertensive patients, 18 placebo-treated hypertensive patients, and 7 CoQ-treated normotensive patients. Plasma was collected at baseline, and again after 12 weeks of treatment (before the morning dose for trough CoQ determination). Blood was obtained in sterile EDTA-containing tubes, immediately spun at 1,500 g for 2 minutes in the dark, and the plasma stored at -80[degrees]C in light tight cryogenic vials until analysis by high-performance liquid chromatography (HPLC). (17) For HPLC, 2 mL of 100% ethanol was added to 0.5 mL of plasma and extracted with 5 mL of hexane. Then 4 mL of the hexane layer was dried under nitrogen and the residue was dissolved in 50 [mirco]L of 100% ethanol. To this was added 0. 5 mL of 5% (wt/vol) potassium ferric cyanide in ethanol, and the mixture was allowed to stand at room temperature for 10 minutes to oxidize reduced CoQ. The solution was re-extracted with 2 mL ethanol and 5 mL hexane, 4 mL of the hexane phase was again dried under a stream of nitrogen, and the residue was dissolved in 250 [mirco]L of ethanol. A C18 column was used for HPLC; mobile phase methanol:hexane 75/25; UV detection at 275 nm.

RESULTS

The average reduction in SBP in the ISH CoQ group after 12 weeks of treatment was 17.8 [+ or -] 7.3 mm Hg (mean [+ or -] sem) (Table 3). There were no significant changes in DBP in any of the groups before and after treatment. There were no significant orthostatic changes in SBP in the ISH CoQ or normotensive CoQ groups. Analysis of individual patient data revealed that 55% of patients in the ISH CoQ treatment group achieved a reduction in SBP of [greater than or equal to]4 mm Hg, while 45% of patients were non-responders. In that subset of patients who were responders, the average reduction in SBP was 25.9 [+ or -] 6.4 mm Hg. The study was not designed to evaluate dose-response relationships between CoQ plasma level and blood pressure response. Linear regression analysis suggested a trend, but this did not reach statistical significance (P = .09). The average plasma CoQ levels at baseline did not differ between groups (Table 3). After 12 weeks of treatment, the mean plasma CoQ level increased from 0.47 [+ or -] 0.19 [mirco]g/mL to 2.69 [+ or -] 0.54 [micro]g/mL, an increase of approximately 2.2 [micro]g/mL.

Five patients failed to complete the study. One had mild nausea after day 1 and chose not to continue; one was lost to follow-up for unknown reasons; and two patients dropped out of the study after weeks 4 and 5, (the reason cited was not wanting to take pills twice daily). One patient was hospitalized for treatment of orthopedic trauma and could not complete the protocol. All normotensive patients completed the study.

About one third of patients (27/80) were taking a statin for elevated lipids during the study. There were no significant differences between groups in the percentage of patients using a statin.

DISCUSSION

In 1965, Yamamura et al (18) first used coenzyme Q10 clinically in the treatment of cardiovascular disease. Clinical investigation on the use of CoQ for treatment of hypertension began when Igarashi et al (19) reported that CoQ reduced elevated blood pressure in unilaterally nephrectomized rats treated with desoxycorticosterone and saline. A deficiency in activity of leukocyte succinate dehydrogenase-CoQi10-reductase was then reported in hypertensive rats (20 and humans, (21) and several small clinical trials followed showing a consistent reduction in SBP and DBP in patients with essential hypertension. (10-14,22-24) Yamagami et al (24) treated 20 patients in a blinded fashion with 100 mg per day and reported a mean reduction in pressure of 19 mm Hg systolic and 6 mm Hg diastolic. Langsjoen et al (11) treated 109 patients in an open study in which the dose varied (mean, 225 mg/day) and patients had comorbid conditions. Digiesi et al (10,13) treated 9 hypertensive patients with CoQ (100 mg daily) and 9 hyperte nsive patients with placebo in a blinded study, showing a reduction in blood pressure similar to that reported in previous studies. Plasma renin activity, urinary aldosterone, and 24-hour sodium and potassium levels were unchanged, while peripheral resistance was shown to be significantly reduced in five patients evaluated with radionuclide angiocardiography. (10) In addition, a blinded, controlled study was recently reported using hypertensive patients with coronary artery disease (12) and a CoQ preparation with documented improved bioavailabillity. (15) Using this same CoQ preparation, the current study is the first to examine the antihypertensive effects of CoQ in a cohort of patients with ISH, a prevalent problem in the elderly. Reductions in SBP found in this study are in general agreement with those found by other investigators.

