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.
Kurbaan and Sutton provide a balanced view of the role of pacing in
vasovagal syncope[1] - a common but complex and challenging medical
condition.
However, we feel that attention should be drawn to the methodological
problems that bedevil interpretation of the North American Vasovagal
Pacemaker Study (VPS).[2] This was not a randomised study of cardiac
pacing, but rather a randomised trial...
Kurbaan and Sutton provide a balanced view of the role of pacing in
vasovagal syncope[1] - a common but complex and challenging medical
condition.
However, we feel that attention should be drawn to the methodological
problems that bedevil interpretation of the North American Vasovagal
Pacemaker Study (VPS).[2] This was not a randomised study of cardiac
pacing, but rather a randomised trial of pacemaker prescription and
implantation. The control group did not undergo an operation with
subsequent reprogramming to an "inactive" mode, and so did not receive the
attendant medical follow-up afforded the paced group.
Recent data from a trial examining the role of cardiac pacing in
hypertrophic cardiomyopathy have clearly demonstrated the profound placebo
effect of pacemaker implantation[3] on both symptoms and objective
echocardiographic evidence of outflow tract obstruction. These
improvements were apparent despite programming the pacemaker to an
inactive mode. There is no direct evidence from the North American study
that it was appropriate pacemaker therapy that was the cause of the
reduction in symptoms seen in the paced group. Patients were highly
selected and very symptomatic, with an imbalance in symptom burden between
the 2 arms that would favour pacing (median number of lifetime episodes 14
paced versus 35 non-paced). The only way to address these issues
satisfactorily would be by implanting systems in all patients, and blindly
randomising groups to "active" or "inactive" pacing.
For the present we agree that "there are limitations to the benefits
of pacing in vasovagal syncope", particularly in young patients whom would
be subject to a lifelong burden of cardiac pacing with its inevitable
complications. Several alternative approaches are available, and should
be tried first. Leaving aside pharmacological treatment,[4] simple
orthostatic training[5] has demonstrated a greater reduction in symptom
burden than that seen in the North American VPS. This technique is both
simple and proved to be extremely effective: over a median follow-up of 18
months, spontaneous syncope was seen in 0% versus 56% in the trained and
control group respectively.
Until further randomised data become available, pacemaker
implantation should be regarded as a last resort in vasovagal syncope.
Dr Adrian Morley-Davies
Senior Registrar, Department of Cardiology
Glasgow Royal Infirmary, Glasgow G31 2ER, UK
Dr J Byrne
Specialist Registrar in Cardiology, Department of Cardiology
Western Infirmary, Glasgow
References
1. Kurbaan AS, Sutton R. Pacing for vasovagal syncope. Heart 1999;
82:649-50.
2. Connolly SJ, Sheldon RS, Roberts R. The North American Vasovagal
Pacemaker Study: A randomised trial of permanent cardiac pacing for the
prevention of vasovagal syncope. JACC 1999; 33:16-20.
3. Linde C, Gadler F, Kappenberger L, Ryden L. Placebo effect of
pacemaker implantation in obstructive hypertrophic cardiomyopathy. Am J
Cardiol 1999; 83:903-7.
5. Di Girolamo E, Di Iorio C, Leonzio L, Sabatini P, Barsotti A.
Usefulness of a tilt-training program for the prevention of refractory
neurocardiogenic syncope in adolescents: a controlled study. Circulation
1999; 100:1798-801.
We share many of the reservations that Morley-Davies and Byrne have
regarding the North American Vasovagal Pacemaker Study (VPS).[1] However,
this study should be considered in the context of the other available data
supporting the role of pacing in selected patients. We also are
interested in the study by Di Girolamo et al[2] suggesting a benefit for
orthostatic training in those with neurocardio...
We share many of the reservations that Morley-Davies and Byrne have
regarding the North American Vasovagal Pacemaker Study (VPS).[1] However,
this study should be considered in the context of the other available data
supporting the role of pacing in selected patients. We also are
interested in the study by Di Girolamo et al[2] suggesting a benefit for
orthostatic training in those with neurocardiogenic (vasovagal) syncope.
