Dear Editor,

We read with great interest the British Cardiac Society’s (BCS) recommendations regarding proposed nomenclature for acute coronary syndromes (ACS) [1]. These experts attempt to alter the new definition of myocardial infarction (MI) established by the European Society of Cardiology (ESC) /American College of Cardiology (ACC) that rely predominately on increased concentrations of serum biomarkers of myocardial necrosis when there is evidence of myocardial ischemia (symptoms, electrocardiographic changes, intervention, or pathology) [2]. While the recommendations are well written and thus may help clinicians understand the spectrum of acute coronary syndromes; in our opinion, there are apt to increase the existing confusion [3-6] with regard to the appropriate cut off values for troponin T and I.

These recommendations move us backwards, not forwards. In 1999, the National Academy of Clinical Biochemistry (NACB) and the International Federation of Clinical Chemistry (IFCC) recognized the inadequacy of the 1971 World Health Organization's (WHO) definition of MI with the development of highly sensitive (non-enzyme) protein markers such as cardiac troponin [7,8].

These laboratory medicine groups recognized the diagnostic importance of detecting minor myocardial increases in troponin in patients with symptoms suggestive of MI, since these patients have on-going myocardial damage. They were also aware that such elevations stratify patients at high very short-term risk for death (e.g., during hospitalization) and recurrent MI, similar in frequency to other non-Q- wave MIs. The NACB and IFCC suggested two cutoff concentrations for cardiac troponin. The first one was established using receiver operating characteristic (ROC) curve analysis to select an optimum cutoff to differentiate between unstable angina and WHO-defined MI. Although widely practiced at the time, this first cutoff recommendation was not evidence- based, as there were no prospective studies to validate this approach, purposefully lowered to be useful for risk stratification. The second (lower) cutoff was set at the 97.5th percentile of a healthy reference population. These guidelines stopped short of redefining MI and suggested that this was the prerogative of international cardiology organizations. In 2000, the ESC/ACC subsequently recommended the use of a single cutoff for MI diagnosis at the 99th percentile of a healthy reference population, a value that was slightly higher than the 97.5th percentile. The redefinition of MI by the ESC/ACC and endorsed by other groups such as the Italian Federation of Cardiology, [9] the IFCC, and the international epidemiology community [10] simplified the criteria by obviating the need for multiple troponin cutoffs.

The BCS Working Group now has recommended a return to two cutoff concentrations. They suggest that patients with “ACS with clinical MI” are defined as cTnT >1.0 ng/ml and cTnI (AccuTnI) >0.5 ng/ml. It is alleged that these cutoffs approximates the traditional WHO definition of MI, but some of them are very different from what the NACB indicated would fulfill this criterion. They further suggest that patients with detectable troponin values at concentrations below these MI cutoff limits be designated as having “ACS with myocyte necrosis.” Although no concentrations were cited, the working group intimated that the 99th percentile could be used as the lower limit of this rage if the assay had acceptable precision (i.e., coefficient of variance of less than 10%). Patients with “ACS with unstable angina” would then have ECG evidence or history of coronary disease but with undetectable troponin concentrations.

The return to a two-cutoff designation is a departure from the concept that when there is evidence of myocardial injury induced by ischemia that MI has occurred. This deviates from the well established data that the release of serum biomarkers into blood reflects the continuum of ACS disease severity. There is no pathophysiologic basis with which to subdivide troponin-positive patients into those with myocyte necrosis vs. MI. Moreover, from a risk stratification view, the risk of adverse events is also continuous, i.e., there is no troponin threshold for which cardiovascular risk becomes exponentially increased (as for example, total cholesterol).

