I read with great interest the report of Law et al [1]. The authors examined one-year mortality risk in 432 patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) to detect useful biomarkers. The adjusted hazard ratio (HR) (95% confidence interval [CI]) of the change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) per 500 ng/L increase for mortality was 1.04 (1.01 to 1.07). In addition, the adjusted HRs (95% CIs) of the increases in ∆ NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L for mortality were 1.65 (1.18-2.31), 1.92 (1.37-2.70), and 2.87 (1.93-4.27), respectively. They concluded that the change in NT-proBNP concentration during the first year was an independent predictor of mortality in patients with wtATTR-CM. I have a comment about this study.
Ochi et al. examined two-year mortality risk in 47 patients with wtATTR-CM [2], and low serum albumin (≤3.75 g/dL), elevated high-sensitivity cardiac troponin T (hs-cTnT; >0.086 ng/mL), and low left ventricular ejection fraction (LVEF; <50%) are significantly associated with mortality in patients with wtATTR-CM. According to the total number of these 3 risk factors, patients were stratified into 4 subgroups: low risk (no risk factors), intermediate-low risk (1 risk factor), intermediate-high risk (2 risk factors), and high risk (3 risk factors). The estimated two-year survival rate of patients classified as low risk, intermediate-low risk, intermediate-high r...
I read with great interest the report of Law et al [1]. The authors examined one-year mortality risk in 432 patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) to detect useful biomarkers. The adjusted hazard ratio (HR) (95% confidence interval [CI]) of the change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) per 500 ng/L increase for mortality was 1.04 (1.01 to 1.07). In addition, the adjusted HRs (95% CIs) of the increases in ∆ NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L for mortality were 1.65 (1.18-2.31), 1.92 (1.37-2.70), and 2.87 (1.93-4.27), respectively. They concluded that the change in NT-proBNP concentration during the first year was an independent predictor of mortality in patients with wtATTR-CM. I have a comment about this study.
Ochi et al. examined two-year mortality risk in 47 patients with wtATTR-CM [2], and low serum albumin (≤3.75 g/dL), elevated high-sensitivity cardiac troponin T (hs-cTnT; >0.086 ng/mL), and low left ventricular ejection fraction (LVEF; <50%) are significantly associated with mortality in patients with wtATTR-CM. According to the total number of these 3 risk factors, patients were stratified into 4 subgroups: low risk (no risk factors), intermediate-low risk (1 risk factor), intermediate-high risk (2 risk factors), and high risk (3 risk factors). The estimated two-year survival rate of patients classified as low risk, intermediate-low risk, intermediate-high risk, and high risk was 93%, 80%, 83%, and 11%, respectively. Although they conducted a longer follow-up period, the number of samples was limited. In addition, they used baseline data as predictors of prognosis. Regarding to the results by Law et al [1], changes in serum albumin, hs-cTnT, and LVEF did not became significant predictors for one-year mortality.
Ochi et al. used B-type natriuretic peptide concentration, which was different in clinical meaning of NT-proBNP [2]. Taken together, further studies with longer follow-up is recommended to evaluate prognosis in patients with wtATTR-CM.
REFERENCES
1 Law S, Petrie A, Chacko L, et al. Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.. Heart 2021 May 14. doi: 10.1136/heartjnl-2021-319063
2 Ochi Y, Kubo T, Baba Y, et al. Prediction of Medium-Term Mortality in Japanese Patients With Wild-Type Transthyretin Amyloidosis. Circ Rep 2020;2:314-21.
I am one of the 95 survivors in your article having had the mustard operation in 1980 and would just like to thank everyone who took part in putting this together. I found it very usefull and interesting.
Adam Timmis gives an excellent overview of risk stratification in acute coronary syndromes and he outlines recommended management strategies.[1] We were confused however by his suggestion that "the diagnostic value of exertional ST segment depression and thallium perfusion defects are equivalent, making the treadmill more cost effective than the gamma camera". It is not clear whether the diagnostic value to which he refers is...
Adam Timmis gives an excellent overview of risk stratification in acute coronary syndromes and he outlines recommended management strategies.[1] We were confused however by his suggestion that "the diagnostic value of exertional ST segment depression and thallium perfusion defects are equivalent, making the treadmill more cost effective than the gamma camera". It is not clear whether the diagnostic value to which he refers is the diagnosis of coronary disease, the detection of residual myocardial ischaemia, or the prediction of future coronary events. He quotes a meta-analysis of Shaw and colleagues [2] who reviewed non-invasive tests in assessing the risk of coronary events after myocardial infarction, hence we presume that he intended to say that the exercise ECG is equally effective and hence more cost-effective than the gamma camera for risk stratification. We do not believe that this view is justified and we would like to expand on three points.
First, there are no formal studies of the cost-effectiveness of risk stratification after infarction, and in their absence it is not warranted to extrapolate from the effectiveness and cost of individual tests to a statement on cost-effectiveness. To do so ignores induced costs (for instance when an abnormal exercise ECG leads to angiography without subsequent intervention), it ignores the relatively high failure rate of the exercise ECG after infarction (submaximal exercise, abnormal resting ECG, etc), and it ignores the need for further investigation in the chronic phase (such as myocardial perfusion imaging if this has not already been performed). For the diagnosis of coronary artery disease, there is now powerful evidence to indicate that strategies that include myocardial perfusion imaging are more cost effective than those that do not.[3][4] Because diagnosis involves the detection of ischaemia and because persistent ischaemia after infarction is a key factor in prognosis, it is likely that formal studies of cost effectiveness of risk stratification would provide similar results.
