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  1. 1. 007-014 Belcaro 27/01/10 10:29 Page 7 ARTÈRES 7 Supportive Treatment with CoenzymeQ10 in Heart Failure: The Irvine3 Labs Study on Heart Failure in Vascular Patients G. BELCARO MD, PhD, M. R. CESARONE MD, A. LEDDA MD, U. CORNELLI MD, M. DUGALL BA, S. STUARD MD, E. IPPOLITO MD, M. G. GROSSI, I. RUFFINI MD IRVINE3 CARDIOVASCULAR LABS – DEPT. BIOMEDICAL SCIENCES – CHIETI-PESCARA UNIVERSITY SUPPORTED BY THE MINISTRY OF UNIVERSITY, SCIENCE & TECHNOLOGY (MURST) AND ISVI (Italian Society for Vascular Investigations) Corresponding Author: Gianni Belcaro, MD, PhD, C.So Umberto I, 12, San Valentino Vascular Screening Center, 65020 San Valentino, PE, ITALY – cardres@abol.it Conflict of Interest: There was no conflict of interest. fraction improved (from 25.7%; range 17-40 to 29.2%; 18- None of the authors were connected in any way with the 44*; p<0.05; variation equivalent to a 4.5% increase). The product quoted in this article. CoQ10 was not supplied by a improvement in walking distance was 45.7% of the initial specific company but acquired by commercial producers not value (p<0.05); the Karnofski scale value improved from an related in any way to the study. initial median of 57.7 to 63.2 (p<0.05); (5, 5% increase). Conclusion. CoQ10 supplement improves both clinical Abstract and physiological parameters in HF. Low CoQ10 values may increase mortality in HF, but supplementation may be use- The aim of this registry was the evaluation of the clini- ful to improve clinical parameters and, possibly, outcome cal value of CoQ10 in heart failure (HF) during a 12-week and mortality. observation period. Patients with stable congestive HF (NYHA class II-III), limited exercise capacity (Karnofsky scale Key Words: Heart failure, ejection fraction, NYHA value between 50 and 70) and reduction in ejection fraction classification, ventricular function, cardiovascular (< 41%) were included. A clinical and physiological evalua- disease, Coenzyme Q10 tion (exercise capacity, ejection fraction) was used. The study focused on vascular patients with past symptoms. A single oral dose of CoQ10 (100 mg/day) was used. 107 Résumé patients (out of 120 included) completed at least 12 weeks. Mean age was 62.4 ± 6.9. No side effects due to CoQ10 Le but de cet article était l’évaluation de la valeur cli- were recorded. Dropouts were due to poor compliance or nique de CoQ10 dans l’insuffisance cardiaque pendant une logistics; 2 patients had hospital admission for emergency; période d’observation de 12 semaines. Les patients avec une 3 patients died for causes related to HF. Other cardiovascu- insuffisance cardiaque (IC) congestive stable (classe II-III lar disease was associated in all patients. NYHA), avec diminution des capacités physiques (échelle de Results. There was a mild decrease in systolic pressures Karnofsky entre 50 et 70) et une réduction de la fraction (p<0.05) and a decrease in heart and respiratory rate d’éjection (< 41%) étaient inclus. Une évaluation clinique et (p<0.05). The average weight of patients decreased physiologique (capacité à l’exercice, fraction d’éjection) (p<0.05); (6.24% less than the initial value). Signs/symp- était utilisée. L’étude s’est focalisée sur les patients vascu- toms improved (improvement of at least 3 symptoms was laires présentant des symptômes anciens. Une seule dose observed in 63% of patients). At 12 weeks we had to real- orale de CoQ10 (100 mg/jour) était prescrite. 107 patients locate NYHA classes: 6 out of 44 patients passed from class (parmi les 120 inclus) ont complété l’étude pendant au II to I, and 9 out of 63 passed from class III to II. In total, moins 12 semaines. L’âge moyen était de 62.4 ± 6.9. Aucun 14.01% of patients passed to the lower class. There was a effet secondaire du CoQ10 n’a été noté. Les sorties d’étude significant improvement in “target measurements”: ejection étaient dues à une compliance insuffisante ou à des pro- ANGÉIOLOGIE, 2010, VOL. 62, N° 1
