Cutting Edge Science and Medicine of Adenosine in Patients With Heart Failure

Is adenosine well known by cardiologists working in clinical medicine and by basic scientists? We do not think so, even though adenosine has been known for many years, and researchers have clarified its production pathway, pharmacological actions and role in cardioprotection. Let’s briefly summarize what adenosine is and what adenosine does inside the body and the heart specifically.

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Adenosine is produced by 2 pathways: (1) hydrolysis of S-adenosylhomocysteine (SAH) by SAH hydrolase during normal condition, and (2) hydrolysis of AMP by 5’-nucleotidase during ischemic or hypoxic conditions. Adenosine is eliminated via phosphorylation by adenosine kinase or deamination by adenosine deaminase. Adenosine activates four G-protein-coupled receptors: A₁, A_2A, A_2B, and A₃. The A₁ and A₃ receptors preferentially couple to G_i protein to inhibit adenylate cyclase and consequently the production of cyclic AMP (cAMP), and the A_2A and A_2B receptors stimulate the production of cAMP by coupling to G_s or G_o. Adenosine is a well-established cardioprotective molecule that plays a major role in ischemic preconditioning via activation of the A₁ and A₃ receptors and in experimental models it is cardioprotective via simulation of adenosine receptors as follows: (1) attenuation of release of catecholamine, β-adrenoceptor-mediated myocardial hypercontraction, and Ca²⁺ overload via A₁ receptors; and (2) increase in coronary blood flow, and inhibition of platelet and leukocyte activation via A₂ receptors. Furthermore, adenosine inhibits renin release and tumor necrosis factor (TNF)-α production. These observations suggest that increased plasma adenosine levels may be associated with decreased severity of chronic heart failure (CHF).

Adenosine as a New Treatment Strategy for CHF

CHF results in and from the release of many neurohumoral factors, including catecholamines, renin-angiotensin and cytokines. Despite effective therapies such as angiotensin-converting enzyme inhibitors, β-blockers, aldosterone antagonists and devices, the prognosis of CHF is worse than for most cancers. Because of its high morbidity and mortality, we need new options for the treatment of CHF. Adenosine is reported to attenuate the sympathetic nervous system, renin-angiotensin system, and cytokine system; therefore, elevation of adenosine levels may largely contribute to the beneficial treatment of CHF. Therefore, several decades ago, we performed a prospective, open randomized clinical trial, including a control group, to evaluate the dose-dependent effects of dipyridamole, an inhibitor of nucleoside transport, as well as plasma B-type natriuretic peptide (BNP) status in order to determine whether treatment with either a large or a small dose of dipyridamole for 1 year modulated the pathophysiology of CHF patients with conventional broadly accepted treatments. In that study, we found that dipyridamole, an adenosine uptake inhibitor, improved the echocardiographic ejection fraction, left ventricular (LV) systolic diameter, Specific Activity Scale (SAS) score, maximal oxygen consumption during the exercise test and plasma BNP levels in patients with CHF.¹ Adenosine may be a potential candidate for a new treatment strategy of CHF.

Adenosine as a Biomarker for CHF

Biomarkers have been classified according to their functional effects on cardiac myocytes and resulting pathophysiological processes in patients with CHF and include (i) myocardial stretch, (ii) myocyte injury, (iii) extracellular matrix remodeling, (iv) inflammation, (v) renal dysfunction, (vi) neurohumoral activation, and (vii) oxidative stress.² BNP and its prohormone fragment, N-terminal proBNP (NT-proBNP) have clinical significance both as diagnostic and prognostic markers in the management of CHF, and these are now the most widely used biomarkers in the care of patients with CHF. However, it is necessary to note that elevated BNP and NT-proBNP levels are associated with advancing age, anemia, renal failure, pulmonary hypertension and chronic hypoxia, and that obese and overweight individuals have relatively lower BNP levels. Furthermore, both BNP and NT-proBNP are secreted in response to myocardial stretch, which represents only a single pathophysiologic pathway. Therefore, BNP or NT-proBNP may not be an appropriate biomarker for all cardiovascular conditions. On the other hand, plasma adenosine levels and the activity and amount of ecto-5’-nucleotidase are increased in patients with CHF and the magnitude of the increase has been correlated with the severity of CHF.^3,4 Furthermore, the gene expression of the A_2A, A_2B, and A₃ receptors is downregulated in human failing myocardium compared with non-failing myocardium,⁵ which implies that the downregulation of adenosine receptors plays an important role in the pathophysiology of CHF by impairing adenosine signal transduction. These lines of clinical research together imply that increased adenosine levels in CHF patients may be compensating for the worsening of CHF. Although the action of adenosine is considered to be involved in various pathophysiological processes of CHF, the possible contribution of plasma adenosine to the LV function and LV remodeling has not yet been clarified in patients with CHF. Importantly, in this issue of the Journal, Kinomura et al⁶ investigate the relationship between the plasma adenosine concentration and LV function or LV remodeling in patients with ischemic and non-ischemic heart diseases. Because adenosine is thought to be degraded rapidly, blood samples were conventionally collected in tubes containing dipyridamole, 2’-deoxycoformycin or EDTA to avoid degradation of adenosine. They firstly confirmed that the blood collection method without dipyridamole and 2’-deoxycoformycin (i.e., EDTA) gave relatively accurate levels of adenosine in plasma. Therefore, they used tubes containing only EDTA to collect blood samples and measured the plasma adenosine concentration using the highly sensitive ESI-MS/MS method for the determination of adenosine in human plasma combined with HILIC separation after simple pretreatment consisting of deproteinization and ultrafiltration.⁷ In their study, they demonstrated that the plasma adenosine concentration was significantly higher in (1) patients with LV ejection fraction (LVEF) <47% than in those with LVEF ≥47% (P=0.027), (2) patients with LV end-diastolic dimension (LVDd) ≥50 mm than in those with LVDd <50 mm (P=0.030), (3) patients with interventricular septum thickness (IVSth) <8 mm than in those with IVSth ≥8 mm (P=0.015) and (4) patients with LV posterior wall thickness (LVPWth) <8 mm than in those with LVPWth ≥8 mm (P=0.020). Although the plasma adenosine concentration inversely correlated with IVSth (P=0.003) or LVPWth (P=0.0007), there was no difference between the plasma adenosine concentration and E/e’, an indicator of LV diastolic function. Thus the authors conclude that endogenous plasma adenosine may counteract LV dysfunction and LV remodeling in cardiac patients. These results imply that the plasma adenosine level may be a good marker for CHF. The study was conducted in a single center and the numbers of patients with NYHA class III (n=5) and class IV (n=6) were relatively small. Therefore, further study with a larger number of HF patients is required. Because adenosine may counteract the pathophysiology of CHF, the combination of several biomarkers including adenosine will improve the diagnosis and prognosis of CHF (Table).

