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Letters to the Editor |
1 Department of Medicine, Internal Intensive Care, and Nephrology, and, 2 Department of Cardiology, Charité–University Medicine in Berlin, Campus Virchow-Klinikum, Berlin, Germany
aAddress correspondence to this author at: Department of Medicine, Internal Intensive Care and Nephrology, University Medicine in Berlin/Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Fax 49-30-4505-59918; e-mail oliver.danne{at}charite.de.
To the Editor:
Whole-blood choline (WBCHO) and plasma choline (PLCHO) have been reported to be predictive for cardiac events in patients with suspected acute coronary syndromes (1)(2). The differential information of whole-blood vs plasma choline offers insights into the biochemistry and pathophysiology of acute coronary syndromes. A previous study has shown that mean (SD) WBCHO concentrations are significantly increased in patients with non-ST-elevation myocardial infarction [31.1 (18.8) µmol/L] and high-risk unstable angina [47.4 (22.8) µmol/L] compared with patients with noncardiac chest pain [19.4 (6.8) µmol/L] (1) or healthy volunteers [15.8 (9.5) µmol/L]. For interpretation of WBCHO, a cutoff of 28.2 µmol/L has been proposed (1), which also represents the 90th percentile of a reference population. For PLCHO, the optimum cutoff has not been determined, and 25 µmol/L (99th percentile of a reference population) and lower cutoffs (18.5 µmol/L) have been used for risk stratification. We have selected 3 cases with the constellation of increased WBCHO in combination with low PLCHO to discuss potential pathophysiologic implications. All choline analyses were performed with HPLC–mass spectrometry (1), and choline concentrations were not available for clinical decision-making.
Case 1.
A 68-year-old man presented to the emergency department with acute chest pain for 1.5 h. He had a history of stable angina pectoris, arterial hypertension, and type II diabetes mellitus treated with glibenclamide. The patient had no history of bleeding or thrombosis, and results of routine blood cell analyses, including platelet count, mean platelet volume, coagulation indices, and renal function, as well as the physical examination were normal. Serial electrocardiographic (ECG) recordings demonstrated dynamic anterior ST changes and T-wave inversions, a left anterior hemiblock, and frequent ventricular premature beats. Serial measurements of cardiac troponin I (cTnI; Stratus CS) and T (cTnT; Elecsys 2010) were positive (0.99, 1.28, and 2.65 µg/L for cTnI and 0.23, 0.30 and 0.69 µg/L for cTnT) and confirmed acute myocardial infarction. C-Reactive protein (CRP) was below the detection limit (<6 mg/L).
Whole blood samples drawn on admission and after 4, 12, and 24 h demonstrated persistent and marked increases in WBCHO (110.1, 110.8, 115.5, and 111.2 µmol/L), whereas PLCHO was low (14.8 µmol/L). Coronary angiography was performed 16 h after admission with a diagnosis of multiple high-grade coronary artery stenoses of the left anterior descending artery (LAD) and with medial occlusion as well as occlusion of the circumflex artery. A hazy filling defect was seen in a diagonal branch.
Three stents were successfully implanted without use of glycoprotein IIb-IIIa inhibitors but with subsequent treatment with clopidogrel and aspirin. The ejection fraction was reduced (36%) with impaired anterior and apical wall motion. In addition to antiplatelet therapy and treatment with unfractionated heparin, the patient was treated with an angiotensin-converting enzyme inhibitor and nitrates.
On days 2 and 3, the patient was clinically stable without symptoms and was discharged from the hospital on day 3. On day 4, the patient died of sudden death attributable to refractory ventricular fibrillation with unsuccessful out-of-hospital cardiopulmonary resuscitation. No autopsy was performed, but subacute stent occlusion was the most probable cause of fatal arrhythmias and sudden cardiac death.
Case 2.
A 64-year-old patient with 2-vessel disease, a history of coronary artery bypass grafting (3 years previously), previous myocardial infarction, and a recent coronary intervention with implantation of a drug-eluting stent (paclitaxel nonpolymeric-coated ACHIEVETM Drug-Eluting Stent; DELIVER II registry) in the right coronary artery because of in-stent restenosis 3 months previously was admitted to the emergency room with chest pain for 3 h. He reported that he had not taken his medication, including clopidogrel, for 5 days; he also had a history of diabetes, hyperlipidemia, hypertension, and smoking. The ECG demonstrated no significant changes, and cTnI (Stratus CS) and myoglobin were not increased (0.01 µg/L and 33 µg/L, respectively). His high-sensitivity CRP was 6 mg/L, and D-dimers were 92 µg/L. WBCHO was increased to 57.2 µmol/L, whereas PLCHO was low (16.3 µmol/L).
Because his symptoms seemed atypical with pain radiating to the lower jaw and zygomatic bone and he reported that a recent stress test was normal, the patient was discharged from the emergency room with the diagnosis of noncardiac chest pain. The next day the patient was readmitted with acute chest pain and ST-elevation myocardial infarction. Coronary angiography demonstrated acute stent thrombosis in the right coronary artery with successful treatment with aspiration-thrombectomy and coronary angioplasty. The left internal mammary artery bypass was occluded (old) with a 75% stenosis of the native LAD, and the venous bypass to the ramus diagonalis was open. Antiplatelet therapy included aspirin, clopidogrel, and 48 h of tirofiban.