  2. 2. 007-014 Belcaro 27/01/10 10:29 Page 8 8 ARTÈRES blèmes logistiques ; 2 patients ont été hospitalisés en mortality in HF. CoQ10 deficiency may alter the long-term urgence ; 3 patients sont décédés de cause liée à l’IC. Une prognosis of HF. This study (3) suggested that there is a autre pathologie cardiovasculaire était associée chez tous rationale for interventional studies using CoQ10 as a sup- les patients. plement in most patients with HF. Other studies (4-8) also Resultats. On a noté une légère diminution des pres- indicate the important potential role of CoQ10 in patients sions systoliques (p<0.05) et une diminution des fré- with heart failure. quences cardiaques et respiratoires (p<0.05). Le poids CoQ10 is considered a key, essential element within moyen des patients a diminué (p<0.05); (6.24% de moins the mitochondrial chain as it contributes to the produc- que le poids initial). Les signes et symptômes se sont amé- tion of ATP (3,9). CoQ10, present in myocardial biopsies liorés (une amélioration d’au moins 3 symptômes a été from patients, tends to be decreased in patients with HF observée chez 63% des patients). A 12 semaines, nous (10). Its correct levels may contribute to the modulation avons reclassé les patients selon la classification NYHA : 6 of the most effective performance of normal hearts and patients sur 44 sont passés de la classe II à la classe I, et particularly of failing hearts. 9 sur 63 de la classe III à II. Au total, 14,01% des patients Several studies show the effects of CoQ10 supple- sont repassés dans une classe inférieure. Il y a une amé- mentation to be the “best cardiological therapy” in lioration significative des « objectifs cibles »: la fraction improving HF, particularly when CoQ10 levels are low d’éjection a été augmentée de 25.7% (écart type : 17-40) (2-3,11-16), i.e., in patients using statins. It has been à 29.2% (écart-type : 18-44*); (p<0.05); (variation équi- shown that both low levels of total cholesterol and valente à une augmentation de 4.5%). L’amélioration du CoQ10 (linked to the same metabolic pathways) contri- périmètre de marche était de 45.7% par rapport aux bute to higher mortality in HF patients and that higher valeurs initiales (p<0.05); l’échelle de Karnofski était amé- total cholesterol levels (and CoQ10 levels) are associa- liorée d’une moyenne initiale de 57.7 à 63.2 (p<0.05); (5, ted to a decreased mortality in these patients. 5% d’augmentation). In prospective studies it has been shown that after Conclusion. La supplémentation en CoQ10 améliore à la administration of CoQ10 for 2-4 weeks there is an fois les paramètres cliniques et physiologiques dans l’IC. Des increase in ejection fraction and workload capacity. This valeurs basses en CoQ10 peuvent augmenter la mortalité generally results in an improvement in NYHA functional dans l’IC, mais la supplémentation pourrait être utile pour class (17) and in a significantly lower mortality rate in améliorer les paramètres cliniques et, vraisemblablement, le long-term studies (11,14) when CoQ10 is added to the pronostic et la mortalité. most updated therapy for HF. The aim of this prospective study – still in progress – Mots-Clés : Insuffisance cardiaque, fraction was the evaluation of the clinical value of CoQ10 sup- d’éjection, maladie d’éjection, maladie cardiovas- plements in a 12-week observation period. We included culaire, coenzyme Q10 in the registry (according to the protocol of the Italian Multicenter Study) (2) subjects with stable (within the *** previous 6 months) congestive HF (NYHA class II-III), limited exercise capacity, a Karnofsky scale (18-21) Introduction value ranging between 50 and 70, and a stable reduc- tion in ejection fraction < 40%. In patients with heart failure (HF), the reduced effi- According to the NYHA classification, Class II (mild) ciency of the myocardium is generally associated with a includes patients with slight limitation of physical acti- reduced supply of calcium ions to contractile muscular vity. They are comfortable at rest, but ordinary physical proteins. The impairment of energy-dependent calcium activity results in fatigue, palpitation, or dyspnea. ion transport is a very early key element that has an Patients in Class III (moderate) show a marked limitation important role in the progression of signs and symptoms of physical activity. They are comfortable at rest, but linked to HF (1, 2). less than ordinary activity causes fatigue, palpitation, or An important Italian multicenter study that included a dyspnea. large number (2664) of patients with HF has indicated that The registry protocol was initially comparable to the signs and symptoms significantly and clinically improve, as study protocol of the Italian Multicenter study on the well as the quality of life (2), with the use of coenzyme Q10 Safety and Efficacy of CoQ10 in HF (Baggio E et al, (1)). (CoQ10) as an adjunctive treatment for HF for only 3 Even with some modifications in our study, this protocol months. A recent study from Molyneux (3) has shown that offers comparative data specific to our population. To plasma CoQ10 concentrations are independent predictors of this study protocol we added a more functional and ANGÉIOLOGIE, 2010, VOL. 62, N° 1