Previous studies have had methodologic problems such as small sample size, lack of controls, lack of blindedness, or presence of potentially confounding comorbid conditions. In addition, few previous studies have measured CoQ plasma levels before and after treatment. The aqueous solubility of CoQ is low, leading to poor oral bioavailability of most preparations. (25) Endogenous CoQ levels in this study were slightly lower than those reported elsewhere. (26,27) However, treatment with an HMG-CoA reductase inhibitor has been shown to lower endogenous CoQ plasma levels, (28) and baseline plasma levels in the subset of patients not taking a statin was 0.61 [+ or -] 0.29 [micro]g/mL, closer to previously published values. (26,27) Statins inhibit synthesis of mevalonate, a precursor of ubiquinone, which is central to mitochondrial respiratory chain function. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction. (28) Thus, concerns have been raised regarding the poten tial deleterious effects of lowered CoQ plasma levels as a result of statin use. (28,29) De Pinieux et al (29) have recently shown lowered plasma CoQ levels and elevated blood lactate/pyruvate ratios in patients treated with a statin, consistent with mitochondrial dysfunction in these patients.

The absence of any antihypertensive response in 45% of the study participants suggests the possibility of a threshold effect in CoQ's mechanism of action; study participants blood pressure seemed either to respond well or not at all. This result differs from those in previous studies, and the reasons for this are not clear. However, blood pressure regulation is a complex phenomenon under control by multiple homeostatic systems, (30-32) and further studies will be needed to clarify CoQ's mechanism of action.

Aging is associated with a variety of cardiovascular alterations that increase the incidence of pathologic processes such as myocardial infarction and stroke. (30) Elderly patients with systolic hypertension usually have lower vascular elasticity, lower cardiac output, lower ejection fraction, lower plasma volume, and increased peripheral vascular resistance compared with age-matched normotensive controls. (1,30,31) The most common age-related change in arterial function, however, is impaired vasodilation. (30,31) Both [beta]-adrenoceptor-mediated vasodilation and endothelium-dependent arterial relaxation are reduced during aging in humans and animals. (30-33) Lonnrot et al (34) found that in isolated mesenteric arterial rings isolated from aged Wistar rats, long-term dietary CoQ supplementation enhanced endothelium-independent arterial relaxation in response to isoprenaline and improved the endothelium-dependent vasodilation response to acetylcholine (ACh) in arterial rings precontracted with noradrenalin. Cyclooxygenase inhibition with diclofenac abolished the improved response to ACh, suggesting that the improved endothelium-dependent vasodilation observed was largely mediated by prostacyclin ([PGI.sub.2]). Consistent with possible direct effects on regulating vascular tone, Digiesi et al(10)found that oral CoQ decreased total peripheral resistance in a small cohort of patients evaluated with radionucide angiocardiography. Plasma renin activity, urinary aldosterone, and 24-hour sodium and potassium levels were all unchanged. (10)

The mechanisms underlying essential hypertension remain uncertain. A causal role for insulin resistance has been suggested, (35) and high levels of plasma insulin have frequently been found in patients with high blood pressure. (35,36) Recent studies suggest that enhanced sympathetic tone may induce both insulin resistance and hypertension. (36-38) Insulin causes sympathetic excitation with modification of baroreflexes, norepinephrine release, and central sympathetic outflow, (38) and sympathetic overdrive leads to endothelial damage and impairment of the vasodilatory response (37) through a free radical--mediated mechanism. (12,39) Singh et al (12) have shown that 60 mg of CoQ twice daily in hypertensive patients with coronary artery disease resulted in lowering of fasting and 2-hour plasma insulin levels, as well as decreased blood pressure. Thus, it is possible that CoQ's antioxidant capacity mediates its blood pressure lowering effect.