Although his cTnI (Stratus CS) concentrations had increased to 6.5 µg/L, his WBCHO showed a modest reduction to 48.3 µmol/L 4 h after coronary intervention and 45.2 µmol/L after 6 days with no return to reference values. The corresponding PLCHO concentrations were 12.7 (4 h) and 12.3 µmol/L (6 days). His additional short-term follow-up remained uneventful, with treatment with clopidogrel, aspirin, metoprolol, atorvastatin, ramipril, torasemide, and pantoprazole.
Case 3.
A 65-year-old male patient presented with recurrent chest pain for 6 h and a history of a myocardial infarction and coronary artery bypass grafting 8 years previously. The ECG showed no significant changes, but his cTnI (Stratus CS) was increased to 4.3 µg/L, and his high-sensitivity CRP was 3.1 mg/L. WBCHO was increased to 69.7 µmol/L on admission and remained unchanged at 69.6 µmol/L after 6 h. The corresponding concentrations of PLCHO were 8.7 and 10.3 µmol/L.
Coronary angiography demonstrated a massive intravascular thrombus in the saphenous coronary bypass graft to the right coronary artery, which was treated successfully with aspiration-thrombectomy and a protection system against intracoronary thromboembolism (GuardWire® System) and 2 stents. The other coronary artery bypass grafts (left internal mammary artery bypass to the LAD and saphenous bypass graft to the ramus diagonalis) were open. His ejection fraction was mildly impaired (64%). The antiplatelet and antithrombotic therapy included aspirin, clopidogrel, tirofiban, and unfractionated heparin. WBCHO increased to 102.4 µmol/L, whereas PLCHO remained low (10.3 µmol/L). Serial concentrations of D-dimers were low (55, 49, and 75 µg/L). His short-term follow-up was uneventful, with treatment with clopidogrel, aspirin, metoprolol, atorvastatin, and ramipril.
Choline is an indicator of phospholipase D activity, which also generates potent platelet activators such as phosphatidic acid and lysophosphatidic acid. Phospholipase D is involved in platelet activation by collagen and thrombin (3)(4)(5)(6)(7), monocyte and macrophage activation by oxidized LDL (8), matrix metalloproteinase secretion, and endothelial cell dysfunction (9). We hypothesize that in these 3 patients increased concentrations of WBCHO reflected increased phospholipase D activity, platelet hyperreactivity, and advanced coronary plaque vulnerability.
In case 1, coronary intervention and antiplatelet medication without glycoprotein IIb-IIIa inhibitors was not sufficient to treat severe coronary plaque instability and platelet hyperreactivity, as indicated by excessive and persistent whole-blood hypercholinemia (>100 µmol/L), and the patient died of sudden cardiac death shortly after hospital discharge.
In case 2, WBCHO was the only test indicating evolving stent occlusion at an early stage, whereas other biomarkers such as cTnI, myoglobin, D-dimers, and the ECG were nondiagnostic. We were lucky that case 2 returned to the emergency room the next day. The integration of choline testing into routine clinical decision-making would have prevented inappropriate discharge from the emergency room. Whole-blood hypercholinemia in the setting of evolving stent thrombosis after clopidogrel withdrawal clearly points to platelet hyperreactivity as a major component for increased WBCHO in this patient.
In case 3, high concentrations of WBCHO were present in a massive thrombosis of a coronary bypass graft requiring aspiration-thrombectomy and stent implantation. This case is interesting because it demonstrates that exceptionally high concentrations of WBCHO (>100 µmol/L) may evolve in forms of massive intravascular (platelet) thrombosis, whereas other thrombosis markers (D-dimers) remain low.
In contrast to WBCHO concentrations, the PLCHO concentrations were low in all 3 cases. The difference between WBCHO and PLCHO concentrations are explained by several mechanisms: intracellular generation of choline in blood cells by intracellularly located phospholipase D and cell activation pathways (3)(4)(5)(6)(7), existence of a choline transport system in blood cells (10), and the fact that choline is removed to a certain extent from plasma via cellular uptake by other tissues (11). PLCHO is also a significant predictor of cardiac events, and concentrations increase in acute coronary syndromes complicated by acute left-ventricular failure and severe tissue ischemia (2), which was not evident in these cases. PLCHO concentrations were helpful in identifying the risk associated with phospholipase D activation in these patients more precisely as related to coronary plaque destabilization and coronary platelet thrombosis rather than to tissue ischemia.
It should be emphasized that these cases were selected for a discussion on the pathophysiology of whole-blood hypercholinemia in the absence of increased PLCHO and are not suitable for generalized conclusions on the differential clinical value of these markers, which should be based on clinical trials. Individual concentrations of whole blood and plasma choline have to interpreted with respect to the pathophysiology of acute coronary syndromes (12). Early biochemical detection of high-risk patients, as presented in these case reports, remains an important issue to target potentially life-saving advanced treatment strategies and to perform coronary angiography and intervention early and with sustained success.
References
IIb ß3-independent mechanism. Biochem J 1995;310:623-628.
The following articles in journals at HighWire Press have cited this article:
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  B. Yue, E. Pattison, W. L. Roberts, A. L. Rockwood, O. Danne, C. Lueders, and M. Mockel Choline in Whole Blood and Plasma: Sample Preparation and Stability Clin. Chem., March 1, 2008; 54(3): 590 - 593. [Abstract] [Full Text] [PDF]
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