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Noninvasive evaluation of cardiac hemodynamics during exercise in patients with chronic heart failure: Effects of short-term Coenzyme Q10 treatment
Pergamon
Molec. Aspects Med. Vol. 15 (Supplement),pp. s155-s163, 1994 Copyright (~)1994 ElsevierScience Ltd Printed in Great Britain. All rights reserved. 0098-2997/94 $26.00
0098-2997(94)00022--0
Noninvasive Evaluation of Cardiac Hemodynamics during Exercise in Patients with Chronic Heart Failure: Effects of Short-term Coenzyme Qlo Treatment C. Morisco*~, A. Nappit, L. Argenziano*, D. Sarno*, D. Fonatana*, M. Imbriacot, E. Nicolai*, M. Romano*, G. Rosiello* and A. Cuocolot
"1 ^ Clinica Medica, and tlnstituto di Medicina Nucleare, Universit& degfi Studi 'Federico I1', Napoli, Italy
Abstract--In patients with chronic heart failure (CHF), the addition of coenzyme Q10 to conventional therapy reduces the hospitalization rate for worsening of heart failure and the incidence of serious cardiovascular complications. The present study was planned to assess the hemodynamic mechanisms underlying this phenomenon. Cardiac hemodynamics was evaluated continuously using an ambulatory radionuclide detector (VEST) which allows a noninvasive monitoring of left ventricular function. Six patients wit CHF (mean ejection fraction (EF): 29%) clinically documented were studied. This study was organized as a randomized double-blind, placebo controlled, cross-over trial. The enrolled patients, after a washout period, underwent the first hemodynamic evaluation with VEST. Subsequently they were randomized to receive placebo or coenzyme Ql0 for 4 weeks. At the end of this period they underwent the second VEST study. The third VEST study was performed after a further 4-week period with inverted treatment. Cardiac hemodynamics were evaluated during bicycle exercise. The EF in control conditions (CC) changed from 27 + 11%, at rest, to 24 + 8%, at peak exercise. During coenzyme Q~o treatment EF showed a significant increase both at rest (33 + 13%, P < 0.05 vs CC) and at peak exercise (30 + 12%, P < 0.05 vs CC). The same trends were recorded for the stroke volume and the cardiac output. Our results demonstrate that coenzyme Q10 improves cardiac hemodynamic response to exercise in patients with CHF and suggest that noninvasive monitoring of left ventricular function allows a more reliable assessment of therapy efficacy.
*$To whom correspondence should be addressed, at the 1" Clinica Medica, Universith degli Studi 'Federico II', Via S. Pansini n. 5, 80131-Napoli, Italy.
s155
s156
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et aL
Introduction In patients with chronic heart failure (CHF) there is a clear evidence that the addition of coenzyme Qlo (CoQlo) to conventional therapy reduces the hospitalization rate for worsening of heart failure and the incidence of serious cardiovascular complications such as pulmonary edema, cardiac asthma and arrhythmias (Morisco et al., 1993). Previous studies showed that in patients with cardiomyopathies, treatment with coenzyme Q10 improves cardiac function at rest and at peak exercise (Langsjoen etal., 1991; Swedberg etal., 1992). Exercise tolerance is commonly used for the clinical judgement of the efficacy of drug treatments (Massie, 1988). In patients with CHF the functional capacity is the final result of the interaction among myocardial function (systolic and diastolic function), central factors (pulmonary hemodynamics, neurohumoral mechanisms), peripheral factors (blood flow abnormalities, skeletal muscle biochemical and histological abnormalities) and ventilatory abnormalities (increase of ventilatory dead space) (Myers and Froelicher, 1991). Static measurements of myocardial function at rest have been of little value for the assessment of functional capacity (Franciosa et al., 1981), even if both left venticular ejection fraction and exercise tolerance have an important prognostic value (Szlachcic etal., 1985). The corollary of these observations is that in patients with CHF, an improved myocardial function at rest does not necessarily imply a normal hemodynamic response during exercise (Jennings and Esler, 1990). On the contrary, this goal may be obtained with ACE-inhibitors which exert their therapeutic activity primarily on the peripheral vasculature (McGrath etal., 1985). Recently, the development of an ambulatory radionuclide detector (VEST) for continuous monitoring of left ventricular function has allowed the noninvasive evaluation of the cardiac response to daily activities and to exercise in normal subjects (Bairey et al., 1990), in patients with coronary artery disease (Cuocolo et al., 1992), CHF (Morisco et al., 1993) and arterial hypertension (Breisblatt etal., 1991). Thus, we planned the present study to evaluate the effects of coenzyme Qm treatment on the hemodynamic response to exercise in patients with CHF.