Treatment with CoQ was well tolerated, and side effect rates were comparable in the CoQ and placebo groups. Flatulence or nausea were reported in 2 patients and headache in 1 patient, for an adverse event rate of 6.2% (3/48) in those patients treated with CoQ. Only one patient failed to complete the study because of inability to tolerate CoQ (nausea). Baggio et in a multicenter study with more than 2,300 patients and 3 years of follow-up, found less than 6% of patients reporting adverse reactions, none of which were serious. No patient in our study showed electrocardiographic changes after 12 weeks of therapy, nor reported any palpitations, syncope, near syncope, or dizziness related to treatment.

Blood was drawn at the end of 12 weeks to determine trough plasma CoQ levels, but the plasma half-life of oral CoQ is 20 to 36 hours, with peak blood levels achieved 6 hours after an oral dose. (41) Thus, after 12 weeks of treatment, peak-trough differences would be expected to be slight. Twice a day dosing was chosen to attempt to maximize absorption.

Given as a single agent, CoQ achieved a reduction in blood pressure in 55% of patients (>7 mm Hg in 43 of patients), which is less than some prescription agents. However, CoQ is well tolerated and has a high therapeutic index. (40) With the increasing interest of patients in alternative or complementary forms of treatment, (42) a trial of CoQ may be welcomed by patients with hypertension. Further studies to investigate the clinical utility and mechanism of action of this unique antihypertensive agent seem warranted.

Acknowledgments: We thank Raj Chopra, president of Tischon Corp, New York, for the CoQ used in this study; Mohammed Abdel Barr for performing the high-performance liquid chromatography analysis; and Hemmi Bhagavan, MD, and Barry Gusack, MD, for their suggestions and advice.

References

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TABLE 1. Patient Exclusion Criteria

Type 1 or type 2 diabetes mellitus 

History of myocardial infarction, cerebrovascular accident, transient ischemic attack, congestive heart failure, cardiac arrythmia, angina, or renal disease

Body mass index > 40

Presence of proteinuria > trace

Creatinine > 1.8 mg/dL

Any cause of secondary hypertension

Abnormal electrocardiogram 

Use of vitamin, mineral, or nutritional supplements other than a simple multiple vitamin

Age < 50 yr or > 75 yr

Currently using tobacco products

TABLE 2. Characteristics of Patients With Isolated Systolic Hypertension
(ISH) at Enrollment

Characteristic                          ISH Placebo

Age (yr)                              67.3 [+ or -] 3.4
Creatinine (mg/dL)                     0.9 [+ or -] 0.1
AST                                   35.3 [+ or -] 6.0
Sodium                               136.2 [+ or -] 4.5
Potassium                              4.2 [+ or -] 0.7
BMI                                     23 [+ or -] 2.2
Average SBP (mm Hg)                  164.4 [+ or -] 5.2
Average DBP (mm Hg)                   82.0 [+ or -] 2.2
ECG                                  Sinus; no Q waves
Time since diagnosis (yr)              6.7 [+ or -] 41
Male/female                                18/14
Percent of patients taking a statin        10/32

Characteristic                            ISH CoQ

Age (yr)                              69.7 [+ or -] 4.1
Creatinine (mg/dL)                     1.1 [+ or -] 0.2
AST                                   29.9 [+ or -] 4.3
Sodium                               142.1 [+ or -] 3.8
Potassium                              3.7 [+ or -] 0.4
BMI                                     24 [+ or -] 1.9
Average SBP (mm Hg)                  165.1 [+ or -] 4.9
Average DBP (mm Hg)                   80.9 [+ or -] 1.6
ECG                                  Sinus; no Q waves
Time since diagnosis (yr)              8.1 [+ or -] 6.3
Male/female                                21/18
Percent of patients taking a statin        14/39