Second, although the positive predictive value of any form of pre-discharge non-invasive testing is low,[2] Dr Timmis ignores the superior positive predictive value of perfusion imaging compared with the exercise ECG in patients who have not received thrombolysis (13% versus 9% for death and 24% versus 18% for death or reinfarction). Since the distinction between patients who have and who have not received thrombolysis is mainly the size of their infarcts, it seems to us that a test that is capable of assessing infarct size and prognosis in those with large infarcts should not be cast aside so easily. Shaw and colleagues[2] also emphasised the relatively poor quality of the studies available. For instance, three quarters of the studies were retrospective and one third reported fewer than 5 deaths, and they recognised the need for further studies to provide more reliable information. Further high quality studies are now available and we believe that the weight of evidence is that perfusion imaging is more effective than the exercise ECG for risk stratification after myocardial infarction.
Numerous studies have shown that inducible perfusion abnormalities are more common than ST segment changes on the exercise ECG.[5][6][7] This extends observations from the era before thrombolysis when an inducible thallium defect was shown to be better than the exercise ECG for detecting and localising ischaemia and for identifying multi-vessel disease. However, because thrombolysis has reduced the event rate after infarction, there are those who argue that the event rate is now so low that myocardial perfusion imaging is less valuable after infarction than it was.[5] [8] However these studies included a relatively low risk group with younger patients, preserved left ventricular function, and a low prevalence of multi-vessel disease. The higher risk patients were excluded because they mainly went straight to angiography and revascularisation and it is precisely these who would have been best identified by myocardial perfusion imaging if doubt remained after clinical assessment. In addition, selection bias was operating against perfusion imaging because when it was performed the results were used to guide intervention and hence to exclude the patient from follow-up. It is not surprising that non-invasive testing was not found to be valuable in the few remaining low risk patients.
In better designed studies there is now ample evidence that perfusion imaging is a valuable tool for risk stratification after infarction. Dakik and colleagues[7] reported that a predischarge exercise myocardial perfusion scan in patients who had received thombolysis provided incremental prognostic information over and above clinical and ejection fraction data. In contrast, none of the variables from the exercise ECG contributed to the assessment of prognosis. Similarly, Travin and colleagues[9] found that myocardial perfusion imaging within 14 days of infarction frequently revealed residual ischaemia and was better than clinical and exercise ECG variables in identifying patients at high risk. More recently, Brown and colleagues[10] reported a multi-centre trial in patients with first acute infarction. Three hundred and thirty nine patients were randomised to early (2 to 4 days) dipyridamole myocardial perfusion imaging followed by predischarge (6 to 12 days) sub-maximal exercise imaging, and 112 patients were randomised to submaximal predischarge imaging alone. The findings of the early perfusion study were not available to the responsible physicians and hence patient management was not affected. Early dipyridamole imaging was safe and was predictive of both in-hospital and late cardiac events, and it was a stronger predictor than predischarge submaximal exercise ECG or submaximal exercise perfusion imaging. This prognostic value was independent of thrombolytic status.
Third, with regard to the influence of left ventricular function on prognostic power, Mahmarian and colleagues[11] compared adenosine perfusion imaging and ejection fraction after infarction and found them to have complementary roles. They found that even patients with an ejection fraction greater than 40% were further stratified into low and high risk groups by the extent of the inducible perfusion defect. This study and the guidelines of the American College of Physicians[12] contradict Dr Timmis's recommendation that further risk stratification is not required in asymptomatic patients with an ejection fraction greater than 40%. Indeed, the ACP guidelines suggest that these are the patients in whom non-invasive risk stratification is most successful.
With the growing pressure to reduce costs but maintain quality of care, accurate risk stratification at an early stage using myocardial perfusion imaging with vasodilator stress in all but the highest risk patients could have important benefits. Low risk patients could be discharged earlier than those at a higher risk and in-hospital cardiac events might be prevented. Because of the complementary role of perfusion and functional information, it is conceivable that combined assessment of both using gated SPECT could be highly effective in routine use, particularly since left ventricular end systolic volume appears to be more powerful in prognostic terms than ejection fraction alone.
In summary, we believe that there is sufficient evidence to modify Dr Timmis's algorithm to require early myocardial perfusion imaging rather than exercise ECG in all but the highest risk patients assessed by clinical criteria, and to include patients with relatively preserved LVEF in this strategy. We predict that such an approach will be cost-effective.
S Richard Underwood, MD, FRCP, FRCR, FESC
Imperial College School of Medicine
Royal Brompton Hospital
Sydney St, London SW3 6NP
Constantinos Anagnostopoulos MD, PhD
Royal Brompton Hospital
Sydney St, London SW3 6NP
Leslee J Shaw PhD
Emory University School of Medicine
1518 Clifton Road NE, Rm638
Atlanta, Georgia 30322, USA
References
1 Timmis A. Acute coronary syndromes: risk stratification. Heart 2000;83:241-6.
2 Shaw LJ, Peterson ED, Kesler K, et al. A metaanalysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion and ventricular function imaging. Am J Cardiol 1996;78:1327-37.
3 Underwood SR, Godman B, Salyani S, et al. Economics of myocardial perfusion imaging in Europe: the EMPIRE study. Eur Heart J 1999;20:157-66.
4 Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterisation ischaemia. J Am Coll Cardiol 1999;33:661-9.
5 Tilkemeier PL, Guiney TE, LaRaia PJ, et al. Prognostic value of predischarge low-level exercise thallium testing after thrombolytic treatment of acute myocardial infarction. Am J Cardiol 1990;66:1203-7.
6 Haber HL, Beller GA, Watson DD, et al. Exercise thallium-201 scintigraphy after thrombolytic therapy with or without angioplasty for acute myocardial infarction. Am J Cardiol 1993;71:1257-61.
7 Dakik HA, Mahmarian JJ, Kimball KT, et al. Prognostic value of exercise 201Tl tomography in patients treated with thrombolytic therapy during acute myocardial infarction. Circulation 1996;94:2735-42.