The Working Group recommended values of 1.0 ng/ml for cTnT and 0.5 ng/ml for cTnI is without evidence and are apparently based on unpublished personnel communications. In fact, while the 0.5 ng/ml cutoff for the Beckman AccuTnI agrees with the manufacturer’s ROC cutpoint, the 1.0 ng/ml for Roche cTnT is 3 to 10-fold higher than the manufacturer’s recommendation [11]. Assuming the values provided by the companies are data driven, it is likely that this suggestion will widen the differences in the frequency of the diagnosis of AMI between cTnT and cTnI assays [10,12]. Furthermore, the concept that one can determine similar cutoff values by relying on their relationship to the values for cTnT (only 1 assay manufactured by Roche) and for cTnI with the Beckman assay (one of more than a dozen assays in the international marketplace) ignore the important facts that individual assays use different antibodies, different chemical matrixes, and thus will give different signals for the troponin [11]. While harmonization is possible, complete standardization will likely never be possible given these differences in commercial assays.

Finally, although we agree with the Working Group that there is a continuous relationship between troponin and MI disease severity, there is only limited data that suggests that the higher cutoff provides indirect evidence of left ventricular dysfunction [13,14]. Such a statement is particularly surprising given the marked disparity chosen between the cTnT ROC value and the one for cTnI. Until data to support this apporach is forth coming, we would argue that such a determination might best rely on for B-type natiruretic peptide15 or NT-proBNP16 or imaging techniques rather than troponin. The international community needs to be educated that all cardiac troponin assays are not created equal and that absolute cardiac troponin concentrations cannot be assumed to be interchangeable for diagnosis, risk stratification, and therapeutic decisions.

References

(1). Fox FAA, Birkhead J, Wilcox R, et al. British Cardiac Society Working Group on the definition of myocardial infarction. Heart 2004;90:603-9.

(2). Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-69.

(3). Norris RM. Dissent from the consensus on the redefinition of myocardial infarction.[comment]. Eur Heart J. 2001; 22:1626-7.

(4). Tormey W, Birkhead JS, Norris RM, et al. Redefinition of myocardial infarction. Lancet 2001; 358:764.

(5). Richards AM, Lainchbury JG, Nicholls MG. Unsatisfactory redefinition of myocardial infarction. Lancet 2001;357:1635-6.

(6). Tunstall-Pedoe H. Redefinition of myocardial infarction by a consensus dissenter.[comment]. J Am Coll Cardiology 2001; 37:1472-4.

(7). Wu AHB, Apple FS, Gibler WB, Jesse RL, et al. National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for use of cardiac markers in coronary artery diseases. Clin Chem 1999;45:1104-21.

(8). Panteghini M, Apple FS, Christenson RH, et al. Proposals from IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD): recommendations on use of biochemical markers of cardiac damage in acute coronary syndromes. Scan J Clin Lab Invest 1999;59 (suppl):103-12.

(9). Galvani M, Panteghini M, Ottani F, et al. The new definitionl of myocardial infarction: analysis of the ESC/ACC Consensus Document and relections on its applicability to the Italian Health System. Ital Heart J 2002;3:543-57.

(10). Luepker RV, Apple FS, Christenson RH, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies. Circulation 2003;108: 2543-9.

(11). Apple FS, Wu AHB, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J 2002;144:981-6.

(12). Lin JC, Apple FS, Murakami MM, et al. Rates of positive cardiac troponin I and creatine kinase MB among patients hospitalized for suspected acute coronary syndromes. Clin Chem 2004;50: 333-8.

(13). Rao AC, Collinson PO, Canepa-Anson R et al. Troponin T measurement after myocardial infarction can identify left ventricular ejection of less than 40%. Heart 1998;80:223-5.

(14). Panteghini M, Cuccia C, Bonetti G, Giubbini R, Pagani F, Bonini E. Single-point cardiac troponin T at coronary care unit discharge after myocardial infarction correlates with infarct size and ejection fraction. Clin Chem 2002;48:1432-6.

(15). Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST- elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003; 41:1264-72.