  3. 3. 007-014 Belcaro 27/01/10 10:29 Page 9 ARTÈRES 9 Table 1. Inclusion criteria and main measurements. physiological evaluation (exercise capacity and varia- tions in ejection fraction). Also this specific study was Exclusion: Alvular disease (hemodynamically mainly focused on vascular/angiological patients with significant) symptomatic (in the past) vascular problems. Recent, acute MI (previous 3 months), Angina Congenital heart disease Patients and methods Severe hypertension Diabetes and metabolic diseases requiring Inclusion and exclusion criteria are shown in Table 1. treatment Essential for inclusion was a constant treatment in the pre- Surgery for cardiac revascularisation vious 3 months and stability in the NYHA class in the pre- (within previous 3 months) vious 6 months. TIAs or strokes within the previous 6 months Adverse reactions to CoQ10 or other comparable com- Severe (requiring treatment) neurological, pounds forced exclusion. We also excluded subjects using renal, hepatic or metabolic disease statins or other lipid-lowering agents, focusing, in the case NYHA functional class I and IV of high cholesterol levels (>220), on a specific diet, as sta- Inclusion: Heart failure diagnosed and stable for at tins may have an important effect on CoQ10. least 6 months before Inclusion. Informed consent Clinical evaluation MAIN TARGET MEASUREMENTS: A: Ejection Fraction <41% A 2 to 7 point scale for signs and symptoms (Table 2) was B: Walking Distance <200 m used to evaluate the clinical picture according to the IMS C: Karnofsky Scale (between 50 and (2). Cyanosis was scaled between 0 and 3; edema 0-3; pul- 70%) monary crepitations/rales 0-4; enlargement of the liver 0-3; jugular reflux 0-2; dyspnea 0-6; palpitations 0-3, insomnia Table 2. Assessment of signs and symptoms. The 2 to 7 0-3; sweating 0-1; subjective arrhythmia 0-3; vertigo 0-3; point scale according to Baggio E (2) used for assessment and nocturia 0-3. of signs/symptoms in the IMS. Patients SIGN/SYMPTOM SCORE Cyanosis 0-3 Edema 0-3 A group of 234 patients was screened; 107 were inclu- Pulmonary rales 0-4 ded mainly due to their stability and possible compliance. Enlargement of liver 0-3 The therapy used for these patients was considered to be Jugular reflux 0-2 the “best treatment” according to the AHA guidelines (15) Dyspnea 0-6 as given by their cardiologists. There was no interference on Palpitations 0-3 the treatment prescribed by the cardiologists. Insomnia 0-3 Sweating 0-1 Subjective Arrhythmia 0-3 Evaluation of the Left Ventricular Function Vertigo 0-3 Nocturia (voiding at night) 0-3 A Terason, Prosound ultrasound system, (Aloka, Japan) with a 4V2 A probe was used. Left ventricular volume was calculated according to the Simpson rule following the gui- km/h for 3 minutes or less, depending on patients’ condi- delines issued by the American Society of Echocardiography. tions and signs/symptoms; the total distance was the mea- The analysis of the left ventricular volumes includes measu- surement in meters of the total distance the patient was rements of end-diastolic and end-systolic left ventricular able to walk. No patient was actually able to complete the volumes. Calculation of the ejection fraction (EF%) was 3-minute test. made from the apical projection (4-chambers). An EF < 40% (23-26) was part of the inclusion criteria for all patients. Main “Target” Measurements Exercise treadmill (27) The main physiological and clinical targets (in addition to the observations replicating the IMS) were the evaluation of: The test was performed according to our vascular labo- A. Ejection Fraction: measured as percent of left ventri- ratory standards. A treadmill was used at the speed of 3 cular volume (expressed as median and range). ANGÉIOLOGIE, 2010, VOL. 62, N° 1