8 Miller TD, Gersh BJ, Christian TF, et al. Limited prognostic value of thallium-201 exercise treadmill testing early after myocardial infarction in patients treated with thrombolysis. Am Heart J 1995;130:259-66.
9 Travin MI, Dessouki A, Cameron T, et al. Use of exercise technetium-99m sestamibi SPECT imaging to detect residual ischemia and for risk stratification after acute myocardial infarction. Am J Cardiol 1995;75:665-9.
10 Brown KA, Heller GV, Landin RS, et al. Early dipyridamole (99m)Tc-sestamibi single photon emission computed tomographic imaging 2 to 4 days after acute myocardial infarction predicts in-hospital and postdischarge cardiac events: comparison with submaximal exercise imaging. Circulation 1999;100:2060-6.
11 Mahmarian JJ, Mahmarian AC, Marks GF, et al. Role of adenosine thallium-201 tomography for defining long-term risk in patients after acute myocardial infarction. J Am Coll Cardiol 1995;25:1333-40.
12 Peterson ED, Shaw LJ, Kesler K, et al. Clinical guideline: part II. Risk stratification after myocardial infarction. Ann Intern Med 1997;126:561-82.
In my review on risk stratification in acute coronary syndromes,
"diagnostic value" was used conventionally to refer to the ability of
predischarge tests to predict future coronary events, particularly death
and myocardial infarction.
In response to the 3 additional points:
1. Cost-effectiveness Underwood et al are correct to caution me on
statements of cost-effectiveness. My contention was (...
In my review on risk stratification in acute coronary syndromes,
"diagnostic value" was used conventionally to refer to the ability of
predischarge tests to predict future coronary events, particularly death
and myocardial infarction.
In response to the 3 additional points:
1. Cost-effectiveness Underwood et al are correct to caution me on
statements of cost-effectiveness. My contention was (and remains) that
predischarge stress testing is usually as effective as perfusion imaging
for risk stratification and costs less. The superior quality of SPECT
compared with conventional perfusion imaging may confer some advantage
(see below) but the considerable capital costs involved will inevitably
limit its application.
2. Exercise ECG versus Perfusion Imaging Underwood et al are
incorrect to infer superiority of predischarge perfusion imaging from the
data presented in the metaanalysis of Shaw et al (1). Cardiac event rates
were higher in the studies of myocardial perfusion imaging, readily
accounting for the apparent difference between positive predictive values
for these diagnostic tests. It is for the same reason, incidentally, that
both tests appear to perform better in patients who have not received
thrombolytic therapy. Shaw emphasises in her metaanalysis that both the
exercise ECG and the radionuclide perfusion scan are blunt tools for risk
stratification and my algorithm recommends use of either test, without
expressing a preference. Underwood et al draw attention to 3 papers
comparing the exercise ECG with SPECT imaging that post-dated ShawÆs
metaanalysis (2-4). Two showed some advantage for SPECT imaging although
positive predictive values for events after hospital discharge appeared
low (specific data not provided), confirming previous reports (2-3). The
other was a small (n=71) retrospective series, in which the only
multivariate predictor of death and recurrent infarction was LV ejection
fraction (4). Only when the endpoint was extended to incorporate unstable
angina and heart failure did perfusion imaging provide independent
prognostic information. Set against the 36 studies (16,960 patients)
included in ShawÆs metaanalysis, the additional 3 selected by Underwood et
al are not overly persuasive but suggest that SPECT technology may have an
edge over the exercise ECG for risk stratification.
3. Incremental value of perfusion imaging Although one of the
studies quoted by Underwood et al found that SPECT perfusion imaging was
not independently predictive of death and recurrent infarction if LV
ejection fraction was included in the multivariate model (4), they quote
another in which incremental value was demonstrated (5). Data for stress
testing are similarly contradictory. For this reason I recommended
application of these tests (exercise ECG or perfusion scan) only in
patients with advanced LV dysfunction (LVEF <_40 in="in" whom="whom" risk="risk" is="is" greatest.="greatest." unpublished="unpublished" data="data" for="for" our="our" own="own" low="low" patients="patients" discharged="discharged" with="with" lvef="lvef"/>40% by GUSTO criteria (6)) show the estimated risk of death in
the first year is only 3.8% (2.1-5.4%) and of death and recurrent
infarction 9.8% (7.1-12.4%). The idea that these relatively low risk
survivors of acute myocardial infarction would benefit from further risk
stratification using perfusion imaging (or stress tesing) seems barely
credible. This does not of course mean that the tests should not be done
but it does mean that incautious predictions of "cost-effectiveness" may
be incorrect.
In summary, SPECT imaging may offer a small advantage over the
exercise ECG for detection of residual ischaemia in patients with acute
coronary syndromes, although it remains a blunt tool for risk
stratification. Speaking from the perspective of the coronary care unit,
there is no doubt that the availability and low cost of exercise testing
(as opposed to the relative nonavailabiltiy and high cost of SPECT
imaging) will make it a more practical solution for predischarge risk
stratification in most centres. However, perfusion imaging is a
reasonable, perhaps better, alternative in those units able to provide a
predischarge service for upward of 700 coronary patients per year, and my
algorithm allows for this.
Adam D Timmis MD, FRCP
References
1. Shaw LJ, Peterson ED, Kesler K, Hasselblad V, Califf RM. A
metaanalysis of predischarge risk stratification after acute myocardial
infarction with stress electrocardiographic, myocardial perfusion, and
ventricular function imaging. Am J Cardiol 1996;78:1327-37.
2. Travin MI, Dessouki A, Cameron T, Heller GV. Use of exercise
technetium-99m sestamibi SPECT imaging to detect residual ischemia and for
risk stratification after acute myocardial infarction Am J Cardiol
1995;75:665-9.