Table. Classification of Biomarkers in Heart Failure

	Prevention	Diagnosis	Prognosis
i) Myocardial stretch BNP, NT-proBNP (Adenosine)	◎	◎	◎
ii) Myocyte injury and apoptosis cTnI, cTnT, hsTn (Adenosine)		○	◎
iii) Extracellular matrix remodeling MMPs (2, 3, 4, 8, and 9) (Adenosine)			○
iv) Inflammation CRP, TNF-α, IL-6 (Adenosine)			○
v) Renal dysfunction BUN, creatinine, cystatin C, NGAL			◎
vi) Neurohumoral activation Norepinephrine, AngII, aldosterone, copeptin (Adenosine)			○
vii) Oxidative stress MPO (Adenosine)			○

AngII, angiotensin II; BUN, blood urea nitrogen; copeptin, C-terminal segment of preprovasopressin; CRP, C-reactive protein; cTn, cardiac-specific troponin; hsTn, high-sensitivity troponin; IL-6, interleukin-6; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; NGAL, neutral gelatinase-associated lipocalin; TNF-α, tumor necrosis factor-α.

Taking these findings together, we need to further accumulate evidence of the role of adenosine in CHF and test the cardioprotective action of adenosine in clinical settings to overcome the future pandemic state of CHF in Japan.

Conflicts of Interest

M.K. reports grants from Japanese government, grants from Japan Heart Foundation, grants from Japan Cardiovascular Research Foundation, grants and personal fees from Takeda, Astellas, Sanofi, Pfizer, Novartis, Boehringer Ingelheim, Tanabe-Mitsubishi, Kyowa-Hakko-Kirin, Abott, and Otsuka outside the submitted work; personal fees from Daiichi-Sankyo, Ono, Bayer, from Kowa, Dainihon-Sumitomo, Sawai, MSD, Calpis, Shionogi, AstraZeneca, Asahikasei Med., Novo Nordisk, Fuji-film RI, and Japan Medical Data, outside the submitted work; grants from Nihon Kohden.

References

• 1.   Sanada S, Asanuma H, Koretsune Y, Watanabe K, Nanto S, Awata N, et al. Long-term oral administration of dipyridamole improves both cardiac and physical status in patients with mild to moderate chronic heart failure: A prospective open-randomized study. Hypertens Res 2007; 30: 913–919.
• 2.   Braunwald E. Heart failure. JACC Heart Fail 2013; 1: 1–20.
• 3.   Funaya H, Kitakaze M, Node K, Minamino T, Komamura K, Hori M. Plasma adenosine levels increase in patients with chronic heart failure. Circulation 1997; 95: 1363–1365.
• 4.   Fujita M, Asakura M, Sanada S, Funaya H, Tsukamoto O, Komamura K, et al. Activation of ecto-5’-nucleotidase in the blood and hearts of patients with chronic heart failure. J Card Fail 2008; 14: 426–430.
• 5.   Asakura M, Asanuma H, Kim J, Liao Y, Nakamaru K, Fujita M, et al. Impact of adenosine receptor signaling and metabolism on pathophysiology in patients with chronic heart failure. Hypertens Res 2007; 30: 781–787.
• 6.   Kinomura Y, Tanaka T, Aoyama T, Hatasa M, Minatoguchi S, Iwasa M, et al. Endogenous adenosine may be related to left ventricular dysfunction, dilation, and wall thinning in patients with heart disease. Circ J 2018; 82: 1319–1326.
• 7.   Murakami H, Otani E, Iwata T, Esaka Y, Aoyama T, Kawasaki M, et al. Simple Pretreatment and HILIC Separation for LC-ESI-MS/MS Determination of Adenosine in Human Plasma. Anal Sci 2015; 31: 1189–1192.