However, they do not classify the tilt test induced haemodynamic responses
seen in their population. In those with vasovagal syncope the different
haemodynamic collapse patterns seen on tilt testing[3] may have a very
useful role in identifying not only those who may benefit from pacing but
also those in whom pacing may be inappropriate even as a 'last resort'.
The consensus is that pacing is of the greatest benefit in those with a
predominantly bradycardiac (cardioinhibitory) response on tilt testing.
Furthermore, the population in Di Girolamo et al's study[2] is not
comparable to that in VPS and most other studies of pacing in vasovagal
syncope. The former's population were all adolescents (mean age 16
years), whereas much older patients were recruited into VPS (mean age 43
years). Our experience suggests that many adolescents will over time
'grow out of' their fainting episodes. Hence, in the majority of cases
our advice to this group is simply reassurance.
Since the beginning of 1997 we have run a prospective register of the
all tilt tests that we have undertaken including the management suggested.
Up until December 1999 over 600 patients had been tilted. Of these 186
were under 35 years of age. Only 5 (2.7%) of these young patients have
been paced. In each cases multiple non-pacing strategies (though not
orthostatic training) were attempted prior to offering pacing.
In selected patients with vasovagal syncope pacing offers excellent
symptomatic relief, enabling a return to normal life.
Dr A S Kurbaan
Department of Cardiology, London Chest Hospital,
London E2 9SX, UK
Dr R Sutton
Department of Cardiology, Royal Brompton Hospital,
London SW3 6NP, UK
References
1. Connolly SJ, Sheldon R, Roberts RS, Gent M on behalf of the
Vasovagal Pacemaker Study investigators. The North American Vasovagal
Pacemaker Study (VPS). A randomised trial of permanent cardiac pacing for
the prevention of vasovagal syncope. J Am Coll Cardiol 1999;33:16-20.
2. Di Girolamo E, Di Iorio C, Leonzio L, Sabatini P, Barsotti A.
Usefulness of a tilt training program for the prevention of refractory
neurocardiogenic syncope in adolescents: a controlled study. Circulation
1999;100:1798-1801
3. Kurbaan AS, Franzén A-C, Bowker TJ, Williams TR, Kaddoura S,
Petersen MEV, Sutton R. Usefulness of tilt test induced patterns of heart
rate and blood pressure using a two stage protocol with glyceryl
trinitrate provocation in patients with syncope of unknown origin. Am J
Cardiol 1999;84:695-670.
Iemura et al's hypothesis that endothelial dysfunction is associated with coronary aneurysms which have regressed after Kawasaki disease (KD) is interesting[1]; however, there are two issues with respect to their study design that need to be considered, in addition to the issues reported before.[2, 3]
(1) Is endothelial dysfunction associated with regressed coronary aneurysms per se late after KD?
Iemura et al's hypothesis that endothelial dysfunction is associated with coronary aneurysms which have regressed after Kawasaki disease (KD) is interesting[1]; however, there are two issues with respect to their study design that need to be considered, in addition to the issues reported before.[2, 3]
(1) Is endothelial dysfunction associated with regressed coronary aneurysms per se late after KD?
Iemura et al showed that acetylcholine-induced vasodilatation is impaired in regressed coronary aneurysms (groups 1 and 2) but there is preserved vasodilatation in patients without coronary involvement during the acute illness of KD (group 3). This could be explained either by the direct effect of the regressed aneurysm or the difference among the study groups (groups 1 and 2 versus group 3). The Kawasaki vasculitis was severe enough to cause coronary aneurysms in some segments during the acute illness.
Although in Fig 1 Iemura et al showed that there is acetylcholine-induced vasoconstriction in the regressed aneurysm, readers might note that the rest of the segments in the right coronary artery without coronary lesions from the onset, including segments remote from the regressed aneurysms, also seem to constrict in response to acetylcholine. This might suggest that the regressed aneurysm per se does not impair endothelial function after KD.