3. Brown KA, Heller GV, Landin RS, Shaw LJ, Beller GA, Pasquale MJ,
Haber SB. Early dipyridamole (99m)Tc-sestamibi single photon emission
computed tomographic imaging 2 to 4 days after acute myocardial infarction
predicts in-hospital and postdischarge cardiac events: comparison with
submaximal exercise imaging. Circulation 1999;100:2060-6.
4. Dakik HA, Mahmarian JJ, Kimball KT, Koutelou MG, Medrano R, Verani
MS. Prognostic value of exercise 201Tl tomography in patients treated with
thrombolytic therapy during acute myocardial infarction. Circulation.
1996;94:2735-42.
5. Mahmarian JJ, Mahmarian AC, Marks GF, Pratt CM, Verani MS. Role of
adenosine thallium-201 tomography for defining long-term risk in patients
after acute myocardial infarction. J Am Coll Cardiol 1995;25:1333-40.
While December's editorial on non-cardiac chest pain is thoughtful
and thorough,(1) there is a strange lack of emphasis on skeletal chest
pain. I am not sure if this is due to selection of patients, but I wonder
if it is the lack of a diagnostic test for skeletal pain. Since this may
involve up to 73% of patients referred with chest pain to cardiac
clinics,(2) it would seem to be of paramount importance. The author...
While December's editorial on non-cardiac chest pain is thoughtful
and thorough,(1) there is a strange lack of emphasis on skeletal chest
pain. I am not sure if this is due to selection of patients, but I wonder
if it is the lack of a diagnostic test for skeletal pain. Since this may
involve up to 73% of patients referred with chest pain to cardiac
clinics,(2) it would seem to be of paramount importance. The authors
comment on the possibility that "abnormalities" (namely oesophageal and
respiratory) may be "coincidental rather than causative" and that 60% of
patients with normal coronary angiograms and non-cardiac chest pain have a
psychiatric disorder. We all occasionally recommend angiography in
patients who cannot adapt to the pidgeonhole we offer to give more
strength to our arm, which suggests that a higher percentage of patients
with non-cardiac chest pain and psychiatric disorders will get angiography
than those who are mentally more balanced; in addition Mayou and his
colleagues have themselves demonstrated that patients who are told that
their hearts are normal but are not given a clear diagnosis remain in
trouble,(3) so it is perhaps not surprising that psychiatrists find a high
level of psychiatric disorder in these people.
In a letter to Heart,(4) I reported the reproduction of chest pain by
testing the passive range of movements and found that of 27 patients with
clinically non-cardiac chest pain one had oesophageal reflux (and
responded to treatment for this), one had costochondral joint pain and 22
had their symptoms reproduced by spinal movements. Incidentally at one
year some still had symptoms but none had been off work because of their
presenting symptoms or admitted to hospital with chest pain. This pain can
sometimes be both reproduced and relieved by intercostal nerve block (C
Davidson, personal communication). We are doing a larger study at present
but it does seem that manipulating the spine as described by Chambers et al is a
sound way of demonstrating to patient and doctor that the the pain is
mechanical. Only 7 out of 27 responded to non-steroidal anti-inflammatory
drugs; I think it is likely that postural training or (pace the
unbelievers) manipulation will do better. The hardest patients to manage
seem to be those with cardiac and skeletal pain.
The authors suggest a psychological cause if there is a situational
or phobic component to the somatic symptoms; but anxiety appears to
increase mechanical symptoms such as sciatica due to a lumbar disc,
perhaps by increased muscle tone; it is not the cause of the
symptoms.
Exercise testing is a two edged sword (did they ever make single
edged swords?). The authors mention the value of a negative test, but of
equal importance is the danger of a positive in someone with coronary
disease but non-cardiac chest pain, and the risk of intervention with no
relief of symptoms, further angiography etc.
Finally the authors suggest that for patients with "continuing
symptoms---with coexisting psychological problems" a specialist nurse who
has received additional training should be employed in the cardiac clinic
to help them. Surely if the patient has been told that they have no
cardiac disease the last place they should be followed is the cardiac
clinic whatever the actual cause of their symptoms.
I know the north-south divide involves more than house prices, but I
find it hard to believe that chest pain in Oxford or London is too
different from that in Lancashire, assuming that referral is not biased.
To demonstrate a physical cause is of tremendous importance as we are
looking at thousands of referrals per year who, if managed by their
general practitioner, would contribute to a significant drop in our
waiting lists. I suggest that some of those thousands have demonstrable
skeletal pain, and that we are missing them.
References
1 Chambers J, Bass C, Mayou R. Non-cardiac chest pain: assessment and
management. Heart 1999;82:656-7.
2 Jain D, Fluck D, Sayer JW, et al. Ability of a one-stop chest pain clinic
to identify high risk patients... J R Coll Phys Lond 1997;31:401-4.
3 Mayou R, Bryant B, Sanders D, et al. A controlled trial of cognitive
behavioural therapy for non-cardiac chest pain. Psychol Med 1997;27:1021-31.
4 Best RA. Non-cardiac chest pain: a useful physical sign? [letter] Heart 1999;81:450.
Sir,
We read with interest the editorial on homocysteine, B vitamins and the
risk of cardiovascular disease.(1) The editorial highlighted that the B
vitamins are being used to treat homocysteine - mediated vascular
disease. However, this presupposes that the absolute levels of
homocysteine are the only determinants of the pathological impact of the
amino acid.
We have recently proposed an alternative mechan...
Sir,
We read with interest the editorial on homocysteine, B vitamins and the
risk of cardiovascular disease.(1) The editorial highlighted that the B
vitamins are being used to treat homocysteine - mediated vascular
disease. However, this presupposes that the absolute levels of
homocysteine are the only determinants of the pathological impact of the
amino acid.