Material and Methods
Study population Six patients with clinically documented CHF were studied. None had evidence of primary pulmonary disease. Patients with myocardial infarction within the previous 3 months or with unstable angina or angina severe enough to require revascularization procedures were excluded. Patients with hemodynamically significant aortic or mitral valve stenosis or regurgitation requiring surgery, with clinical severe renal failure (serum creatinine higher than 2 mg/dl) or hepatic or endocrine disorders were also excluded. All patients were in normal sinus rhythm. The protocol was approved by Ethical Board of our Institution.
Short-term CoQ~o Treatment in Heart Failure Patients
s157
Study design This study was organized as a randomized, double-blind, placebo controlled, crossover trial. The enrolled patients, after 3-week pharmacological washout period (only antiarrhythmic and nitroderivates were allowed), underwent the first hemodynamic evaluation with VEST (control conditions), subsequently they were randomized to receive placebo or CoQ~0 (50 mg x 3/die P.O.) for 4 weeks. At the end of this period all patients underwent the second VEST study. The third VEST study was performed after a further 4-week period with crossed-over treatment, i.e. patients previously treated with placebo received CoQ~0, and vice versa.
Hemodynamic Assessment The cardiac hemodynamics during exercise were assessed by VEST (Capintec), an ambulatory ventricular function monitor that continuously records two channels of ECG in analog form (frequency response > 300 Hz), and beat by beat left ventricular time-activity curve in parallel. The principal components of VEST are: (1) two radionuclide detectors: one is used to monitor the left ventricle, and the other to monitor activity in the lung, (2) a plastic garment to hold radionuclide detectors in place, and (3) associated electronic devices (batteries and recorder). After the patient's red blood cells were labeled in vivo with 15-20 mCi of technetium 99-m, the VEST was positioned in the left-anterior-oblique position that best showed the septum. Then gated blood-pool scans were recorded. Thus, the patient could perform his ambulatory activities. During activity, data were recorded on a modified Holter style cassette tape. At the conclusion of monitoring, the tape was read into a dedicate computer system (PDP-11/73, DEC; IBM PC/RT, IMB, USA) for analysis. Before the analysis, the data were reviewed for technical adequacy. From time-activity curves we were able to calculate: left ventricular ejection fraction, stroke volume, end-diastolic (EDV) and end-systolic volumes, and cardiac output. Ejection fraction was computed as the stroke counts divided by the background corrected end-diastolic counts. Relative end-diastolic volume was expressed as 100% at the beginning of the study, end-systolic volume was expressed as relative to end-diastolic volume, cardiac output was calculated as relative stroke volume multiplied by heart rate.
Exercise protocol All patients were previously familiarized with the bicycle ergometer test. All tests were performed in the fasting state. The exercise test was performed using electromagnetically brake bicycle ergometer (Kem 3). After a 5-minute rest on the ergometer, required for stabilization of the hemodynamic parameters, exercise began with a 2-minute warm-up at 20 W, 60 rpm, followed by a 1 W increase in the work rate every 3-6 seconds (ramp protocol) until a symptom-limited end-point was reached. The end-point of exercise for all patients was leg fatigue or dyspnea. None of the tests was interrupted for angina, ST depression, arrhythmias or hypotension. Cuff blood pressure was also measured every minute with an automatic indirect manometer, and 12 leads ECG was recorded continuously during exercise.
s158
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Statistical analysis All values are expressed as mean + 1 SD. Paired t test was used to compare the hemodynamic values during exercise between the different treatments. A P < 0.05 was considered significant.
