Dear Editor

Reagarding the article by Collinson and Stubbs.[1]

Background

In their editorial of cardiac troponin, Collinson and Stubbs described its usefulness in diagnosis and predicting prognosis in patients with acute coronary syndromes.[1] They also summarised the conditions in which troponin may be elevated. This included rhythm disturbances such as prolonged tachyarrhythmia in the presence of ischaemic heart disease. We describe two cases of supraventricular tachycardia associated with a rise in troponin I in the absence of significant coronary artery disease. We suggest that an elevated troponin should only guide management in the context of the clinical findings.

Case 1

A 46-year-old Caucasian man who was previously fit and well presented to the emergency department with a two-hour history of palpitations and chest tightness. On examination he had a tachycardia of approximately 200 beats per minute but was not haemodynamically compromised with a blood pressure of 143/103. An ECG confirmed supraventricular, likely atrioventricular re-entrant, tachycardia. This was successfully terminated with the valsalva manoeuvre and his symptoms resolved. A repeat ECG showed a sinus rhythm of 96 beats per minute with no other abnormality. However, the patient had a troponin I of 1.2 (normal range Case 2

A 78-year-old Caucasian lady was admitted to the emergency department with chest tightness lasting three hours. There was no associated nausea, vomiting, sweating or palpitations. She had a past history of type II diabetes, hypertension and atrial fibrillation. On examination she had some chest discomfort. She had a tachycardia of 150 beats per minute and a blood pressure of 125/94 with no signs of cardiac failure. An ECG showed atrial flutter with 2:1 block and left ventricular hypertrophy with a strain pattern. CK on presentation was normal at 72 (normal range 20- 183iu/l). The pain resolved spontaneously and a repeat ECG showed sinus rhythm with no other abnormality. A second CK of 154 remained within normal range but troponin I 12 hours after onset of symptoms was raised at 1.1. Four days later the patient underwent coronary angiography, which showed concentric left ventricular hypertrophy but preserved systolic function. All coronary arteries were angiographically normal. The patient was discharged two days later with medical therapy.

Discussion

The patients described had elevated cardiac troponin in the presence of angiographically normal coronary arteries. Although this has been well described in association with a range of conditions, the association with tachyarrhythmias remains largely unrecognised.

A case series published this year described four cases of atrioventricular nodal re-entry tachycardia associated with a rise in troponin in the absence of coronary artery disease.[2] The degree of troponin elevation was unrelated to the duration and rate of tachycardia, a finding consistent amongst our cases. A second report describes 21 patients in whom the troponin was elevated despite normal coronary arteries or mild coronary artery disease (<_50 diameter="diameter" loss="loss" without="without" complex="complex" features="features" or="or" thrombus="thrombus" on="on" coronary="coronary" angiography.3="angiography.3" in="in" six="six" of="of" these="these" patients="patients" the="the" rise="rise" troponin="troponin" was="was" attributed="attributed" to="to" tachyarrhythmia="tachyarrhythmia" four="four" supraventricular="supraventricular" two="two" ventricular.="ventricular." p="p"/> Collinson and Stubbs stated that troponin may be elevated in prolonged arrhythmias in the presence of underlying ischaemic heart disease.[1] They postulated that this was due to secondary ischaemic myocardial injury caused by supply-demand mismatch. Myocardial damage sustained during tachycardia is reflected by the rise in troponin. Increased oxygen demand combined with a shortened diastole and reduced oxygen supply may be responsible.[2] Our findings suggest that supply- demand mismatch in tachyarrhythmia also occurs with normal coronary arteries. Our case reports also suggest arrhythmias do not have to be prolonged to cause secondary ischaemic myocardial injury. A tachyarrhythmia as brief as 120 minutes duration can induce a significant rise in troponin I. It has been stated that only 15 minutes of mild cardiac ischaemia is sufficient to cause release of cardiac troponin I degradation products and an elevation in troponin level.[4]

There is supportive evidence for the use of cardiac troponin levels in predicting prognosis and hence guiding management in selected patients with a high pre-test probability of acute coronary syndrome. This evidence does not extend to all patients presenting with chest pain. Troponin therefore should not be used to guide treatment or diagnose myocardial infarction in the absence of clinical features of an acute coronary syndrome. In these cases assuming that the rise is caused by plaque rupture requiring intervention or classifying the patient as acute myocardial infarction might simply delay instigation of the appropriate management. We suggest that an elevated troponin should only be used to diagnose myocardial infarction and guide management in the context of the clinical findings.