We have recently proposed an alternative mechanism that may
be central to the pathophysiology of hyperhomocysteinaemia that would
not be prevented wholly by the B vitamins.
As was stressed in the editorial,(1) it is now widely accepted that
homocysteine auto-oxidises to form hydrogen peroxide (H2O2) and
superoxide (O2-). In turn, H2O2 and O2- elicit a number of
pro-atherogenic effects including damage to the vascular endothelium and
the promotion of vascular smooth muscle cells proliferation.(2-4)
Homocysteine also reduces nitric oxide (NO) activity, which has been
widely implicated in the aetiology of atherogenesis.(2-4) In both young
and elderly patients with hyperhomocysteinaemia there is impaired
endothelium (NO)-dependent relaxation of arteries.(5,6) In vitro,
homocysteine attenuates endothelial production of bioactive NO(7,8)
through its reaction with O2- generated by homocysteine to form
peroxynitrite (ONOO), effectively reducing the bioavailability of NO.
However, in these latter in vitro studies, tissues were exposed to high
levels of homocysteine (1 millimolar and greater), whereas the
vasculopathic levels of homocysteine are accepted as being 15
micromolar and greater.(2-4)
This indicated to us that homocysteine may
be interacting with another substance in vivo to promote atherogenesis.
We thus demonstrated that bivalent copper (20 micromolar [equivalent to
total blood levels]) markedly increases the inhibitory potency of
homocysteine (from 1 millimolar to 100 micromolar) on NO-mediated
arterial relaxation.(9,10) These inhibitory effects were reversed by
catalase and superoxide dismutase, demonstrating that copper interacts
with homocysteine to generate H2O2 and O2- which reduces NO through the
formation of ONOO.(9,10)
Under normal conditions free copper is virtually absent and is tightly
bound to proteins including caeruloplasmin. It has been shown that
copper bound to caeruloplasmin catalyses the generation of H2O2 from
homocysteine.(11,12) Thus, copper need not necessarily be dissociated from
protein binding sites for redox cascade reactions to take
place. ONOO also releases copper from protein binding sites,(13)
indicating that in regions where there are high levels of ONOO, that
copper may exist in its free form, albeit transiently. It is notable
that copper levels are elevelated in patients with
hyperhomocysteinaemia.(14)
Copper, in its own right has long been
implicated in atherogenesis.(15)
At present, the principal treatment for reducing plasma levels of
homocysteine is the administration of folic acid, alone or with vitamin
B6 or B121. However, it is still not clear whether a reduction in
homocysteine levels by this vitamin supplementation leads to prevention
of arterial disease. If indeed the absolute level of homocysteine is not
the only determinant of vasculopathy and copper (and possibly other
transition metals) plays an augmentory role, then alternative
therapeutic strategies should be considered. These include the
administration of free radical scavengers, antioxidants and copper
chelators such as penicillamine.
JY Jeremy, A Lotto, R Ascione, I Wan and GD Angelini
Department of Cardiac Surgery
Bristol Royal Infirmary
Bristol BS2 8HW, UK
References
1) Robinson K. Homocysteine, B vitamins and risk of cardiovascular
disease. Heart 2000; 83: 127-130
2) Loscalzo J. The oxidant stress of hyperhomocysteinemia. J Clin Invest
1996; 98: 5-7.
3) Emsley AM, Plane F, Jackson CL, Miller AL, Jeremy JY. Oxidant stress,
nitric oxide and transition metals in homocysteinaemic angiopathy: novel
mechanisms. Vasc Dis 1998; 1: 66-72.
4) Jeremy JY, Rowe D, Emsley AM, Newby AC. Nitric oxide and vascular
smooth muscle cell proliferation. Cardiovasc Res 1999; 43: 658-665.
5) Kamp C, Jakobs JA, Rauwerda C. Hyperhomocysteinaemia and endothelial
dysfunction in young patients with occlusive peripheral arterial
disease. Eur J Clin Invest 1995; 25: 176-181.
6) Tawakoi A, Omland T, Gerhard M, Wu JY, Creager MA.
Hyperhomocysteinaemia is associated with impaired endothelium-dependent
vasodilation in humans. Circulation 1997; 95: 1119-1121.
7) Jia L, Furchgott RF. Blockade of nitric oxide mediated relaxation of
rabbit aorta by cysteine and homocysteine. Acta Pharmacologica Sinica
1997; 18: 11-20.
8) Lang D, Hussain SA, Lewis MJ. Homocysteine inhibits
endothelium-dependent relaxation in isolated rabbit aortic rings. Br J
Pharmacol 1997; 120: 145P.
9) Emsley F, Plane F, Angelini GD, Jeremy JY. Copper interacts with
homocysteine to inhibit nitric oxide mediated relaxation in the rat
aorta. Br J Pharmacol 1997; 122: 47P
10) Emsley A, Jeremy JY, Gomes G, Angelini GD, Plane F. Copper interacts
with homocysteine to inhibit nitric oxide formation in the rat isolated
aorta. Br J Pharmacol 1999; 126: 1034-1040.
11) Starkebaum G, Harlan JM. Endothelial cell injury due to
copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin
Invest 1986; 77: 1370-1376.
12) Cappelini-Bigazzi M, Ambrosio G, Musci G, Battaglia C, Bonaccorsi di
Patti MC, Golino P, Ragni M, Chiariello M, Calabrese L. Ceruloplasmin
impairs endothelium-dependent relaxation of rabbit aorta. Am J Physiol
1997; 273: H2843-H2849
13) Swain JA, Darley-Usmar V, Gutteridge JMC. Peroxynitrite releases
copper from caeruloplasmin: implications for atherosclerosis. FEBS Lett
1994; 342: 49-52.