Iemura et al did not present any data analysing the acetylcholine-elicited responses in normal segments from disease onset in groups 1 and 2; therefore the alternative hypothesis remains possible i.e. that coronary segments, regardless of their association with regressed aneurysms, constrict in response to acetylcholine in patients with a history of severe Kawasaki vasculitis. Consistent with this hypothesis, previous reports concluded that endothelial function is impaired in unaffected coronary segments and brachial arteries (usually uninvolved with aneurysms during the acute illness) in patients with severe acute Kawasaki vasculitis in the long term follow up period:
1.5-12.5 years (mean (SE) 6.5 (1.1)) after acute KD in Mitani et al[2]
5.3-17.1 years (median 11.3) after KD in Dhillon et al[4]
16-28 years old (mean 22) at the time of examination in Kamiya et al[5]
1-14 years old (median: 3.5) at the time of examination in Sano et al[6]
(2) Is endothelial function entirely preserved in KD patients without coronary involvement during the acute illness (group 3)?
This is an issue that we did not specifically address in our previous study.[2] Iemura et al showed that coronary arteries normally dilate in response to acetylcholine in patients without coronary lesions during the acute illness (group 3) on the basis of analysing multiple coronary segments.[1] However, in KD patients some coronary segments (ie, proximal segments) are characteristically more susceptible to severe abnormalities than others in terms of morphological, angiographic findings and vasomotor function.[2, 7, 8] Abnormal vasomotor function might be unmasked by specifically focusing on some "susceptible" segments in group 3, as we did in uninvolved proximal coronary segments in patients with coronary aneurysms in other segments.[2] An alternative hypothesis that some susceptible segments are associated with impaired acetylcholine-induced vasodilatation even in group 3 remains to be tested.
Iemura et al's conclusion might not be consistent with a previous report showing that endothelial function is impaired in KD patients without aneurysms in any segment during the acute illness.[4] This inconsistency remains to be addressed.
References
1. Iemura M, Ishii M, Sugimura T, et al. Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function. Heart 2000;83:307-11.
2. Mitani Y, Okuda Y, Shimpo H, et al. Impaired endothelial function in epicardial coronary arteries after Kawasaki disease. Circulation 1997;96:454-61.
3. Mitani Y. Coronary endothelial dysfunction after Kawasaki disease. J Am Coll Cardiol 2000;35:821-3
4. Dhillon R, Clarkson P, Donald AE, et al. Endothelial dysfunction late after Kawasaki disease. Circulation 1996;94:2103-6.
5. Kamiya Y, Onouchi Z, Hamaoka K. Arteriosclerosis long after Kawasaki disease: endothelial function. Acta Cardiol Paediat Jpn 1997;13:252 (Japanese).
6. Sano T, Tagawa T, Itagaki Y, et al. Endothelial dysfunction after Kawasaki vasculitis. Jpn Circ J 1999;63:338 (Japanese).
7. Naoe S, Takahashi K, Masuda H, et al. Kawasaki disease: with the particular emphasis on arterial lesions. Acta Pathol Jpn 1991;41:785-97.
8. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease: a 10-21 year follow-up study of 594 patients. Circulation 1996;94:1379-85
We appreciate the kind comments of Dr Mitani regarding
our article in the March 2000 issue of Heart and for
sharing their experiences with us.[1]
In group 1 and 2 patients who had regressed coronary aneurysm after Kawasaki disease, there was significantly more vascular constriction with acetylcholine and poorer dilatation with isosorbide
dinitrate at the regressed site, than in group 3 patient...
We appreciate the kind comments of Dr Mitani regarding
our article in the March 2000 issue of Heart and for
sharing their experiences with us.[1]
In group 1 and 2 patients who had regressed coronary aneurysm after Kawasaki disease, there was significantly more vascular constriction with acetylcholine and poorer dilatation with isosorbide
dinitrate at the regressed site, than in group 3 patients
who had no coronary artery lesions after Kawasaki disease.
Fourteen patients in group 1 and group 2 in the acute stage
of illness had coronary artery lesions on one side of the
coronary artery but no coronary artery lesion on the
opposite side.