Characteristic                        Normotensive CoQ

Age (yr)                              64.9 [+ or -] 5.9
Creatinine (mg/dL)                     1.2 [+ or -] 0.1
AST                                   43.4 [+ or -] 8.7
Sodium                               139.7 [+ or -] 6.6
Potassium                              4.4 [+ or -] 0.5
BMI                                     21 [+ or -] 2.4
Average SBP (mm Hg)                  137.6 [+ or -] 7.1
Average DBP (mm Hg)                   78.6 [+ or -] 3.8
ECG                                  Sinus; no Q waves
Time since diagnosis (yr)              5.5 [+ or -] 7.1
Male/female                                 5/4
Percent of patients taking a statin         3/9

AST = Aspartate aminotransferase, BMI = body mass index, SBP = systolic
blood pressure, DBP = diastolic blood pressure, ECG = electrocardiogram
TABLE 3. Blood Pressure Response, Orthostatic Changes, and CoQ Plasma
Levels in Patients Treated with CoQ or Placebo

                             Isolated Systolic
                               Hypertension
                                    CoQ
Parameter                        Before

SBP (mm Hg)                165.1 [+ or -] 4.9
DBP (mm Hg)                 80.9 [+ or -] 1.6
Orthostatic change in SBP   -4.4 [+ or -] 5.3
Plasma CoQ (mg/mL)          0.47 [+ or -] 0.19

                                Isolated Systolic
                                  Hypertension
                                       CoQ
Parameter                           After

SBP (mm Hg)                147.3 [+ or -] 7.6 (*)(+)
DBP (mm Hg)                 78.3 [+ or -] 2.9
Orthostatic change in SBP   -5.6 [+ or -] 6.4
Plasma CoQ (mg/mL)          2.69 [+ or -] 0.54 (*)

                                 Isolated Systolic Hypertension
                                            Placebo
Parameter                        Before               After

SBP (mm Hg)                164.4 [+ or -] 5.2   162.7 [+ or -] 5.8
DBP (mm Hg)                 82.0 [+ or -] 2.2    81.5 [+ or -] 3.1
Orthostatic change in SBP   -6.1 [+ or -] 7.1    -4.2 [+ or -] 8.2
Plasma CoQ (mg/mL)          0.55 [+ or -] 0.24   0.53 [+ or -] 0.31

                                            Normotensive
                                                CoQ
Parameter                        Before                 After

SBP (mm Hg)                137.6 [+ or -] 7.1   140.2 [+ or -] 6.3
DBP (mm Hg)                 78.6 [+ or -] 3.8    79.0 [+ or -] 2.4
Orthostatic change in SBP   -4.3 [+ or -] 6.6    -3.9 [+ or -] 7.9
Plasma CoQ (mg/mL)          0.49 [+ or -] 0.14   2.50 [+ or -] 0.61 (*)

SBP = systolic blood pressure, DBP = diastolic blood pressure.

(*)P<.01 compared with before treatment values (one-way ANOVA); values
expressed as mean [+ or -] SEM.

(+)P<.01 compared with after placebo treatment (one-way ANOVA); mean
[+ or -] SEM.

RELATED ARTICLE: KEY POINTS

* CoQ has a high therapeutic index and is well tolerated.

* Patient compliance with BID dosing was more than 90%.

* Although less effective than many prescription drugs as a single agent, patient satisfaction was high in those patients where CoQ was effective.

* CoQ is a safe, well-tolerated agent that may be offered to hypertensive patients who have an interest in alternative or complementary treatment modalities.

* Cost for a 60 mg BID regimen is in the range of $25 to $35 per month.