14) Dudman NPB, Wilcken DEL. Increased plasma copper in patients with
homocysteinuria due to cystathionine b-synthase deficiency. Clin Chim
Acta 1983; 127: 105-113.
15) Iskra M, Patelski J, Majewski W. Concentrations of calcium,
magnesium, zinc and copper in relation to free fatty acids and
cholesterol in serum of atherosclerotic men. J Trace Elem Electrolytes
Health Dis 1993; 7: 185-188.
We read with great interest the review "Cardiocutaneous fistula"
published by Dr. Danias and co-workers. At our Institution, we encountered
a similar case, concerning a 72-year-old female, who developed this
complication eleven months after coronary bypass sugery and linear
resection of an anteroapical left ventricular aneurysm; the postoperative
course had been complicated by mediastinitis necessit...
We read with great interest the review "Cardiocutaneous fistula"
published by Dr. Danias and co-workers. At our Institution, we encountered
a similar case, concerning a 72-year-old female, who developed this
complication eleven months after coronary bypass sugery and linear
resection of an anteroapical left ventricular aneurysm; the postoperative
course had been complicated by mediastinitis necessitating surgical
debridement and irrigation with 0.5% povidone-iodine until removal of
chest tubes. Initially, the patient presented mimicking subacute
endocarditis and subsequently developed the fistulous tract from the
cardiac apex through the chest wall. As stated by others [1] [2] [3] there
was no tendency to spontaneous healing, and bleeding was only mild and
transient, resembling chronic fistula secondary to chronic sternal
osteomyelitis; cultures were negative. Elective operation was not planned
because of poor general state and relative paucity of symptoms. Conditions
gradually declined until, during hospitalization, massive hemorrhage
ensued; no hemodynamic instability was observed during compressive
maneuvers. Emergency operation was accomplished through re-sternotomy
after institution of moderately hypothermic (28 °C) cardiopulmonary bypass
through the femoral vessels. Cooling was continued during dissection of
extremely dense adhesions and fragile tissues to obtain complete exposure
the left ventricle, avoiding free dissection of the great vessels; the
defect was repaired during circulatory arrest (20 °C) removing all foreign
material and infected tissue along with two chronically eroded costal
segments. The patient died on the fourth postoperative day in multi-organ
failure.
It is difficult to give guidelines, but some points should be
stressed:
High-risk surgery is probably the only therapeutic option and should
be planned electively avoiding life-saving emergency operations.
In our case, infection was not secondary to chest wall erosion due to
prosthetic material (a theoretical possibility previously stated by others
[3]). Mediastinitis may represent the inital cause, but also a consequence
of implantation of contaminated prosthetic material during aneurysmectomy.
The role of extensive use of prosthetic material (in particular,
Teflon felt) outside the heart is unclear, but may be important. This
specifically applies to patients undergoing left ventricular aneurysm
repair, who often present additional risk factors for infection (advanced
age, associated heart failure, longer cardiopulmonary bypass times, etc).
In case of postoperative mediastinitis should extracardiac Teflon be
replaced with autologous pericardium? This is a very difficult issue, due
to the different extensiveness of surgical options, but may be important
in the development of fistulae/pseudaneurysms of the heart/great vessels.
In case of extensive use of prosthetic material, removal should probably
be considered.
Re-sternotomy [1] may not be the optimal approach for repair. If
operation involves the left ventricle alone, an anterior thoracotomy
through the 5th or 6th intercostal space [4] is more appealing and less
cumbersome, despite the necessity of extrathoracic cannulation, deep
hypothermia and low-flow bypass/circulatory arrest. Sternotomy may prolong
surgery rather than represent a more expeditious technique. We reccomend
to avoid re-sternotomy whenever possible, especially in case of previous
mediastinitis.
Marco Pocar, MD - Francesco Donatelli, MD - Adalberto Grossi, MD
Istituto di Malattie dell'apparato cardiovascolare e respiratorio -
Università degli Studi di Milano
Divisione di Cardiochirurgia - IRCCS, Ospedale Maggiore Policlinico -
Via Francesco Sforza, 35 - 20122 Milano, Italy
References
1 McHenry MC, Longworth DL, Rehm SJ, et al. Infection of the cardiac
suture line after left ventricular surgery. Am J Med 1988;85:292-300.
2 Stanford W, Reuben CF, Flemma RJ, et al. Management of long-standing
cardiocutaneous fistulas after resection of left ventricular aneurysms. J
Thorac Cardiovasc Surg 1980;79:789-792.
3 Deuvaert FE, Wellens F, De Paepe J, at al. Cardiocutaneous fistula
after left ventricular anuerysm repair. Case report and review of the
literature. J Cardiovasc Surg (Torino) 1984;25:560-562.
4 Wellens F, Vanermen H. Treatment of the infected cardiac suture line.
J Cardiac Surg 1988;3:109-118.
I would like to acknowledge the interesting work published by Coulden
et al [1] in the February 2000 edition of the journal. The concept of
noninvasive arterial wall imaging with MR is an exciting new field with
numerous potential implications, including atherosclerotic plaque
characterisation. However, I would like to raise a few questions about the
selection of MR imaging parameters.
I would like to acknowledge the interesting work published by Coulden
et al [1] in the February 2000 edition of the journal. The concept of
noninvasive arterial wall imaging with MR is an exciting new field with
numerous potential implications, including atherosclerotic plaque
characterisation. However, I would like to raise a few questions about the
selection of MR imaging parameters.