  4. 4. 007-014 Belcaro 27/01/10 10:29 Page 10 10 ARTÈRES Table 3: the Karnofsky Performance Scale Index classifies B. Walking Distance: measured in meters (mean and SD). patients according to their functional impairment. The The patients were able to walk. scale is used to compare effectiveness of different thera- C. Karnofsyi Scale (Table 3). Patients were unable to pies and to assess the prognosis in individual patients. The work but were able to live at home and care for most lower the Karnofsky score, the less chance for survival. personal needs. Varying amounts of assistance were needed. Subjects with scores (%) between 50 and 70 KARNOFSKY PERFORMANCE STATUS SCALE DEFINI- were included. Patients with a score of 70 were able TIONS RATING (%) CRITERIA to care for themselves but were unable to carry on normal activity or to do active work. Patients with a Able to carry on normal activity and to work; no spe- cial care needed. score of 60 required occasional assistance but were able to care for most of their personal needs. Patients 100 Normal, no complaints; no evidence of disease. 90 Able to carry on normal activity; minor signs or with a score of 50 required considerable assistance symptoms of disease. and frequent medical care. All measurements were 80 Normal activity with effort; some signs or expressed in percentage (median and range). symptoms of disease. Unable to work; able to live at home and care for Daily dosage of Pycno-CoQ10 most personal needs; varying amount of assistance needed. The daily dosage (according to the Italian Multicenter 70 Cares for self; unable to carry on normal acti- Study, IMS) was initially established at 100 mg of oral vity or to do active work. CoQ10. Overweight subjects (>95 Kg) and smaller or 60 Requires occasional assistance, but is able to underweight subjects (<50 Kg) were excluded to keep the care for most of his personal needs. doses geared to a standard population sample. Non-bran- 50 Requires considerable assistance and frequent medical care. ded, commercially available 100mg capsules were used and given in unmarked boxes of 150 capsules. Interactions Unable to care for self; requires equivalent of institu- tional or hospital care; disease may be progressing with other drugs or products active on the gastrointesti- rapidly. nal tract and on the absorption of CoQ10 were carefully 40 Disabled; requires special care and assistance. excluded. One single daily dose was used between 8 and 30 Severely disabled; hospital admission is indica- 10 am. ted although death not imminent. 20 Very sick; hospital admission necessary; active Statistical Anaylsis supportive treatment necessary. 10 Moribund; fatal processes progressing rapidly. Statistics were analyzed with a Sigma-Plot program. The 0 Dead variability of testing was considered: a variation in ejection fraction <4% was considered normal in both intra-indivi- Differences in demographic parameter (in patients survi- dual and inter-individual measurements. A variation of ving the 3-month study period) were compared using the <5% of treadmill distance was considered within normal Mann-Whitney rank sum U-test and chi-square test intra-individual and inter-individual measurements when (Pearson chi-square-2 sided asymptotic significance) accor- repeating the test. Therefore, to be clinically significant an ding to Molineux (3). improvement in ejection fraction and in treadmill distance >4% was considered the cut-off point necessary to define Informed Consent “improvement” in time that may be attributed to treatment or management. Descriptive statistics with median and Oral, witnessed consent was obtained by all incuded range (percentages) or mean with standard deviation and subjects. range were used for continuous or parametric variables while non-continuous variables (i.e. signs/symptoms) were Results expressed as percentage and frequency. Analysis of the variations between inclusion and after- Details of patients are shown in table 4: 107 patients treatment values was made with the t test (for normally out of 120 completed the follow up (at least 12 weeks). distributed parameters) or using the Wilkoxon signed-rank Their mean age was 62.4 ±6.9 (range 45-70); the mean test for scores (signs/symptoms); chi-squared and Mann duration of heart failure before inclusion was of 32.2 ± Whitney U-test were used for frequency data and percen- 4.3 months. tages. P< 0.05 was considered as the significance level. No side effects due to CoQ10 treatment were recorded. ANGÉIOLOGIE, 2010, VOL. 62, N° 1