References

1. Collinson PO, Stubbs PJ. Are troponins confusing? Heart 2003; 89: 1285-7.

2. Zellweger MJ, Schaer BA, Cron TA, Pfisterer ME, Osswald S. Elevated troponin levels in the absence of coronary artery disease after supraventricular tachycardia. Swiss Medicine Weekly 2003; 133: 439-41.

3. Bakshi TK, Choo MK, Edwards CC, Scott AG, Hart HH, Armstrong GP. Causes of elevated troponin I with a normal coronary angiogram. Intern Med J 2002; 32: 520-5.

4. Higgins JP, Higgins JA. Elevation of cardiac troponin I indicates more than myocardial ischaemia. Clin Invest Med 2003; 26: 133-47.

Dear Editor

In the manuscript "Catheter based intracoronary brachytherapy leads to increased platelet activation" the authors observe an increased platelet activation as assessed by the activation markers CD63 (content of platelet lysosomes) and thrombospondin (content of platelet a-granules) immediately following intracoronary intervention. This occurred only when patients had received catheter-based irradiation, but not when conventional PCI was performed.[1]

We have previously performed a more detailed analysis of the time- course of platelet activation patterns following intracoronary irradiation using a similar experimental design, which was substantiated by assessment of samples obtained from intracoronary and peripheral locations [2]. In accordance with the findings by Jaster and colleagues, we found sings for degranulation of platelets, which occurred 6 hours following the intervention and remained sustained for up to 6 months. We also observed activation parameters to be elevated at 6 hours in patients treated with conventional PCI only. These patients, however, returned to baseline platelet activation levels at 6 months following the intervention, which is a clear sign that indirect effects on platelets, such as disturbed reendothelialisation, which may prevail in irradiated vessels [3], should be responsible for the increase in platelet activation. In accordance with this, clinical data show that thrombotic occlusions of irradiated vessels preferentially occur at later time points following intracoronary irradiation.[4]

In addition to the findings presented here, we observed not only an increase in markers that appear solely upon activation of platelets (such as CD63 and thrombospondin), but also markers that are constitutively expressed on platelets, such as the fibrinogen receptor subunit CD41, which was upregulated 6 hours following the intervention. Moreover, we could observe long-term upregulation of platelet CD40 ligand, a molecule associated with atherothrombotic disease [5] and decreased endothelial cell migration,[6] which thus could be involved in delayed reendothelialisation.[7]

Partly diverging from the conclusions that are drawn by Jaster and colleagues, we think that both studies give a strong evidence of indirect effects being responsible for sustained platelet activation following intracoronary irradiation rather than a thrombogenic surface of the source trains or a direct effect on platelets that may take place in vivo only. This is corroborated by the findings of Jasper and colleagues, who cannot induce platelet activation by direct irradiation of isolated platelets [1]. Mechanically damaged endothelium that shows altered and possibly impaired healing in irradiated vessels seems to be a more likely pathophysiological cause for late thrombotic occlusion to us.

References

1. Jaster M, Fuster V, Rosenthal P, Pauschinger M, Tran QV, Janssen D et al. Catheter based intracoronary brachytherapy leads to increased platelet activation. Heart 2004;90:160-4.

2. Krotz F, Schiele TM, Zahler S, Konig A, Rieber J, Kantlehner R et al. Sustained platelet activation following intracoronary beta irradiation. Am.J.Cardiol. 2002;90:1381-4.

3. Salame MY, Verheye S, Mulkey SP, Chronos NA, King SB, III, Crocker IR et al. The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries. Circulation 2000;101:1087-90.

4. Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J.Am.Coll.Cardiol. 2000;36:65-8.

5. Andre P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO et al. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat.Med. 2002;8:247-52.

6. Urbich C, Dernbach E, Aicher A, Zeiher AM, Dimmeler S. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. Circulation 2002;106:981-6.

7. Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet- derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002;106:896-9.

Dear Editor

I was disappointed to read the case report describing a catastrophic outcome in a neonate with an arrhythmia. While I agreed with each statement in the Discussion, the title suggested a direct causal relationship between the flecainide and ventricular fibrillation. In my opinion, this relationship was not proven, nor could it be.

