Plasma Adenosine Levels Increase in Patients With Chronic Heart Failure
Background Adenosine is believed to be cardioprotective; however, it has not been elucidated whether the plasma adenosine level is increased in chronic heart failure.
Methods and Results Seventy-one patients attending a specialized heart failure clinic during a 6-month period were grouped according to the cause of chronic heart failure and the New York Heart Association function class. There were 40 patients with chronic heart failure due to ischemic heart diseases and 31 patients with valvular heart diseases and dilated cardiomyopathy. Control subjects consisted of 64 healthy laboratory staff members and patients without chronic heart failure. We found that the plasma adenosine levels were increased in patients with ischemic and nonischemic heart failure (218±23 and 211±21 nmol/L, respectively, versus 62±3 nmol/L for healthy subjects) and that the extent of increases in adenosine levels correlated well with the severity of chronic heart failure.
Conclusions We conclude that adenosine levels in the systemic blood increase in patients in ischemic and nonischemic chronic heart failure. Because adenosine counteracts catecholamine-, renin-angiotensin–, and cytokine-induced cellular injury, increased adenosine levels may be endogenous compensatory mechanisms for heart failure.
Chronic heart failure is characterized by the reduction of cardiac performance; however, several neurohumoral factors are reported to deteriorate chronic heart failure.1 Catecholamine, renin-angiotensin, and cytokines are thought to be involved in the pathophysiology of chronic heart failure.2 3 4 Indeed, chronic heart failure is effectively treated by β-adrenoceptor antagonists and ACE inhibitors,2 3 4 and these drugs have proved effective for the treatment of chronic heart failure in large studies. Interestingly, activation of protein kinase C by norepinephrine and angiotensin II activates ecto-5′-nucleotidase, an enzyme responsible for production of adenosine, and cytokines increase transcriptional and protein levels of ecto-5′-nucleotidase,5 both of which may increase plasma adenosine levels. Adenosine, produced not only in cardiomyocytes but also in endothelial cells, is known to be cardioprotective via adenosine receptors6 7 through the following mechanisms: (1) attenuation of release of catecholamine, β-adrenoceptor–mediated myocardial hypercontraction, and Ca2+ overload via A1 receptors; and (2) increases in coronary blood flow and inhibition of platelet and leukocyte activation via A2 receptors. Furthermore, adenosine inhibits renin release and tumor necrosis factor-α production in experimental models.8 9 However, there has been no report of the metabolism of endogenous adenosine in chronic heart failure.
Therefore, the present study was undertaken to examine whether plasma adenosine levels are increased or decreased in patients with chronic heart failure.
Subjects and Study Design
Seventy-one patients (mean age, 52±2 years old; range, 25 to 81) attending a specialized heart failure clinic during a 6-month period were grouped according to causes of chronic heart failure and the New York Heart Association (NYHA) function class. Use of drugs for the treatment of chronic heart failure was noted. The Table⇓ presents the patients’ characteristics. There were 40 patients with chronic heart failure due to ischemic heart diseases and 31 patients with chronic heart failure due to valvular heart diseases (12 with mitral regurgitation and 5 with aortic regurgitation) or dilated cardiomyopathy (14). These diseases were diagnosed by a catheterization examination and myocardial biopsy. Control subjects were 64 healthy laboratory staff members and patients without chronic heart failure (mean age, 50±2 years old; range, 25 to 79). All of the subjects refrained from smoking and drinking alcohol for ≥30 days during hospitalization. Seventeen of 40 patients with ischemic heart failure, 18 of 31 with nonischemic heart failure, and 19 of 64 control subjects were smokers before hospitalization; 21 of 40 patients with ischemic heart failure, 23 of 31 with nonischemic heart failure, and 26 of 64 control subjects were alcohol drinkers before hospitalization. Plasma adenosine levels were determined by radioimmunoassay as previously reported.10 We also measured plasma norepinephrine levels11 in 65 patients with chronic heart failure. Blood was sampled ≥15 minutes after patients had been resting in bed. We measured adenosine levels at 7:30 am, before breakfast, with patients in a fasting condition. In another 16 control subjects (mean age, 54±2 years old; range, 30 to 68), we confirmed that the day-to-day differences were not significant (plasma adenosine levels: 59±6 nmol/L at the time of the first measurement, 53±8 nmol/L 14 days later, and 63±7 nmol/L 28 days later). Furthermore, we measured plasma adenosine levels in another 10 healthy laboratory staff members before breakfast (at 7 am; 57±6 nmol/L), before and after lunch (at 11 am and 1 pm; 63±9 and 65±8 nmol/L, respectively), before and after dinner (at 6 and 8 pm; 54±9 and 67±7 nmol/L, respectively), and just before sleep (at 10 pm; 60±6 nmol/L) and found that the variation of plasma adenosine levels during the course of a day was not significant. In this preliminary study, we confirmed that there were no significant time- or fasting condition–dependent differences in plasma adenosine levels in a day.
Data are presented as mean±SEM, and ANOVA was used to test differences in plasma adenosine levels. When the levels of plasma adenosine reached significance, the Bonferroni test was used to obtain a probability value. A value of P<.05 was considered significant. The dependency of plasma adenosine levels on the administered drugs was tested by use of multiple regression analysis.