(16).Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol 2003

Dear Editor,

The authors are to be congratulated on providing a 5 year follow up report on their groups of Wilm’s tumour and acute lymphoblastic leukaemia (ALL) patients first studied in 1991-2.

It is very interesting that their findings are very similar to our own follow-up cohort [1] and that these abnormalities are more noticeable than at a shorter post-treatment interval [2]. What is odd is that clear increases in both peak early filling velocity (E) and Early to Atrial filling velocity ratio (EA ratio) as well as prolongation of the Isovolumic Relaxation (IVRT) and Deceleration times are noted in both groups of patients.

These abnormalities do not usually occur together. Impaired myocardial relaxation in the absence of mitral regurgitation is generally associated with increased atrial phase filling and a reduction in EA ratio. It is not commented whether these abnormalities are common to all patients but the authors do note that patients with reduced fractional shortening at later study had reduced early filling at earlier examination (similar to the association reported in our own studies [3]). Neither do the authors comment on the prevalence of potential cardiac irradiation in either study group. It seems likely that these patients groups are not as uniform as the authors assert; not only will there be a range of cumulative anthracycline doses received but also different diastolic and systolic susceptibilities; as reported in both our prospective (on-treatment [2]) and follow-up [1] studies. The Wilm’s tumour patients may also have variable elevation of the blood pressure.

One of the real difficulties with interpreting group diastolic filling data for use in clinical practice is that the bimodal effects of impaired relaxation, myocardial restriction due to fibrosis (most marked after radiotherapy to the cardiac field) and elevated end diastolic pressure actually require more detailed breakdown of even apparently relatively homogeneous study groups. These grouped data do not support the assertion that ‘routine assessment of diastolic flow characteristics does not offer useful extra clinical information’ except in this group setting.

On an individual basis it may actually be very helpful to have serial information as to the diastolic performance of an individual patient’s heart, particularly where symptoms or systolic decompensation subsequently ensue. The authors also miss the opportunity to emphasise the importance of the progressive nature of myocardial abnormalities as compelling justification for life-long cardiac surveillance in these patients.

I would also like to point out that our prospective study [2] (referred to by the authors as cross-sectional) was a true prospective cohort study during anthracycline treatment, and that neither of our study groups [1,2] contained patients who had received non-anthracycline containing treatment regimes.

References

(1). Left ventricular diastolic function after anthracycline chemotherapy in childhood: Relation with systolic function, symptoms and pathophysiology Bu'Lock F A, Mott M G, Oakhill A, Martin R P Br Heart J 1995; 73: 340-50

(2). Left ventricular diastolic filling patterns associated with progressive anthracycline induced myocardial damage; A prospective study Bu'Lock FA, Mott MG, Oakhill A, Martin RP Pediatric Cardiology 1999; 20: 252-263

(3). Early identification of anthracycline cardiomyopathy: Possibilities and implications Bu'Lock FA, Mott MG, Oakhill A, Martin RP Archives of Diseases in Childhood 1996; 75: 416-22

Dear Editor,

We read with interest the image report by Ahn et al[1] However, we differ regarding the mechanism of the pseudolesions described. The right iliac artery is not having spasm as reported but the narrowings are because of concertina effect. Concertina or accordian effect is the appearance of artefactual or pseudolesions which appear in a tortuous vessel when it is straightened by a guidewire or a catheter.[2]

The mechanism suggested is partial straightening of a tortuous artery by the guidewire or catheter that causes mechanical invagination of the arterial wall at various sites. During straightening of a curve, the total vessel length remaining constant, the excess vessel wall heaps up appearing as pseudolesions, resulting in varying degrees of luminal encroachment and obstruction to the flow.[3] Pseudolesions may be single or multiple, the number and extent being proportional to the degree of curvature and the extent of straightening.[3] Pseudolesions have been well defined in coronary arteries but also have been reported in the external iliac artery.[4]

The authors comment that the pseudolesions disappeared after removing the guidewire without any medication or intervention further proves that they were because of concertina effect and not guidewire induced spasm as reported. In fact, familiarity with the appearance and mechanism thereof are of extreme importance, as failure to do so may lead to inappropriate intervention with its attendant risks. We have frequently encountered concertina effect in tortuous external iliac arteries in our high volume catheterization laboratory in a tertiary care hospital.