We also evaluated the vascular function of
these sites (n = 19) using intracoronary infusion of
acetylcholine chloride and isosorbide. The mean (SD)
change in the coronary artery diameter after infusion of
acetylcholine was 12.5 (3.0)% in group 1 and 2, and
11.3 (5.6)% in group 3. The mean (SD) change in the
coronary artery diameter after infusion of isosorbide
dinitrate was 17.3 (9.5)% in group 1 and 2, and 18.0
(8.2)% in group 3. There was no significant difference in
responses to the infusion of either acetylcholine or
isosorbide dinitrate between these two groups.
These
findings suggested that such coronary arteries had finctionally normal
endothelium and smooth muscle even in
patients with a history of severe Kawasaki vasculitis.
The coronary arteries in group 3 patients had normal
responses to the infusion of either acetylcholine or
isosorbide dinitrate, according to the analysis of multiple
coronary artery segments involving proximal coronary artery
segments. We assessed differences in responses to the
infusion of acetylcholine or isosorbide dinitrate
between proximal coronary artery segments and distal
coronary artery segments in group 3 patients and in controls. The mean (SD) change in the coronary artery
diameter after infusion of acetylcholine was 11.9 (3.5)% at
the proximal artery coronary segments and 12.8 (4.0)% at
the distal coronary artery segments in group 3. The mean
(SD) change in the coronary artery diameter after infusion
of isosorbide dinitrate was 16.8 (4.2)% at the proximal
coronary artery segments and 17.1 (8.0)% at the distal
coronary artery segments in group 3.
These results
suggested that there was no significant difference in
responses to the infusion of either acetylcholine or
isosorbide dinitrate between the proximal coronary artery
segments and the distal coronary artery segments in group 3
patients. Similar findings were found in the control
patients.
In a new study,[2] we investigated
the vascular morphology of the coronary artery, in 6
Kawasaki disease patients who had completely normal first
coronary angiography findings, using intravascular
ultrasound imaging; we found no differences in wall
morphology between the proximal coronary artery segments
and the distal coronary artery segments.
From the basis of our studies, we conclude that long-term
persistent coronary aneurysms and regressed coronary
aneurysms after Kawasaki disease exhibit vascular
dysfunction.[1-5] These patients should be counseled to
avoid potential risk factors for atherosclerosis, and they
should be advised that long-term follow-up is needed into
adulthood. However, patients with normal coronary arteries after
Kawasaki disease had no significant difference from the
controls in response to either acetylcholine or isosorbide
dinitrate infusion. These findings suggested that such
coronary arteries had normal function of the endothelium
and smooth muscle even in the long term.
References
(1) Iemura M, Ishii M, Sugimura T, Akagi T, Kato H. Long-
term consequences of regressed coronary aneurysms after
Kawasaki Disease: vascular wall morphology and function.
Heart 2000;83:307-11.
(2) Ishii M, Hashino K, Iemura M, Yamakawa R, Muta H, Himeno
W, Akagi T, Kato H. Long-term consequences of coronary
aneurysms after Kawasaki disease: vascular wall morphology
and endothelium function (abstract). J Am Coll Cardiol 2000;35:513A.
(3) Yamakawa R, Ishii M, Sugimura T, Akagi T, Eto G, Iemura
M, Tsutsumi T, Kato H. Coronary endothelial dysfunction
after Kawasaki disease: evaluation by intracoronary
injection of acetylcholine. J Am Coll Cardiol 1998;31:1074-
80.
(4) Sugimura T, Kato H, Inoue O, et al. Vasodilatory
response of the coronary arteries after Kawasaki disease:
evaluation by intracoronary injection of isosorbide
dinitrate. J Pediatr 1992;121:684-8.
(5) Sugimura T, Kato H, Inoue O, Fukuda T, Sato N, Ishii M,
Takagi J, Akagi T, Maeno Y, Kawano T, Takagishi T, Sasaguri
Y. Intravascular ultasound of coronary arteries in
children: assessment of the wall morphology and the lumen
after Kawasaki disease. Circulation 1994;89:258-65.
