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PANMINERVA MED 2010;52(Suppl.

1 to No 2):21-5

Investigation of Pycnogenol in combination with coenzymeQ10 in heart failure patients (NYHA II/III)

Aim. In this study we investigated benefits of a Pycnogenol coenzyme Q10 combination (PycnoQ10) taken as an adjunct to medical treatment in stable heart failure patients. The aim of this single-blinded, 12-week observational study was to provide functional parameters such as exercise capacity, ejection fraction and distal edema. Methods. The essential element for inclusion was a stable level of heart failure within the past three months and stable NYHA class II or III (6 months). The heart failure management was in accordance with AHA guidelines for best treatment. The treatment and control groups were comparable at baseline. The mean age of the PycnoQ10-treated patients was 61.37.1 years and 62.13.7 in the control group. All patients were taking medication and most patients (>75%) used three or more drugs for heart failure treatment. There were two dropouts in the PycnoQ10 treatment group and 6 in the control group (5 NYHA III patients). Results. Nine PycnoQ10 treated patients (out of 32) and 3 (out of 21) taking placebo improved NYHA class. Systolic and diastolic pressure as well as heart rate and respiratory rate were significantly lowered with PycnoQ10 as compared to the control group (P<0.05). No significant changes were observed in controls. Heart ejection fraction increased by 22.4% in the treatment group (P<0.05) versus 4.0% in controls. Walking distance on treadmill increased 3.3-fold in PycnoQ10 treated patients (P<0.05) but marginally improved in the control group. Distal edema decreased significantly in PycnoQ10 treated patients and only slightly in controls. Conclusion. The association of Pycnogenol and CoQ10 may offer an important therapeutic option with a very good tolerability that improves heart failure management without side effects. KEY WORDS: Heart failure - Cardiovascular disease, prevention and control - Ventricular function - Pycnogenol.
Conflict of interest.None. Acknowledgements.This study was supported by the Ministry of University, Science & Technology (MURST) and ISVI (Italian Society for Vascular Investigations). Corresponding author: G. Belcaro, MD, PhD, Irvine3 Circulation/ Vascular Labs, Chieti-Pescara University, SS 16bis, 94 (A), Spoltore, 65100 Pescara, Italy. E-mail: cardres@abol.it

Irvine3 Labs Department Biomedical Sciences Chieti-Pescara University, Pescara, Italy

eart failure is a clinical syndrome in which signs and symptoms are due to increased extravascular fluid and decreased tissue/organ perfusion. The etiologies leading to heart failure are diverse; major characteristics are a weakened myocardium and progressive ventricular remodeling.1 The Italian multicenter study with 2664 patients has indicated that using coenzyme Q10 (CoQ10) as an adjunct to standard treatment for 3 months significantly improved clinical signs and symptoms of heart failure as well as the quality of life of these patients.2 An investigation of chronic heart failure patients showed that plasma CoQ10 concentrations represent an independent predictor of mortality.3 CoQ10 deficiency may alter the long-term prognosis of HF. CoQ10 is a key, essential element within the mitochondrial chain that contributes to the production of ATP in heart muscle.4 CoQ10 in myocardial biopsies is decreased in most patients with heart failure.5 The usefulness of coenzyme Q10 in clinical cardiology has been demonstrated in long-term studies.6 Cardiovascular risk factors involved in the etiology of heart failure may be improved by Pycnogenol (trademark of Horphag Research) pine bark.7 Pycnogenol significantly improves endothelial function and consequently improves hypertension as well as long-term consequences such as renal function problems.8-10 In preclinical studies Pycnogenol was shown to counter-

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act left ventricular remodeling as myocardial total collagen increased and cardiac gene expression patterns for matrix metalloproteinases MMP-2, -9, and -13, and MMP-9 activity were significantly decreased.11 It was previously proposed that the activities of CoQ10 and Pycnogenol would mutually and perhaps synergistically act to improve vascular and heart health.12 The aim of this single-blinded, prospective study was the evaluation of the efficacy of combined CoQ10 and Pycnogenol PycnoQ10 (trademark of Horphag Research) supplementation in a 12-week single blinded, placebo-controlled observation period with stable congestive heart failure patients (NYHA class II and III).
Materials and methods

and CoQ10, and the second group received comparable placebo capsules in addition to their individual medications. The PycnoQ10 and placebo capsules were manufactured by Pharmanord (Vejle, Denmark) PycnoQ10 capsules contained 50 mg CoQ10 (Kaneka) and 15 mg Pycnogenol (Horphag Research). The gelatin capsules are filled with palm oil and weigh 0.73 g. Patients were instructed to take 7 capsules a day, in the morning after breakfast.