References

(1). Ahn Y, Hong YJ, Jeong MH. Catheter induced multiple spasms in the right iliac artery during a percutaneous coronary intervention. Heart 2004; 90: 207.

(2). Rauh RA, Ninneman RW, Joesph D, Gupta VK, Senior DG, Miller WP. Accordian effect in tortuous right coronary arteries during percutaneous transluminal coronary angioplasty. Cathet Cardiovasc Diagn 1991; 23:107- 110.

(3). Doshi S, Shiu MF. Coronary pseudo-lesions induced in the left anterior descending and right coronary artery by the angioplasty guide-wire. Int J Cardiol 1999; 68: 337-342.

(4). Joseph D, Idris M. Catheter-Induced “accordian effect” in tortuous right external artery during peripheral angiography. Cathet Cardiovasc Diagn 1995;34:318-320.

Dear Editor,

Looking at the problem from a metabolic perspective it would seem to me that the therapeutic objective in these patients might be to achieve the highest cardiac reserve at rest by increasing the nutrient energy density per unit volume of flowing blood. This should optimise their capacity for increasing ATP resynthesis by oxidative phosphorylation in response to a sudden increase in need for energy from ATP hydrolysis precipitated by physical exertion or even metabolic exertion such as that induced by eating.

Perhaps this is what is being achieved in inotrope-dependent patients, an infusion of adrenaline in a ambulatory patient increasing glucose uptake and utilisation. If so an infusion of glucose, K+ and insulin might be safer and even more effective option than inotropes for it should not increase myocardial workload as much [1]. [It is the dynamics of energy demand/supply balance that is critical, the time taken in restoring tissue pH to baseline levels possibly being the critical measurable variable in these patients].

From my conversation with a cardiac surgeon at the Texas Heart Institute, administering an inotrope to patients awaiting cardiac transplantation is a very risky business because it can precipitate fatal myocardial events. Certainly an IV infusion of adrenaline is not without risk. He was also of the opinion that these patients, whose cardiac index can be much less than two, might do better without any inotropes.

Might the degree of lipid shift present at rest be the determining factor in the energy demand/supply balance of these patients. The higher the degree of shift the greater the nutrient energy density per unit volume of blood available for delivery to tissues and hence need for a increase in cardiac output to deliver the nutrient needed for ATP resynthesis? If so might an IV infusion of omega-3-fatty acids be of therapeutic benefit in these patients? The danger is that, being an uncoupler, polyunsaturated fatty acid supplementation might have an adverse effect upon outcome if not in the short-term then in the longer- term [2].

Intelligent exploration of the metabolic options for treating patients is dependent upon the ability to measure and monitor their effects sensitively and objectively both at the systemic and the regional level. Pharmacological interventions could cause sudden and variable changes in either direction. Until this is done the effects of any pharmacological intervention will be unpredictable especially in patients such as these with such compromised myocardial tissue energetics.

References

(1). Glucose-K+-insulin and/or omega-3 fatty acid infusions for prolonged anaesthesia/surgery? Richard G Fiddian-Green (2 August 2004) eLetter re: T Tsubo, T Kudo, A Matsuki, and T Oyama Decreased glucose utilization during prolonged anaesthesia and surgery Can J Anesth 1990; 37: 645-649

(2). Might polyunsaturated fatty acid supplementation in infant formula be harmful? Richard G Fiddian-Green bmj.com, 2 May 2003 eLetter re: J S Forsyth, P Willatts, C Agostoni, J Bissenden, P Casaer, and G Boehm Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial BMJ 2003; 326: 953