  5. 5. 007-014 Belcaro 27/01/10 10:29 Page 11 ARTÈRES 11 Table 4: Details of patients completing the study. Table 5: Results. Number Drop outs Deaths BLOOD PRESSURE At inclusion After treatment No. patients Total 107 Supine Systolic 144.3;12.4 141.1;7.8* Class II 44 (41.12%) 7 1 Diastolic 81.2;7.9 80.1;6.6 Class III 63 (58.8%) 6 2 Sitting Systolic 146.3;11.1 142.2;8.4* Diastolic 82.1;6.8 80.2;7.1* Mean age 62.4;6.9 range 45-70 Heart rate 79.2;9.2 76.1;7.7* Mean duration of heart failure 32.2;4.3 months Respiratory rate 22.8;4.1 21.1;4.5* Most used standard treatments at inclusion: Serum Na mmol/l 142.3;11.1 141.5;10.2 TREATMENTS (% of patients) Serum K mmol/l 4.19;0.6 4.2;0.5 Digitalis 36.1 Diuretics 57.2 Table 6: Trial results: variation in signs and symptoms. ACE-inhibitors 33.5 Ca Antagonists 11.3 Present % IMPROVED AT Inotropic agents 12.1 At inclusion LEAST 1 POINT Nitrates 7.9 AFTER TREATMENT Others 14.3 SIGNS - Cyanosis 26% 77.6 There was a total of 13 drop-outs (7 in NYHA class II and - Edema 78% 81 6 in class III): 4 were due to poor compliance, 7 were lost to - Pulmonary follow up for logistical reasons, and 2 had hospital admis- crepitations 75% 79 - Liver enlargement 57% 52 sion for severe emergency care followed by surgery (and - Jugular reflux 33% 76 therefore were considered excluded). Three patients died for causes related to heart failure (one was in NYHA II and 2 in SYMPTOMS NYHA III). - Dyspnea 93% 66 - Palpitations 83% 79 Other cardiovascular disease was associated with HF in - Sweating 45% 72 all patients: 45% of these patients had stenotic carotid - Subjective (22% symptomatic in the past) and/or femoral atherioscle- arrhytmia 46% 76 rotic plaques (symptomatic in the past in 38% patients) - Insomnia or with aortic dilatations (23% of patients) and real aneu- sleep disturbances 61% 71 rysms (12% of patients) with maximum diameter >4 cm. In - Dizziness 58% 78 35% of the subjects symptomatic peripheral arterial disease - Nocturia 62% 51 was associated with intermittent claudication. In most patients the vascular problems were multiple. centage of patients with specific signs/symptoms at inclu- The most used treatments at inclusion are shown in sion and at 12 weeks is also indicated in table 6. Table 4. These treatments were maintained in most patients At 12 weeks we had to reallocate NYHA classes because (89%) during the follow up period, as one of the aims of the 6 out of 44 patients passed from class II to I, and 9 out of study was to evaluate stable patients. One-drug treatment 63 patients passed to class II from the initial class III. In was used in only 6% of patients, but 3 (or more) drugs were total 15 patients out of 107 (14.01%) passed to the lower used for treatment in 79% of these patients. class. Variations in blood pressure and heart rate are shown in No progression (no increase in NYHA class) was observed Table 5. There was a mild decrease in both systolic pressures in these patients. and in the sitting diastolic pressure (p<0.05) and a decrease No significant alterations in blood tests were seen in 3 in heart rate and respiratory rate (p<0.05). Plasma Na and months. K did not have significant changes. The average weight of patients decreased (p<0.05) from Main Target Measurements (table 7) an average value of 86.5;5 Kg to 81.1;4.4 (6.24% less than the initial value). There was a significant improvement in the three “target All clinical signs and symptoms improved at least 1 point measurements” as the ejection fraction improved from the in most patients (Table 6). Improvement of at least 3 symp- initial median value of 24.7% (range 17-40) to 29.2% (18- toms/signs was observed in 63% of all patients. The per- 44)* (p<0.05; variation equivalent to a 4.5% increase). The ANGÉIOLOGIE, 2010, VOL. 62, N° 1