Adenosine levels in the control subjects were as follows: 63±10 nmol/L in 20- to 30-year-olds (n=10), 64±12 nmol/L in 31- to 40-year-olds (n=11), 56±7 nmol/L in 41- to 50-year-olds (n=10), 58±8 nmol/L in 51- to 60-year-olds (n=15), 64±6 nmol/L in 61- to 70-year-olds (n=11), and 65±9 nmol/L in 71- to 80-year-olds (n=7). There was no correlation between adenosine levels and age in the control subjects. The average values of plasma adenosine levels and age in control subjects (n=64) were 62±3 nmol/L and 50±2 years old, respectively. The ages of the control subjects were not significantly different from the ages of patients with chronic heart failure. In contrast, plasma adenosine levels increased according to NYHA classification (Fig 1⇓). Ejection fraction (EF) assessed by echocardiography or ventriculography was 71±5%, 62±4%, 40±4%, and 24±5% in patients classified as NYHA classes I through IV, respectively; however, there was no direct correlation (r=.193, P=NS) between EF and plasma adenosine levels in patients with chronic heart failure. There were no significant differences in plasma adenosine levels in patients with ischemic and nonischemic (valvular diseases and dilated cardiomyopathy) chronic heart failure (Fig 1⇓). Plasma norepinephrine levels were also increased according to NYHA classification: class I, 118±15 pg/mL (122±9 pg/mL in patients with ischemic heart failure [n=14] and 115±5 pg/mL in patients with nonischemic heart failure [n=5]); class II, 337±26 pg/mL (359±39 pg/mL in patients with ischemic heart failure [n=15] and 316±35 pg/mL in patients with nonischemic heart failure [n=9]); class III, 668±44 pg/mL (672±69 pg/mL in patients with ischemic heart failure [n=8] and 663±56 pg/mL in patients with nonischemic heart failure [n=11]); and class IV, 1158±87 pg/mL (1140±174 pg/mL in patients with ischemic heart failure [n=3] and 1173±86 pg/mL in patients with nonischemic heart failure [n=6]) versus 84±7 pg/mL in control subjects (all P<.05). There was a correlation (r=.46, P<.01) between plasma adenosine and norepinephrine levels in patients with chronic heart failure (n=65) (y=130+0.079x, where x represents plasma norepinephrine level [pg/mL] and y is plasma adenosine level [nmol/L]) (Fig 2⇓). We tested the dependency of adenosine concentration on drugs for the treatment of chronic heart failure, ie, diuretics, digitalis, β-blockers, calcium blockers, isosorbide dinitrate, and ACE inhibitors. Plasma adenosine levels were independent of each drug used in the present study (P=.98, P=.24, P=.65, P=.15, P=.59, and P=.17, respectively, by multiple regression analysis). We did not use aminophylline or theophylline, which may modulate plasma adenosine levels, in the present study. Other inotropic drugs, such as dopamine and vesnarinone, and α-blockers were not used in these patients. Plasma adenosine levels were independent of smoking and alcohol-drinking habits (P=.49 and P=.55 by multiple regression analysis, respectively). These results indicate that plasma adenosine levels increase in patients with chronic heart failure and that this increase in plasma adenosine level correlates well with the functional classification of the severity of chronic heart failure according to the NYHA classification system.
Myocardial ischemia is a potent stimulator of adenosine release from the heart. Although there were no differences in plasma adenosine levels in patients with ischemic and nonischemic chronic heart failure in the present study, myocardial ischemia may contribute to adenosine production in patients with chronic heart failure. This is because even nonischemic chronic heart failure may be attributable to latent myocardial ischemia and hypoxia caused by coronary microvascular spasm, myocardial external compressive forces on the small coronary arteries, increased diffusion distances of oxygen due to myocardial distention, and reduced perfusion gradients from the epicardium and endocardium with increased myocardial stress in dilated cardiomyopathy. Because endogenous norepinephrine levels increase due to the progression of the severity of chronic heart failure, and endogenous norepinephrine increases the activity of ecto-5′-nucleotidase, the enzyme responsible for adenosine production,12 13 the increased plasma norepinephrine level may contribute to increases in adenosine production. Indeed, we observed high levels of plasma norepinephrine, which correlate with plasma adenosine levels. Interestingly, norepinephrine is believed to worsen chronic heart failure, and adenosine attenuates the cardiovascular effect of norepinephrine. Therefore, adenosine may contribute to negative feedback mechanisms against the progressive loop between norepinephrine and heart failure. However, we need to consider the effects on plasma adenosine levels of drugs used to treat chronic heart failure. Although we did not obtain significant correlations between each drug and the levels of plasma adenosine, we could not completely rule out the effects of combinations of the drugs used or the combinations of each drug and the pathophysiology of chronic heart failure on plasma adenosine levels.
Increased plasma adenosine levels may be beneficial for the failing heart because many deleterious events in heart failure are attenuated by adenosine. However, excessive increases in plasma adenosine levels may attenuate cardiac performance in the failing heart.6 7
This study was supported by a grant-in-aid for scientific research (No. 07457171) from the Ministry of Education, Science, and Culture, Japan.
Reprint requests to Masafumi Kitakaze, MD, PhD, The First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita 565, Japan.
- Received December 16, 1996.
- Revision received January 15, 1997.
- Accepted January 21, 1997.
- Copyright © 1997 by American Heart Association
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