Results The mean age of the study population was 49.8 + 6.7 years (range 42-61), mean weight was 73.3 + 10.1 kg (range 57-87), mean left ventricular ejection fraction at rest was 29 + 11% (range 14-39%). The etiology of C H F was idiopathic dilated cardiomyopathy in 2 patients and coronary artery disease in 4 patients. The N Y H A class ranged from II to IV. We failed to detect any statistically significant increase in exercise tolerance among control conditions, CoQ10 and placebo treatment. The exercise duration was 570 + 144 sec, 642 + 102 sec, and 602 + 131 sec, respectively (NS). The hemodynamic response to exercise was characterized by a progressive increase in heart rate (Fig. 1) which, in control conditions, started from 77 _+ 9 bpm and progressively increased reaching its peak value, 127 + 7 bpm, at peak exercise. The COQlo and placebo treatment did not change the trend of this parameter during exercise. On the contrary, during CoQ10 treatment, left ventricular ejection fraction (Fig. 2), at rest and during the whole exercise time, was significantly higher compared to the corresponding steps of the exercise performed in control conditions. In particular, in control conditions, ejection fraction changed from 27 _+ 11%, at rest, to 24 + 8% at peak exercise. During CoQ10 treatment, ejection fraction showed a significant
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Fig. 1. Changes in heart rate during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. On Horizontal axis: exercise time expressed as a percentage of the total duration of the exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of heart rate (bpm).
Short-term CoQlo Treatment in Heart Failure Patients
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60Control Conditions
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Fig. 2. Changes in left ventricular ejection fraction during exercise in patients with CHF in control conditions and during Q10 coenzyme treatment. Horizontal axis: the exercise time expressed as a percentage of total exercise (%), (B1, B2: rest, R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of ejection fraction (%).
increase both at rest (33 + 13%, P < 0.05 vs control conditions) and at peak exercise (30 + 12%, P < 0.05 vs control conditions). The same trend was recorded for the stroke volume (Fig. 3). In fact, its value at rest was 26 + 4% E D V , in control conditions, and 35 + 6% E D V during treatment with COQlo (P < 0.05); at peak exercise it was 26 + 4% E D V and 31 + 6% E D V (NS), respectively. However, the increase of this parameter was statistically significant only at rest. The cardiac output was higher during CoQ10 treatment than in the corresponding steps of control condition
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Degree of Exercise (%) Fig. 3. Changes in stroke volume during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. Horizontal axis: exercise time expressed as a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: stroke volume expressed as percent of the end-diastolic volume (%EDV).
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Fig. 4. Changes in cardiac output during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. Horizontal axis: exercise time expressed as a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: cardiac output expressed as the ratio of percent of the end-diastolic volume and time (% EDV/min).
exercise (Fig. 4). At rest, it increased from 19 + 2% EDV/min, in control conditions, to 33 + 5% EDV/min during COQlo treatment (P < 0.05); simultaneously, peak exercise value varied from 24 + 3% EDV/min to 41 + 8% EDV/min (P < 0.05). The enddiastolic volume (Fig. 5) from a basal value of 97 + 2% and 99 + 2% (NS) in control conditions and during CoQ10 treatment, respectively, progressively increased reaching its zenith at the peak of the exercise in both studies. In contrast, the end-systolic volume showed, at rest, during COQlo treatment, a value (64 + 6%) that was significantly smaller than that recorded in control conditions (68 + 6%, P < 0.05). The decrease of end-systolic volume during CoQlo treatment remained unchanged throughout the exercise. In fact, the values of end-systolic volume at peak exercise, were 76 + 5% and 81 _+ 4% (P < 0.05) during CoQ10 treatment and in control conditions, respectively. We did not detect any difference between the values of all hemodynamic parameters recorded during the tests performed in control conditions and during placebo treatment.
Discussion This study was performed in order to investigate the hemodynamic changes which occur during exercise, and the effects of short-term treatment with CoQlo on the hemodynamic response to exercise in patients with CHF. Previous studies showed that VEST has a good accuracy and reproducibility in the assessment of hemodynamic responses to different types of cardiac stimulation, and represents a useful noninvasive method to evaluate the effects of different treatments on left ventricular function in patients with cardiac diseases (Imbriaco et al., 1993; Morisco et al., 1993).
Short-term CoQlo Treatment in Heart Failure Patients
s161
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Fig. 5. Changes in end diastolic volume (upper panel) and in end systolic volume (bottom panel) during exercise in patients with CHF in control conditions and during Q]0 coenzyme treatment. Horizontal axis: exercise time expressed like a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of end diastolic volume (percent), and of end systolic volume (percent), respectively.