There are several important data not available in this case. It is not clear what the original arrhythmia diagnosis in this patient was, the duration of the episode, nor the degree of cardiac dysfunction present at birth. The lack of response to vagal maneuvers (ice) and adenosine are not specific but do raise the possibility that an automatic focus was involved as opposed to a nodal dependent tachycardia. The working diagnosis was excluded by the authors when facing a broad complex tachycardia at 170 bpm. Following the resuscitation, the “ECG showed broad complex tachycardiac arrests and re-entrant supraventricular tachycardia…”. While I am not familiar with the first term, I find it difficult to conceive how the diagnosis of re-entrant SVT was made, particularly in the absence of a response to adenosine. Perhaps an illustrative tracing would be helpful.

I share the authors’ view that neonates with arrhythmias are a clinical challenge, and that the medications we use have potentially life- threatening adverse effects. However, this case has not demonstrated unequivocally that flecainide caused VF in this neonate when there are so many issues not addressed in this report. More importance is sometimes placed on case reports in pediatric cardiology since there are relatively fewer cases than in the adult cardiology sphere, and caution must be used when “sounding the alarm”.

Dear Editor

We have read with great interest the manuscript by Chakrabarti et al.[1] on immunodeficiency in patients suffering from protein losing enteropathy (PLE) after Fontan palliation. The authors reported of lymphopenia and T-lymphocyte loss in two children with PLE. The infrequency of this syndrome and the even rarer immunological investigation of affected patients makes these observations very precious. According to a literature search only four additional references focused on the immunocytes in PLE patients with Fontan palliation. Koch et al. [2] and Garty [3] reported of one child, Cheung et al. of six [4] and our group of eight.[5] This sums up to 18 children with PLE and Fontan circulation in whom T-lymphocyte loss is reported. Furthermore, it was shown that this loss is selective for helper T-lymphocytes (Th) and hardly affects cytotoxic T-lymphocytes (Tc).[2-5] Decrease in B lymphocyte and natural killer cell counts was not observed [2,4] except in one case.[3]

Immunodeficiency

But is this selective loss really an immunodeficiency? With the present knowledge this is still questionable. Immunodeficiency is defined as the defective function of one or more components of the immune system. However, dysfunction of components of the immunesystem has not been shown yet. There is one additional argument that makes the interpretation of the cell loss as immunodeficiency questionable. In patients with immunodeficiency an increased frequency of immunological problems such as recurrent and opportunistic infections, certain types of malignancies among others should be expected. However, in the reported 18 children with PLE and T-cell loss only two (11%) suffered from recurrent infections worth mentioning,[3,6] agreeing with the infection rate of 16% reported by Mertens et al. [7] in their multicentric study. It can not be excluded that this immunodeficiency was the consequence of immunosuppressive therapy. Obviously, this low frequency of reported opportunistic infections does not exclude immunodeficiency and we propose to screen more carefully infection frequency in Fontan patients with and without PLE. There is some additional argument why PLE patients, in spite of massive Th -cell loss, still maintain a relatively intact immunity. Most PLE patients have relatively mature immunesystem. PLE developed in the patients of the above mentioned studies at a median age of 10.3yrs (range: 5.5 – 17yrs).[1-4, 6] This agrees well with the study of Mertens et al. (median: 11.7 yrs).[7] At this age the memory B-cells responding to “known” infections are present and cells responding to viral infections and malignant cells, Tc cells and NK/NKT – cells, remain in the circulation. In a detailed study by Fuss et al. [5] on PLE patients with lymphangiectasia (without congenital heart disease and Fontan palliation) it was shown that by the Th cell loss mostly naive Th cells but not memory cells are affected. This is in agreement with studies of our group on Fontan patients with PLE.[5] Therefore, in spite of the dramatic Th cell loss the level of memory Th cells is maintained and a fairly normal immune defence is possible.