All evaluations were performed as described in our previous study on heart failure.13 LEFT VENTRICULAR FUNCTION

We recruited patients diagnosed with heart failure with an ejection fraction lower than 40%. Patients had been diagnosed for heart failure for at least six months and were required to be in a stable condition and had not required any changes to their medication regimen for at least the past 3 months. The heart failure status was required to be stable as judged by an unchanged NYHA classification class II (mild) or class III (moderate) during the previous six months.

A Terason, Prosound ultrasound system (Aloka, Japan) with a 4V2 A probe was used. Left ventricular volume was calculated using the Simpson rule according to the guidelines issued by the American Society of Echocardiography. The analysis of the left ventricular volumes includes measurements of end-diastolic and end-systolic volumes. Calculation of the ejection fraction (EF%) was made from the apical projection (4chambers).14 WALKING DISTANCE A treadmill was used at the speed of 3 km/h, with no inclination, for up to 3 minutes or longer if the patients conditions and signs/symptoms allowed. The distance was measured in meters of the total distance the patient was able to walk.

Exclusion criteria
Patients requiring medication for severe neurological, renal, hepatic or metabolic diseases were excluded. Patients with myocardial infarction, angina, congenital heart disease or surgery for cardiac revascularisation within the past 3 months were also excluded. Patients with hemodynamically significant vascular diseases were excluded. Patients who had a transient ischemic attack or stroke within the past six months were considered unsuitable. Patients with high cholesterol levels requiring medication with HMG-CoA reductase inhibitors (statins) were excluded as these influence CoQ10 levels. All patients received a therapy regarded as best treatment according to American Heart Association standards. There was no influence or interference with treatment prescribed by the cardiologists.

Karnofsky performance status scale

For judgment of the patients overall health status the Karnofsky scale was employed.15

Leg edema
Edema control below the knee was considered a very important key element. We included edema evaluation using below-knee foot/leg volumetry. The initial volumetric value in all subjects was defined as 100%, and the following variations in volume were measured with variations given as percentages. All measurements were carried out early in the morning before 10 a.m. in a standing position.

Treatment regimen
Patients were divided into two groups: one group received capsules with a combination of Pycnogenol



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TABLE I.Medication classes taken by patients.

Used Treatments PycnoQ10 Controls

TABLE II.Variations in blood pressure, heart and respiration rate and K/Na.
Treatment Controls

Digitalis Diuretics ACE-inhibitors Ca Antagonists Inotropic agents Nitrates Others

12/32 26/32 13/32 7/32 8/32 8/32 17/32

8/21 14/21 7/21 6/21 5/21 4/21 10/21

Statistical analysis
The variation of results (i.e. ejection fraction) were considered to be non-parametric. These observations were evaluated using the analysis of the variance (ANOVA with Bonferroni correction). Considering possible intra-individual and inter-individual data variations, it was considered necessary to have at least 20 subjects complete the study. This figure was based on our previous study in order to overcome spontaneous variations and temporal variability.13 Heart failure and its related signs/symptoms, even in conditions of relative stability, may have periods of variability associated with spontaneous periods of improvement. Clinical variations in ejection fraction, walking distance, edema and the Karnofsky scale may be due to different clinical and non-clinical (i.e environmental or climatic) factors including individual, psychological and drug-related elements.

Systolic pressure (mmHg) Diastolic pressure (mmHg) Heart rate (min-1) Respiratory rate (min-1) Serum Na (mmol/L) Serum K (mmol/L)

Before After Before After Before After Before After Before After Before After

139.210.3 133.28.5* 82.38.2 77.37.4* 78.48.3 74.25.4* 23.13.2 21.23.1* 142.610.2 143.310.1 4.31.1 4.20.8

140.38.2 139.58.3 83.47.3 81.28.5 79.18.2 78.45.3 23.33.4 22.34.1 143.39.8 143.611.2 4.4 ;0.9 4.21.1

*P<0.05; significant difference between initial and final values and in comparison with the control group (Wilcoxon).