In our study the patients with CHF seem unable to increase their stroke volume during exercise so that the increase of cardiac output is mediated only through an increase of heart rate. The analysis of left ventricular volumes demonstrates that the lack of increase in stroke volume is due to a progressive increase of end-diastolic volume, probably accounted for mainly by an increase of venous flow, associated to an increase of end-systolic volume. These findings suggest the failure of systolic function and the impairment of Frank-Maestrini-Starling mechanisms. The short-term effect of CoQ10 treatment is able to improve the hemodynamic response to exercise in patients with CHF, acting primarily on systolic function. In fact, the end-systolic volume recorded during CoQ10 treatment is constantly lower than in control conditions. The reduction of end-systolic volume suggests that COQlo treatment is able to improve systolic function
s162
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in these patients and can also account for the improvement of other hemodynamic parameters such as ejection fraction, stroke volume and cardiac output. According to the results of previous studies (Mortensen et al., 1991) we can speculate that the improvement of the hemodynamic response to exercise in patients with CHF after CoQ10 treatment is mediated by the restoration of myocardial levels of CoQ~0, which are reduced in patients with cardiomyopathies in NYHA Class III or IV. In conclusion, our results demonstrate that CoQ10 improves cardiac hemodynamic response to exercise in patients with CHF and suggest that noninvasive monitoring of left ventricular function allows a more reliable assessment of therapy efficacy.
References Bairey, C. N., de Yang, L., Berman, D. S. and Rozanski, A. (1990). Comparison of physiologic ejection fraction responses to activities of daily living: implication for clinical testing. J. Am. Coll. Cardiol. 16, 847-854. Breisblatt, W. M., Wolf, C. J., McElhinny, B., Salerni, R. and Smith, V. E. (1991). Comparison of ambulatory left ventricular ejection fraction and blood pressure in systemic hypertension in patients with and without increased left ventricular mass. Am. J. Cardiol. 67, 597-603. Cuocolo, A., Nappi, A., Nicolai, E., Pace, L., Imbriaco, M., Morisco, C., Chiariello, M., Trimarco, B. and Salvatore, M. (1992). Monitoraggio ambulatoriale della funzione ventricolare sinistra: valutazione degli episodi transitori di disfunzione ventricolare in pazienti con cardioptia ischemica. G. Ital. Cardiol. 22, 813-824. Franciosa, J. A., Park, M. and Levine, B. T. (1981). Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am. J. Cardiol. 47, 33-39. Imbriaco, M., Cuocolo, A., Pace, L., Nappi, A., Nicolai, E., Maurea, S. and Salvatore, M. (1993). Repeatability of hemodynamic responses to cardiac stimulation by ambulatory monitoring of left ventricular function. J. Nucl. Biol. Med. 37, 238-244. Jennings, G. L. and Esler, M. D. (1990). Circulatory regulation at rest and exercise and the functional assessment of patients with congestive heart failure. Circulation 81 (Suppl. II), II-5-II-13. Langsjoen, P. H., Langsjoen, P. H. and Folkers, K. (1991). Long-term efficacy and safety of coenzyme Qlo therapy for idiopathic dilated cardiomyopathy. Biomedical and Clinical Aspects of Coenzyme Q, pp. 241-246. Elsevier, Amsterdam. Massie, B. M. (1988). Exercise tolerance in congestive heart failure. Role of cardiac function, peripheral blood flow, and muscle metabolism and effect of treatment. Am. J. Med. 84, 75.
Short-term COQlo Treatment in Heart Failure Patients
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McGrath, B. P., Arnold, L., Matthews, Pg., Jackson, B., Jennings, G., Kiat, H. and Johnston, C. I. (1985). Controlled trial of enalapril in congestive cardiac failure. Br. Heart J. 54, 405-414. Morisco, C., Cuocolo, A., Romano, M., Nicolai, E., Nappi, A., Salvatore, M. and Trimarco, B. (1993). Noninvasive evaluation of cardiac hemodynamics during exercise in patients with left ventricular dysfunction. Effects of digitalis. Eur. Heart J. (Abstr. Suppl)14, 170. Morisco, C., Trimarco, B. and Condorelli, M. (1993). Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study. Clin. Investig. 71, S134-S136. Mortensen, S. A., Kondrup, J. and Folkers, K. (1991). Myocardial deficiency of coenzyme Q10 and carnitine in cardiomyopathy. Biochemical rationale for concomitant coenzyme Q10 and carnitine supplementation. Biochemical and Clinical Aspects of Coenzyme Q, pp. 269-281. Elsevier, Amsterdam. Myers, J. and Froelicher, V. F. (1991). Hemodynamics determinants of exercise capacity in chronic heart failure. Ann. Intern. Med. 115, 377-386. Pace, L., Cuocolo, A., Nappi, A., Nicolai, E., Trimarco, B. and Salvatore, M. (1992). Accuracy and repeatability of left ventricular systolic and diastolic function measurements using an ambulatory radionuclide monitor. Eur. J. Nucl. Med. 19, 800-806. Swedberg, K., Hoffman-Bang, C., Rehnquvist, N. and Astrom, H. (1992). Coenzyme Q10 as an adjunctive in treatment of congestive heart failure. The Biomedical and Clinical Aspects of Coenzyme Q, (Abstr) 15, Elsevier, Amsterdam. Szlachcic, J., Massie, B. M., Kramer, B. L., Topic, N. and Tubau, J. (1985). Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am. J. Cardiol. 55, 1037-1042.