Trigger of PLE

As stated by Chakrabarti et al. [1] it is still an open question why PLE occurs with a very heterogeneous time delay after Fontan palliation. Rychik and Spray (9) observed frequently infections at PLE onset and postulated that they may be one trigger for PLE. We have shown that seven of eight patients had at PLE onset acute infections of mostly gastric origin.[6] Infections of different origin are not unusual in children. Therefore, infection can be one stimulus but it must be postulated that other additional factors are necessary to lead to PLE. Obviously, increased systemic venous pressure is one risk factor [7] and clinical difficulties may arise when thereby the lymphatic system begins to fail.[10] Fontan circulation also leads to the impairment of gut, lung and liver perfusion and affects these organs.[10,11,12] Gut perfusion alterations, as an example, may impair the intestinal immune defence.[13] PLE is most certainly the common endpoint of a multifaceted disease. We have postulated that also a specific genetic background or a predisposition for autoimmune disease [14] could be yet unrecognised important factors. Genetic analysis needs in future to be launched to answer this question in detail.

Prediction of PLE

In their paper Chakrabarti et al. [1] make an important point in stating that regular immunological screening of Fontan patients is of importance in order to define risk groups for PLE. We strongly support this approach. We have recently published in a retrospective study on 15 children evidence that immunological screening may be of use for discriminating Fontan patients without PLE risk from those who show transient signs of protein loss or develop manifest PLE.[15] Based on the mathematical approach of data mining we could select a panel of laboratory parameters that seem to be useful for risk assessment and may be tested by other laboratories. Our results show that NK and Tc cell count as well as serum L-selectin, IgE, and Ca₂+ may play role in PLE manifestation after Fontan palliation. Alterations of the cell count of CD8positive T-cell receptor gamma,delta positive lymphocytes in the peripheral blood of risk patients may in addition also indicate an impaired gut mucosal immune function as these cells represent a major population of the gut’s defence line.[13] By further testing and optimising the immunological panel, individual risk assessment may become possible in future. This should lead to the improved prophylactic and therapeutic management of risk patients [1,9] and hopefully to the avoidance of PLE.

References

1. Chakrabarti S, Keeton BR, Salmon AP, et al. Acquired combined immunodeficiency associated with protein losing enteropathy complicating Fontan operation. Heart 2003;89:1130-1.

2. Koch A, Hofbeck M, Feistel H, et al. Circumscribed intestinal protein loss with deficiency in CD4+ lymphocytes after the Fontan procedure. Eur J Pediatr 1999;158:847-50.

3. Garty BZ. Deficiency of CD4+ lymphocytes due to intestinal loss after Fontan procedure. Eur J Pediatr 2001;160:58-9.

4. Cheung YF, Tsang HY, Kwok JS. Immunologic profile of patients with protein-losing enteropathy complicating congenital heart disease. Pediatr Cardiol 2002;23:587-93.

5. Lenz D, Sauer U, Hambsch J, et al. Immune alterations following protein losing-enterophathy (PLE) after Glenn/Fontan surgery are similar to those after systemic lupus erythematosus (SLE) and celiac disease (CD): Indications for an autoimmune disease. Immunbiology 2000;203:217.

6. Lenz D, Hambsch J, Schneider P, et al. Protein-losing enteropathy in patients with Fontan circulation: is it triggered by infection? Crit Care 2003;7:185-90.

7. Mertens L, Hagler DJ, Sauer U, et al. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg 1998;115:1063-73.

8. Fuss IJ, Strober W, Cuccherini BA, et al. Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD 45 RA+ lymphocytes into the gastrointestinal tract. Eur J Immunol 1998;28:4275-85.

9. Rychik J, Spray TL. Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:3- 11.

10. Bull K. The Fontan procedure: lessons from the past. Heart 1998;79:213-4.

11. Yamagishi M, Kurosawa H, Hashimoto K, et al. The role of plasma endothelin in the Fontan circulation. J Cardiovasc Surg (Torino) 2002;43:793-7.

12. Narkewicz MR, Sondheimer HM, Ziegler JW, et al. Hepatic dysfunction following the Fontan procedure. J Pediatr Gastroenterol Nutr 2003;36:352-7.

13. Wang J, Whetsell M, Klein JR. Local hormon networks and intestinal T cell homeostasis. Science 1997; 275:1937-9.

14. Lenz D, Hambsch J, Sauer U, et al. Detection of allo- and autoreactive antibodies in patients with protein losing enteropathy (PLE) who underwent Fontan surgery. Cardiol Young 2003;13:251.

15. Lenz D, Hambsch J, Schneider P, et al. Protein-losing enteropathy after fontan surgery: Is assessment of risk patients with immunological data possible? Cytometry 2003;53B:34-9.