ment group, both with NYHA III classification. In the control group one patient with NYHA II and another five with NYHA III dropped out. Of the latter, one patient suffered from pneumonia and another with a cerebrovascular accident. All other dropouts were due to non-medical problems, such as difficulty reaching the follow-up center, missed appointments, or missed tests. NYHA CLASS Four patients (out of 24) improved and passed from NYHA class II to class I: 3 were treatment patients and 1 was a control (P<0.05). Eight patients (out of 29) in class III passed to class II: 6 were treatment patients and 2 were controls (P<0.05). BLOOD PRESSURE, HEART RATE Table II shows the average values of blood pressure at inclusion and after 12 weeks. All included patients could be defined as having mild to moderate hypertension. Their blood pressure was under stable control with one drug (10 out of 24 in PycnoQ10 patients and 18 out of 29 control patients) or two drugs. There was a significant decrease (-8%) of systolic and diastolic pressure as well as a decrease in heart rate in the PycnoQ10 group as compared to marginal improvements in the control group (P<0.05). There was also a significant decrease (-8.225 %) in respiratory rate in Pycno-CoQ10 patients versus the control group (P<0.05). No significant variations were observed in controls. In blood tests (at inclusion and at 12 weeks

Fifty-three patients were enrolled in the study. The treatment and control groups were comparable for age and sex distribution and for their clinical picture. The mean age of the PycnoQ10 treated patients (7 men + 7 women with NYHA class II; 9 men + 9 women with NYHA class III) was 61.37.1 years (range 45-66 years), comparable to the age of the 21 placebo controls (5 men + 5 women NYHA class II and 6 men + 5 women NYHA class III) aged 62.13.7 (range 4567 years. The mean duration of heart failure before inclusion was 9.92.1 months in the verum group, and 10.2 3.1 months in control patients. Prescribed medications of the patients are detailed in Table I. Most patients (>75%) used a combination of medications that included three or more drugs. There were two dropouts in the PycnoCoQ treat-

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TABLE III.Presented are the changes of the heart ejection fraction as median values and range. Patients walking distance is given as meanSD. The Karnofsky scale is given as meanSD. The edema is presented as percentage change to baseline values (set to 100% at baseline) in median values and range after treatment.
PycnoQ10 Controls

leading to edema. No problems in tolerability or compliance were observed during the study.

Before 39.3% (33-45) 39.6% (33-46) After *#48.1% (42-45)*# 41.2% (34-48) Walking distance (meters) Before 74.811 81.312.1 93.218* After 249.417.3*# Karnofksi scale (0-100) Before 43.24.1 44.14.5 After 54.74.7*# 47.25.2 Distal edema (%) Before 100 100 104 (96-109) After 72 (77-65)*#
*Significance between baseline and after treatment; #significance between treatment and control group

Ejection fraction (%)

plus or minus one week) there were no significant variations in serum Na and K. The treatment with PycnoQ10 was found to significantly increase heart ejection fraction by 22.4% after 12 weeks, whereas it slightly, but non-significantly, decreased in the control group (Table III). The improvement with PycnoQ10 was found to be significant as compared to the control group. The physical abilities of patients improved substantially as evidenced by 3.3 times longer walking distance on a treadmill (P<0.05 vs. controls). In the control group the walking distance also significantly improved versus baseline. The quality of life of patients correspondingly improved with PycnoQ10 as validated with the Karnofsky index. At baseline patients had Karnofsky values of 43%, which is categorized as patients are handicapped and dependent on qualified medical help. After 12 weeks treatment with PycnoQ10 the values were up to 54.7%, which Karfnosky describes as Help and medical assistance are often required. No significant improvement of Karnofsky index was seen in the control group. The distal edema, expressed as the percentage of the initial volumetric value (median and range), decreased to 72% in treatment patients (P<0.05) but was increased (+4%) at 12 weeks in controls. The difference between the two groups was significant (P<0.0025) and clinically very important. There was no significant correlation between the increase in EF and distal edema, indicating that the improvement in edema may be associated with a combination of improved ventricular function and possibly to a local, distal decrease in the capillary filtration