Molec. Aspects Med. Vol. 15 (Supplement),pp. s155-s163, 1994 Copyright (~)1994 ElsevierScience Ltd Printed in Great Britain. All rights reserved. 0098-2997/94 $26.00
0098-2997(94)00022--0
Noninvasive Evaluation of Cardiac Hemodynamics during Exercise in Patients with Chronic Heart Failure: Effects of Short-term Coenzyme Qlo Treatment C. Morisco*~, A. Nappit, L. Argenziano*, D. Sarno*, D. Fonatana*, M. Imbriacot, E. Nicolai*, M. Romano*, G. Rosiello* and A. Cuocolot
"1 ^ Clinica Medica, and tlnstituto di Medicina Nucleare, Universit& degfi Studi 'Federico I1', Napoli, Italy
Abstract--In patients with chronic heart failure (CHF), the addition of coenzyme Q10 to conventional therapy reduces the hospitalization rate for worsening of heart failure and the incidence of serious cardiovascular complications. The present study was planned to assess the hemodynamic mechanisms underlying this phenomenon. Cardiac hemodynamics was evaluated continuously using an ambulatory radionuclide detector (VEST) which allows a noninvasive monitoring of left ventricular function. Six patients wit CHF (mean ejection fraction (EF): 29%) clinically documented were studied. This study was organized as a randomized double-blind, placebo controlled, cross-over trial. The enrolled patients, after a washout period, underwent the first hemodynamic evaluation with VEST. Subsequently they were randomized to receive placebo or coenzyme Ql0 for 4 weeks. At the end of this period they underwent the second VEST study. The third VEST study was performed after a further 4-week period with inverted treatment. Cardiac hemodynamics were evaluated during bicycle exercise. The EF in control conditions (CC) changed from 27 + 11%, at rest, to 24 + 8%, at peak exercise. During coenzyme Q~o treatment EF showed a significant increase both at rest (33 + 13%, P < 0.05 vs CC) and at peak exercise (30 + 12%, P < 0.05 vs CC). The same trends were recorded for the stroke volume and the cardiac output. Our results demonstrate that coenzyme Q10 improves cardiac hemodynamic response to exercise in patients with CHF and suggest that noninvasive monitoring of left ventricular function allows a more reliable assessment of therapy efficacy.
*$To whom correspondence should be addressed, at the 1" Clinica Medica, Universith degli Studi 'Federico II', Via S. Pansini n. 5, 80131-Napoli, Italy.
s155
s156
C. Morisco
et aL
Introduction In patients with chronic heart failure (CHF) there is a clear evidence that the addition of coenzyme Qlo (CoQlo) to conventional therapy reduces the hospitalization rate for worsening of heart failure and the incidence of serious cardiovascular complications such as pulmonary edema, cardiac asthma and arrhythmias (Morisco et al., 1993). Previous studies showed that in patients with cardiomyopathies, treatment with coenzyme Q10 improves cardiac function at rest and at peak exercise (Langsjoen etal., 1991; Swedberg etal., 1992). Exercise tolerance is commonly used for the clinical judgement of the efficacy of drug treatments (Massie, 1988). In patients with CHF the functional capacity is the final result of the interaction among myocardial function (systolic and diastolic function), central factors (pulmonary hemodynamics, neurohumoral mechanisms), peripheral factors (blood flow abnormalities, skeletal muscle biochemical and histological abnormalities) and ventilatory abnormalities (increase of ventilatory dead space) (Myers and Froelicher, 1991). Static measurements of myocardial function at rest have been of little value for the assessment of functional capacity (Franciosa et al., 1981), even if both left venticular ejection fraction and exercise tolerance have an important prognostic value (Szlachcic etal., 1985). The corollary of these observations is that in patients with CHF, an improved myocardial function at rest does not necessarily imply a normal hemodynamic response during exercise (Jennings and Esler, 1990). On the contrary, this goal may be obtained with ACE-inhibitors which exert their therapeutic activity primarily on the peripheral vasculature (McGrath etal., 1985). Recently, the development of an ambulatory radionuclide detector (VEST) for continuous monitoring of left ventricular function has allowed the noninvasive evaluation of the cardiac response to daily activities and to exercise in normal subjects (Bairey et al., 1990), in patients with coronary artery disease (Cuocolo et al., 1992), CHF (Morisco et al., 1993) and arterial hypertension (Breisblatt etal., 1991). Thus, we planned the present study to evaluate the effects of coenzyme Qm treatment on the hemodynamic response to exercise in patients with CHF.