  6. 6. 007-014 Belcaro 27/01/10 10:29 Page 12 12 ARTÈRES Table 7: Main target measurements CoQ10 in the myocardium of patients with HF is INCLUSION 12 WEEKS generally low (3). The association between low levels of CoQ10 and lowered survival rates has promoted a num- A: EJECTION FRACTION 24.7% 29.2% ber of trials to study CoQ10 in HF (12, 31-34). With these (%) (range 17-40) (18-44)* studies it was possible to show improvements in clinical B: WALKING DISTANCE parameters as well as in physiological measurements (m) 105 153 such as stroke volume, ejection fraction, and cardiac C: KARNOFSKY SCALE output after supplementation with CoQ10 for various (%) 57.7(40-69) 63.2 (49-74)* periods (31-35). With an improvement in technology, a better evaluation of the left ventricular function in HF * p<0.05 (36-37) will probably allow a more precise quantitative measurement of ventricular function in association with improvement in walking distance was 45.7% of the initial treatment. value (p<0.05), and the Karnofsky scale value improved The connection between CoQ10 decreased levels and from an initial median of 57.7(range 40-69) to 63.2 (range “statin-related myopathy,” which may be associated to 49-74) (p<0.05; equivalent to a 5,5% increase). some kinds of HF, needs a different investigational approach and a much larger study (38). Conclusions The role of statins in accelerating or even causing HF is often controversial and still in evaluation. It may be particu- In this study blood pressure and heart rate decreased, larly important considering the diffusion of statin treatment. confirming results from previous studies (28). An important At the moment, an international multicenter, randomi- reduction in peripheral vascular resistance is possibly due to zed, double-blind trial (Q-SYMBIO) is focusing on signs and the inhibition by CoQ10 of the sympathetic overactivity symptoms, bloodmarkers (B-type natriuretic peptide) and present early in heart failure in most patients (29,30). long-term outcomes (35) in HF patients. These results suggest that CoQ10 supplements improve HF in most patients in classes II and III. Patients in NYHA Conclusion class II appear to show better results with CoQ10. The improvement was present in more than 85% of all Low CoQ10 may be associated with HF or aggravate the included patients. CoQ10 showed a good tolerability and no clinical situation. Low levels may also increase mortality side effects were recorded. Results in our population sample rates in HF. According to this open preliminary study, sup- are broadly comparable to the observations from the Italian plementation improves clinical and physiological parame- Multicenter Study lead by Baggio, including 173 centers (2). ters and, possibly, outcome and mortality. Also, results from this study repeat the results obtained by Judy (11) and Langsjoen (14) and are comparable to the Acknowledgements results recently obtained by Molyneux (3). The bad tolerability of CoQ10 supplements is usually We are very grateful to Prof. A Barsotti (University of transient or marginal and can be controlled either by redu- Genoa) former director of the school of Cardiology Chieti- cing dosage or suspending treatment. Pescara University, and Prof. F Caciagli, Dept. Biomedical The observed independent association between low Sciences, G D’Annunzio University), Deutsche Bank. levels of CoQ10 and increased mortality due to HF is grea- ter than the strength of the association observed for NT- References proBNP (3). CoQ10 deficiency is observed in HF. This metabolic situa- 1. Wexler LF. Metabolic considerations in excitation- tion compromises mitochondrial functions (10) constituting contraction-relaxation coupling. Heart failure 1990;3: an important cause of worsening outcome in HF. It is pos- 251-4. sible that different levels of HF may respond differently to 2. Baggio E, Gandini R, Placher AC, Passeri M, Garmosino variations (in case of deficiency and after supplementation) G. Italian multicenter study on the safety and efficacy in CoQ10. Dosages, time of duration of treatment for diffe- of Coenzyme Q10 as adjunctive therapy in heart failure. rent types of patients or patients with different ages, and Molec Aspects Med 1994;15:287-94. interaction or interferences with other products used in the 3. Molyneux SL, Florkowski CM, George PM, Pilbrow management of cardiovascular patients (i.e. statins) of HF AP, Frampton CM, Lever M, Richards AM. Coenzyme patients should be evaluated in larger, prospective studies. Q10: an independent predictor of mortality in chro- ANGÉIOLOGIE, 2010, VOL. 62, N° 1
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