In this observational study, blood pressure and heart rate decreased, confirming results from previous studies with CoQ10 as well as with Pycnogenol.10, 16 The decreased blood pressure and heart rate points to a reduction in peripheral vascular resistance as a result of PycnoQ10. Pycnogenol has been extensively researched for endothelial function and anti-hypertensive effects.8-10 Coenzyme Q10 has been ascribed as having a hypotensive effect, which may possibly be prolonged by Pycnogenol.12 These preliminary observations suggest that supplementation with PycnoQ10 as an adjunct to medication may improve heart failure in most patients in NYHA classes II and III. In this study the improvement was present in more than 86% of all patients. PycnoQ10 showed a good tolerability, and no side effects or unwanted effects were recorded. These results in our population sample are comparable to the observations from the Italian Study lead by Baggio which included 173 centers.2 The observations made with CoQ10 in combination with Pycnogenol present with a comparatively better outcome with progressive reduction in heart failure, stabilization of several patients and reduced morbidity. At this stage it is impossible to identify individual contributions of the components of Pycnogenol and CoQ10 that contributed to the improved heart health identified. CoQ10 may be expected to strengthen heart muscle, while Pycnogenol should improve vascular functions. In animal experiments Pycnogenol was found to counteract cardiac extra-cellular matrix remodeling, however, this is unlikely to take place within a short treatment duration of three months.11 Pycnogenol was found to be particularly effective on a number of signs/symptoms present in heart failure, including distal edema (also seen in several clinical conditions).17 Distal edema in these patients may be better controlled using Pycnogenol in association with CoQ10.

In conclusion, the association of Pycnogenol and CoQ10 may offer an important therapeutic option in the



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management and costs of heart failure, without side effects and with a very good tolerability. These initial observations warrant further investigation of the Pycnogenol CoQ10 combination with a much larger number of heart failure patients including a broader range of clinical pictures. References
1. Galderisi M. Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J Am Coll Cardiol 2006;48:154851. 2. Baggio E, Gandini R, Placher AC, Passeri M, Garmosino G. Italian multicenter study on the safety, efficacy of CoQ10 as adjunctive therapy in heart failure. Molec Aspects Med 1994;15:287-94. 3. Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM, Lever M et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol 2008;52:1435-41. 4. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr 2001;20:591-8. 5. Folkers K, Wolaniuk J, Simonsen R, Morishita M, Vadhanavikit S. Biochemical rationale and the cardiac response of patients with muscle disease to therapy with coenzyme Q10. Proc Natl Acad Sci USA 1985;82:4513-6. 6. Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers K. Usefulness of coenzyme Q10 in clinical cardiology: a long-term study. Mol Aspects Med 1994;15 Suppl:s165-75. 7. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse pharmacology. Int J Clin Pharmacol Ther 2002;40:158-68.

8. Nishioka K, Hidaka T, Nakamura S, Umemura T, Jitsuiki D, Soga J et al. Pycnogenol, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertens Res 2007;30:77580. 9. Zibadi S, Rohdewald PJ, Park D, Watson RR. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res 2008;28:315-20. 10. Cesarone MR, Belcaro G, Stuard S, Schnlau F, Di Renzo A, Grossi MG et al. Kidney flow and function in hypertension: protective effects of Pycnogenol in hypertensive participantsa controlled study. J Cardiovasc Pharmacol Ther 2010;15:41-6. 11. Zibadi S, Yu Q, Rohdewald PJ, Larson DF, Watson RR. Impact of Pycnogenol on cardiac extracellular matrix remodeling induced by LNAME administration to old mice. Cardiovasc Toxicol 2007;7:10-8. 12. Watson RR. Nutraceutical Synergism: Pycnogenol and Coenzyme Q10 Enhance Cardiovascular Health. Evid Based Integrative Med 2005;2:67-70. 13. Belcaro G, Cesarone MR, Ledda A, Cornelli U, Dugall M, Stuard S et al. Supportive treatment with coenzymeQ10 in heart failure: the Irvine3 labs study on heart failure in vascular patients. Angeiologie 2010;62:916. 14. Zac V, Ballo P, Galderisi M, Mondillo S. Echocardiography in the assessment of left ventricular longitudinal systolic function: current methodology and clinical applications. Heart Fail Rev 2010;15:23-37. 15. Belcaro G, Cesarone MR, Genovesi D, Ledda A, Vinciguerra G, Ricci A et al. Pycnogenol may alleviate adverse effects in oncologic treatment. Panminerva Med 2008;50:227-34. 16. Digiesi V, Cantini F, Oradei A, Bisi G, Guarino GC, Brocchi A, et al. Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994;15:257-63. 17. Klimas J, Kmecova J, Jankyova S, Yaghi D, Priesolova E, Kyselova Z et al. Pycnogenol improves left ventricular function in streptozotocininduced diabetic cardiomyopathy in rats. Phytother Res 2009;24: 969-74.

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