Material and Methods
Study population Six patients with clinically documented CHF were studied. None had evidence of primary pulmonary disease. Patients with myocardial infarction within the previous 3 months or with unstable angina or angina severe enough to require revascularization procedures were excluded. Patients with hemodynamically significant aortic or mitral valve stenosis or regurgitation requiring surgery, with clinical severe renal failure (serum creatinine higher than 2 mg/dl) or hepatic or endocrine disorders were also excluded. All patients were in normal sinus rhythm. The protocol was approved by Ethical Board of our Institution.
Short-term CoQ~o Treatment in Heart Failure Patients
s157
Study design This study was organized as a randomized, double-blind, placebo controlled, crossover trial. The enrolled patients, after 3-week pharmacological washout period (only antiarrhythmic and nitroderivates were allowed), underwent the first hemodynamic evaluation with VEST (control conditions), subsequently they were randomized to receive placebo or CoQ~0 (50 mg x 3/die P.O.) for 4 weeks. At the end of this period all patients underwent the second VEST study. The third VEST study was performed after a further 4-week period with crossed-over treatment, i.e. patients previously treated with placebo received CoQ~0, and vice versa.
Hemodynamic Assessment The cardiac hemodynamics during exercise were assessed by VEST (Capintec), an ambulatory ventricular function monitor that continuously records two channels of ECG in analog form (frequency response > 300 Hz), and beat by beat left ventricular time-activity curve in parallel. The principal components of VEST are: (1) two radionuclide detectors: one is used to monitor the left ventricle, and the other to monitor activity in the lung, (2) a plastic garment to hold radionuclide detectors in place, and (3) associated electronic devices (batteries and recorder). After the patient's red blood cells were labeled in vivo with 15-20 mCi of technetium 99-m, the VEST was positioned in the left-anterior-oblique position that best showed the septum. Then gated blood-pool scans were recorded. Thus, the patient could perform his ambulatory activities. During activity, data were recorded on a modified Holter style cassette tape. At the conclusion of monitoring, the tape was read into a dedicate computer system (PDP-11/73, DEC; IBM PC/RT, IMB, USA) for analysis. Before the analysis, the data were reviewed for technical adequacy. From time-activity curves we were able to calculate: left ventricular ejection fraction, stroke volume, end-diastolic (EDV) and end-systolic volumes, and cardiac output. Ejection fraction was computed as the stroke counts divided by the background corrected end-diastolic counts. Relative end-diastolic volume was expressed as 100% at the beginning of the study, end-systolic volume was expressed as relative to end-diastolic volume, cardiac output was calculated as relative stroke volume multiplied by heart rate.
Exercise protocol All patients were previously familiarized with the bicycle ergometer test. All tests were performed in the fasting state. The exercise test was performed using electromagnetically brake bicycle ergometer (Kem 3). After a 5-minute rest on the ergometer, required for stabilization of the hemodynamic parameters, exercise began with a 2-minute warm-up at 20 W, 60 rpm, followed by a 1 W increase in the work rate every 3-6 seconds (ramp protocol) until a symptom-limited end-point was reached. The end-point of exercise for all patients was leg fatigue or dyspnea. None of the tests was interrupted for angina, ST depression, arrhythmias or hypotension. Cuff blood pressure was also measured every minute with an automatic indirect manometer, and 12 leads ECG was recorded continuously during exercise.
s158
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Statistical analysis All values are expressed as mean + 1 SD. Paired t test was used to compare the hemodynamic values during exercise between the different treatments. A P < 0.05 was considered significant.