Firstly, I was interested to note that the resolution is different in
all 3 axes. Although a characteristic of 2-D imaging is a loss of z-axis
resolution (slice thickness), previous work in animal models [2] [3] [4]
and humans [5] [6] has generally been with the same resolution in the x-
and y- axes allowing homogeneity of the resolution within the artery wall
and thus the atherosclerotic plaque.
Secondly, using a slice thickness of 3-mm with an image interval of
1.5-mm means that one third of the arterial wall and associated
atherosclerosis is missed. Although consecutive imaging without gaps leads
to cross excitation, one may interleave slices or if more than one
acquisition is performed, acquire alternating slices, to obtain MR images
of the entire arterial segment of interest without this interference.
Finally, the authors note the previously reported utility of T2-
weighted imaging for the characterisation of atherosclerotic plaque [6]
and yet use T1-weighted imaging in their study. Although for the purpose
of documenting arterial plaque burden and vessel wall remodelling T1-
weighted imaging is adequate, data on the relative contribution of
fibrotic and lipidic components to the atherosclerotic process and how
this influences the angioplasty process would be of great interest. I do
appreciate, however, that given the number of patients studied (n=4), and
the need for probably at least two imaging sequences (i.e. T1 and T2
weighted) to discern all components of complex human atherosclerotic
lesions, [6] conclusions regarding these concepts would be limited in this
study.
References
1. Coulden RA, Moss H, Graves MJ, et al. High resolution magnetic
resonance imaging of atherosclerosis and the response to balloon
angioplasty. Heart 2000;83:188-91.
2. Worthley SG, Helft G, Fuster V, et al. Serial in vivo MRI documents
arterial remodeling in experimental atherosclerosis. Circulation
2000;101:586-9.
3. Skinner MP, Yuan C, Mitsumori L, et al. Serial magnetic resonance
imaging of experimental atherosclerosis detects lesion fine structure,
progression and complications in vivo. Nat Med 1995;1:69-73.
4. McConnell MV, Aikawa M, Maier SE, et al. MRI of rabbit atherosclerosis
in response to dietary cholesterol lowering. Arterioscler Thromb Vasc Biol
1999;19:1956-9.
5. Yuan C, Beach KW, Smith LH, Jr., et al. Measurement of atherosclerotic
carotid plaque size in vivo using high resolution magnetic resonance
imaging. Circulation 1998;98:2666-71.
6. Toussaint JF, LaMuraglia GM, Southern JF, et al. Magnetic resonance
images lipid, fibrous, calcified, hemorrhagic, and thrombotic components
of human atherosclerosis in vivo. Circulation 1996;94:932-8.
We have read with great interest the short case in cardiology
reported by E Zakynthinos et al (1) in the March 2000 edition of Heart. The ECG
recordings after acute ingestion of amitriptyline are remarkable,
especially the ST segment elevation in the precordial leads V1 - V3, 6 to
100 hours after admission in the intensive care unit.
The ECG pattern resembles markedly the ones described in...
We have read with great interest the short case in cardiology
reported by E Zakynthinos et al (1) in the March 2000 edition of Heart. The ECG
recordings after acute ingestion of amitriptyline are remarkable,
especially the ST segment elevation in the precordial leads V1 - V3, 6 to
100 hours after admission in the intensive care unit.
The ECG pattern resembles markedly the ones described in the Brugada
syndrome (2). Thus this case could represent a specific effect of the
ionic action of tricyclic agents with selective blockade of the sodium
channels (3,4), mimicking temporarily a Brugada pattern, as an acquired
phenomenon in an otherwise electrically normal myocardium.
Another mechanism could be an unmasking effect of amitriptyline
similar to that of other sodium channel blockers which revealed a silent
dysfunction of the sodium channels in a "concealed" Brugada Syndrome (5).
This has, in our opinion, to be discussed and verified by means of a
pharmacological test with ajmaline (5), at distance of the acute event.
The apparent absence of threatening arrhythmias in the presence of such a
high concentration of amitriptyline is however an argument pleading
against this hypothesis.
In the same issue of Heart, R P Steeds et al (6) report a case of
abnormal ventricular conduction following dothiepin overdose with images
resembling an acute myocardial infarction. The ST segment elevation in
leads V1-V3 is however somewhat different and less suggestive of a Brugada
Syndrome. Nevertheless, the ionic mechanism of intoxication could be the
same, though occurring in an electrically otherwise normal myocardium.
Similarly in this case, an ajmaline pharmacological test could be
appropriate to ensure the integrity of sodium ionic channels. A genetic
study would be also advocated in these two cases.
L DE ROY, MD
C SCAVEE, MD
J MUCUMBITSI, MD
D BLOMMAERT, MD
Department of Cardiology, Arrhythmia Unit
University of Louvain
B 5530 YVOIR Belgium
References
1. E. Zakynthinos, T. Vassilakopoulos, C. Roussos, S Zakynthinos.
Abnormal atrial and ventricular repolarisation resembling myocardial
injury after tricyclic antidepressant drug intoxication. Heart 2000;83:353-354.
2. P Brugada, J Brugada. Right bundle-branch block persistent ST segment
elevation and sudden cardiac death: a distinct clinical and
electrocardiographic syndrome. A multicenter report J Am Coll Cardiol 1992;20:1391-1396.
3. MJ Barber, CF Starmer, AO Grant. Blockade of cardiac sodium channels by
amitriptyline and diphenylhydantoïne.Evidence for two use-dependent binding sites. Circ Res 1991;69:677-96.
4. C Nau, M Seaver, SY Wang, GK Wang. Block of human heart hH1 sodium
channels by amitriptyline.J Pharmacol Exp Ther 2000;292:1015-23.
5. R Brugada, J Brugada, C Antzelevitch, G E Kirsch, D Potenza, J A
Towbin, P Brugada: Sodium channel blockers identify risk for sudden death
in patients with ST segment elevation and right bundle branch block but
structurally normal hearts. Circulation 2000;101:510-515.