Results The mean age of the study population was 49.8 + 6.7 years (range 42-61), mean weight was 73.3 + 10.1 kg (range 57-87), mean left ventricular ejection fraction at rest was 29 + 11% (range 14-39%). The etiology of C H F was idiopathic dilated cardiomyopathy in 2 patients and coronary artery disease in 4 patients. The N Y H A class ranged from II to IV. We failed to detect any statistically significant increase in exercise tolerance among control conditions, CoQ10 and placebo treatment. The exercise duration was 570 + 144 sec, 642 + 102 sec, and 602 + 131 sec, respectively (NS). The hemodynamic response to exercise was characterized by a progressive increase in heart rate (Fig. 1) which, in control conditions, started from 77 _+ 9 bpm and progressively increased reaching its peak value, 127 + 7 bpm, at peak exercise. The COQlo and placebo treatment did not change the trend of this parameter during exercise. On the contrary, during CoQ10 treatment, left ventricular ejection fraction (Fig. 2), at rest and during the whole exercise time, was significantly higher compared to the corresponding steps of the exercise performed in control conditions. In particular, in control conditions, ejection fraction changed from 27 _+ 11%, at rest, to 24 + 8% at peak exercise. During CoQ10 treatment, ejection fraction showed a significant
150-----o---
140
Control Conditions
130 120
E CL
110 100 90 80 7060
i
|
i
!
i
i
i
i
i
i
!
i
,
i
--
B1 B2 lO 20 30 40 50 60 70 80 90 loo R1 R2 R3
Degree of Exercise (%)
Fig. 1. Changes in heart rate during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. On Horizontal axis: exercise time expressed as a percentage of the total duration of the exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of heart rate (bpm).
Short-term CoQlo Treatment in Heart Failure Patients
s159
60Control Conditions
----o.---
Coenzyme QIO
•
50,
40. o) O)
o.
30,
20,
10 B1 '
~ 2 ' 10 20' 30' 4 ~ ' ~ 50
70 . .80. 90 . .100 R1
~,
Degree of Exercise (%)
Fig. 2. Changes in left ventricular ejection fraction during exercise in patients with CHF in control conditions and during Q10 coenzyme treatment. Horizontal axis: the exercise time expressed as a percentage of total exercise (%), (B1, B2: rest, R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of ejection fraction (%).
increase both at rest (33 + 13%, P < 0.05 vs control conditions) and at peak exercise (30 + 12%, P < 0.05 vs control conditions). The same trend was recorded for the stroke volume (Fig. 3). In fact, its value at rest was 26 + 4% E D V , in control conditions, and 35 + 6% E D V during treatment with COQlo (P < 0.05); at peak exercise it was 26 + 4% E D V and 31 + 6% E D V (NS), respectively. However, the increase of this parameter was statistically significant only at rest. The cardiac output was higher during CoQ10 treatment than in the corresponding steps of control condition
70----.-o---
Control
Conditions
60
50
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40-
30'
20
10
i
~
i
i
i
i
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i
i
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i
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i
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Degree of Exercise (%) Fig. 3. Changes in stroke volume during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. Horizontal axis: exercise time expressed as a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: stroke volume expressed as percent of the end-diastolic volume (%EDV).
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Fig. 4. Changes in cardiac output during exercise in patients with CHF in control conditions and during coenzyme Q10 treatment. Horizontal axis: exercise time expressed as a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: cardiac output expressed as the ratio of percent of the end-diastolic volume and time (% EDV/min).
exercise (Fig. 4). At rest, it increased from 19 + 2% EDV/min, in control conditions, to 33 + 5% EDV/min during COQlo treatment (P < 0.05); simultaneously, peak exercise value varied from 24 + 3% EDV/min to 41 + 8% EDV/min (P < 0.05). The enddiastolic volume (Fig. 5) from a basal value of 97 + 2% and 99 + 2% (NS) in control conditions and during CoQ10 treatment, respectively, progressively increased reaching its zenith at the peak of the exercise in both studies. In contrast, the end-systolic volume showed, at rest, during COQlo treatment, a value (64 + 6%) that was significantly smaller than that recorded in control conditions (68 + 6%, P < 0.05). The decrease of end-systolic volume during CoQlo treatment remained unchanged throughout the exercise. In fact, the values of end-systolic volume at peak exercise, were 76 + 5% and 81 _+ 4% (P < 0.05) during CoQ10 treatment and in control conditions, respectively. We did not detect any difference between the values of all hemodynamic parameters recorded during the tests performed in control conditions and during placebo treatment.
Discussion This study was performed in order to investigate the hemodynamic changes which occur during exercise, and the effects of short-term treatment with CoQlo on the hemodynamic response to exercise in patients with CHF. Previous studies showed that VEST has a good accuracy and reproducibility in the assessment of hemodynamic responses to different types of cardiac stimulation, and represents a useful noninvasive method to evaluate the effects of different treatments on left ventricular function in patients with cardiac diseases (Imbriaco et al., 1993; Morisco et al., 1993).
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Fig. 5. Changes in end diastolic volume (upper panel) and in end systolic volume (bottom panel) during exercise in patients with CHF in control conditions and during Q]0 coenzyme treatment. Horizontal axis: exercise time expressed like a percentage of total exercise (%), (B1, B2: rest; R1, R2, R3: 1st, 2nd, 3rd minute of recovery); vertical axis: values of end diastolic volume (percent), and of end systolic volume (percent), respectively.
In our study the patients with CHF seem unable to increase their stroke volume during exercise so that the increase of cardiac output is mediated only through an increase of heart rate. The analysis of left ventricular volumes demonstrates that the lack of increase in stroke volume is due to a progressive increase of end-diastolic volume, probably accounted for mainly by an increase of venous flow, associated to an increase of end-systolic volume. These findings suggest the failure of systolic function and the impairment of Frank-Maestrini-Starling mechanisms. The short-term effect of CoQ10 treatment is able to improve the hemodynamic response to exercise in patients with CHF, acting primarily on systolic function. In fact, the end-systolic volume recorded during CoQ10 treatment is constantly lower than in control conditions. The reduction of end-systolic volume suggests that COQlo treatment is able to improve systolic function
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in these patients and can also account for the improvement of other hemodynamic parameters such as ejection fraction, stroke volume and cardiac output. According to the results of previous studies (Mortensen et al., 1991) we can speculate that the improvement of the hemodynamic response to exercise in patients with CHF after CoQ10 treatment is mediated by the restoration of myocardial levels of CoQ~0, which are reduced in patients with cardiomyopathies in NYHA Class III or IV. In conclusion, our results demonstrate that CoQ10 improves cardiac hemodynamic response to exercise in patients with CHF and suggest that noninvasive monitoring of left ventricular function allows a more reliable assessment of therapy efficacy.
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McGrath, B. P., Arnold, L., Matthews, Pg., Jackson, B., Jennings, G., Kiat, H. and Johnston, C. I. (1985). Controlled trial of enalapril in congestive cardiac failure. Br. Heart J. 54, 405-414. Morisco, C., Cuocolo, A., Romano, M., Nicolai, E., Nappi, A., Salvatore, M. and Trimarco, B. (1993). Noninvasive evaluation of cardiac hemodynamics during exercise in patients with left ventricular dysfunction. Effects of digitalis. Eur. Heart J. (Abstr. Suppl)14, 170. Morisco, C., Trimarco, B. and Condorelli, M. (1993). Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study. Clin. Investig. 71, S134-S136. Mortensen, S. A., Kondrup, J. and Folkers, K. (1991). Myocardial deficiency of coenzyme Q10 and carnitine in cardiomyopathy. Biochemical rationale for concomitant coenzyme Q10 and carnitine supplementation. Biochemical and Clinical Aspects of Coenzyme Q, pp. 269-281. Elsevier, Amsterdam. Myers, J. and Froelicher, V. F. (1991). Hemodynamics determinants of exercise capacity in chronic heart failure. Ann. Intern. Med. 115, 377-386. Pace, L., Cuocolo, A., Nappi, A., Nicolai, E., Trimarco, B. and Salvatore, M. (1992). Accuracy and repeatability of left ventricular systolic and diastolic function measurements using an ambulatory radionuclide monitor. Eur. J. Nucl. Med. 19, 800-806. Swedberg, K., Hoffman-Bang, C., Rehnquvist, N. and Astrom, H. (1992). Coenzyme Q10 as an adjunctive in treatment of congestive heart failure. The Biomedical and Clinical Aspects of Coenzyme Q, (Abstr) 15, Elsevier, Amsterdam. Szlachcic, J., Massie, B. M., Kramer, B. L., Topic, N. and Tubau, J. (1985). Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am. J. Cardiol. 55, 1037-1042.