6. R P Steeds, R Muthusamy: Abnormal ventricular conduction following
dothiepin overdose simulating acute myocardial infarction. Heart 2000;83:289.
We thank Dr. Pocar and his colleagues for contributing their
experience with another case of cardiocutaneous fistula [1], which
confirms several points that we and others have previously discussed [2]
[3] [4]. The clinical presentation of cardiocutaneous fistula is usually
slow and indolent but may rapidly deteriorate. Therefore, when this
diagnosis is established elective operation should be perfo...
We thank Dr. Pocar and his colleagues for contributing their
experience with another case of cardiocutaneous fistula [1], which
confirms several points that we and others have previously discussed [2]
[3] [4]. The clinical presentation of cardiocutaneous fistula is usually
slow and indolent but may rapidly deteriorate. Therefore, when this
diagnosis is established elective operation should be performed without
undue delay, to excise the fistulous tract and remove the infected foreign
bodies. With medical therapy alone the infection cannot be eradicated. The
natural progression of the disease may lead to catastrophic hemorrhage and
grim outcome, as occurred in the case illustrated by Pocar M, et al. [1]
and previous reports [3]. Meticulous surgical technique should always be
employed during left ventricular aneurysm repair to prevent this rare but
serious complication.
Peter G. Danias, MD, PhD
Cardiology Division, Department of Medicine
Beth Israel Deaconess Medical Center and Harvard Medical School
330 Brookline Avenue, Boston, Massachusetts 02215, USA
Dr. Danias is partially supported by the Clinical Investigator Training
Program: BIDMC - Harvard/MIT Health Sciences and Technology - Pfizer Inc.
References
1. Pocar M, Donatelli F, Grossi, A. Cardiocutaneous fistula following
left ventricular aneurysmectomy. Heart Rapid Response, 17 May 2000.
I read with great interest the report of Law et al [1]. The authors examined one-year mortality risk in 432 patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) to detect useful biomarkers. The adjusted hazard ratio (HR) (95% confidence interval [CI]) of the change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) per 500 ng/L increase for mortality was 1.04 (1.01 to 1.07). In addition, the adjusted HRs (95% CIs) of the increases in ∆ NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L for mortality were 1.65 (1.18-2.31), 1.92 (1.37-2.70), and 2.87 (1.93-4.27), respectively. They concluded that the change in NT-proBNP concentration during the first year was an independent predictor of mortality in patients with wtATTR-CM. I have a comment about this study.
Ochi et al. examined two-year mortality risk in 47 patients with wtATTR-CM [2], and low serum albumin (≤3.75 g/dL), elevated high-sensitivity cardiac troponin T (hs-cTnT; >0.086 ng/mL), and low left ventricular ejection fraction (LVEF; <50%) are significantly associated with mortality in patients with wtATTR-CM. According to the total number of these 3 risk factors, patients were stratified into 4 subgroups: low risk (no risk factors), intermediate-low risk (1 risk factor), intermediate-high risk (2 risk factors), and high risk (3 risk factors). The estimated two-year survival rate of patients classified as low risk, intermediate-low risk, intermediate-high r...
Show MoreDear Editor,
I am one of the 95 survivors in your article having had the mustard operation in 1980 and would just like to thank everyone who took part in putting this together. I found it very usefull and interesting.
In my review on risk stratification in acute coronary syndromes, "diagnostic value" was used conventionally to refer to the ability of predischarge tests to predict future coronary events, particularly death and myocardial infarction.
In response to the 3 additional points:
1. Cost-effectiveness Underwood et al are correct to caution me on statements of cost-effectiveness. My contention was (...
While December's editorial on non-cardiac chest pain is thoughtful and thorough,(1) there is a strange lack of emphasis on skeletal chest pain. I am not sure if this is due to selection of patients, but I wonder if it is the lack of a diagnostic test for skeletal pain. Since this may involve up to 73% of patients referred with chest pain to cardiac clinics,(2) it would seem to be of paramount importance. The author...
We read with interest the editorial on homocysteine, B vitamins and the risk of cardiovascular disease.(1) The editorial highlighted that the B vitamins are being used to treat homocysteine - mediated vascular disease. However, this presupposes that the absolute levels of homocysteine are the only determinants of the pathological impact of the amino acid.
We have recently proposed an alternative mechan...
Dear Editor:
We read with great interest the review "Cardiocutaneous fistula" published by Dr. Danias and co-workers. At our Institution, we encountered a similar case, concerning a 72-year-old female, who developed this complication eleven months after coronary bypass sugery and linear resection of an anteroapical left ventricular aneurysm; the postoperative course had been complicated by mediastinitis necessit...
I would like to acknowledge the interesting work published by Coulden et al [1] in the February 2000 edition of the journal. The concept of noninvasive arterial wall imaging with MR is an exciting new field with numerous potential implications, including atherosclerotic plaque characterisation. However, I would like to raise a few questions about the selection of MR imaging parameters.
Firstly, I was interested t...
Dear Editor
We have read with great interest the short case in cardiology reported by E Zakynthinos et al (1) in the March 2000 edition of Heart. The ECG recordings after acute ingestion of amitriptyline are remarkable, especially the ST segment elevation in the precordial leads V1 - V3, 6 to 100 hours after admission in the intensive care unit.
The ECG pattern resembles markedly the ones described in...
Dear Editor,
We thank Dr. Pocar and his colleagues for contributing their experience with another case of cardiocutaneous fistula [1], which confirms several points that we and others have previously discussed [2] [3] [4]. The clinical presentation of cardiocutaneous fistula is usually slow and indolent but may rapidly deteriorate. Therefore, when this diagnosis is established elective operation should be perfo...
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