We read with interest the article by Kubler et al[1]
concerning 3 patients with platypnoea-orthodeoxia syndrome. As reported,
this syndrome is infrequent and the diagnosis can be difficult. It
is characterised by dyspnoea and arterial hypoxaemia induced by upright
position that resolved by recumbency. This is usually the consequence of
right-to-left shunt at the atrial level. Such shunting is frequent in...
We read with interest the article by Kubler et al[1]
concerning 3 patients with platypnoea-orthodeoxia syndrome. As reported,
this syndrome is infrequent and the diagnosis can be difficult. It
is characterised by dyspnoea and arterial hypoxaemia induced by upright
position that resolved by recumbency. This is usually the consequence of
right-to-left shunt at the atrial level. Such shunting is frequent in
patients with congenital heart defects when there is high pulmonary artery
pressure and patent foramen ovale/atrial septal defect (PFO/ASD) but
usually there is no postural change for both dyspnoea and hypoxaemia.
More
surprisingly are the normal right-sided pressures associated with this
syndrome. Moreover, due to the high prevalence of PFO in the "normal" population
(between 25 and 33%) we might expect to observe more and
more patients with this syndrome.
In our experience, this syndrome is not extremely rare; we
collected 18 patients with similar symptoms (10 female and 8
male, meand (SD) age 71 (6) years).[2] Most of them presented with
variable dyspnoea on exercise and/or hypoxaemia. In fact, the postural
character was present in only 55% of our
group, and can be masked when the patient cannot be weaned off the
ventilator! Some of the patients had a history of stroke or
paradoxical embolism (27%).
It is possible that the concept of platypnoea
-orthodeoxia may be too restrictive. In this population, the first
diagnosis advocated is usually pulmonary embolism and this has led to
various investigations. In fact, transthoracic but mainly transoesophageal
echocardiography, as reported by Kubler et al is the most common examination to depict the PFO and interatrial right-to-left shunt. In this
setting, cardiac catheterization is not necessary to confirm the
diagnosis. In contrast, we recommend
transcatheter PFO/ASD occlusion instead of surgery. Indeed, a significant
number of patients are quite debilitated or sick and surgical closure would
increase their risk.
The literature describes many devices that have been
successfully used to close such defects. This technique is easy to perform,
does not require general anaesthesia, and provides complete correction. In
our experience, device implantation was performed successfully in all but 1 patient.
Another interest of cardiac catheterization is to reveal
the underlying causes responsible for this interatrial right-to-left
shunting. First, there is frequently a haemodynamic pressure gradient
between both atria favouring a right-to-left shunt noticed in late
diastole or early systole. Also been reported is lower right atrial
pressure or equal to the left atrial pressure. It is probable that
significant amount of blood flow from the inferior vena cava can easily cross a PFO by
kinetic energy without need of a favourable pressure gradient between both
atria. Second, there is frequently a preferential blood flow streaming
from inferior vena cava, or more rarely from superior vena cava,
towards the left atrium through a PFO. In our experience, we have noticed
frequently horizontalization of the atrial septum so that the PFO is
placed directly in line with the blood flow from the inferior vena cava. This can be the
consequence of different causes such as classic pneumonectomy or
lobectomy, cyphoscoliosis, or ascending aorta aneurysm displacing the
atrial septal orientation. The dilatation of ascending aorta due to age
seems to be in our experience the most frequent cause responsible for this
syndrome.
We hope that publication in Heart of 3 cases of platypnoea-orthodeoxia will heighten awareness of this complication. When this
syndrome is suspected, we strongly recommend transoesophageal echocardiography
with contrast study to depict the interatrial right-to-left shunt and propose transcatheter PFO occlusion. The true incidence of
this syndrome remains to be established and a registry of the complication
would be of interest.
F GODART
C REY
Department of Paediatric Cardiology
CHRU de Lille, 59037 Lille cedex
France
(2) Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causing
severe hypoxaemia despite normal right-sided pressures. Report of 11
consecutive cases corrected by percutaneous closure. Eur Heart J 2000;21:483-9.
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...
Dear Editor
Kurbaan and Sutton provide a balanced view of the role of pacing in vasovagal syncope[1] - a common but complex and challenging medical condition.
However, we feel that attention should be drawn to the methodological problems that bedevil interpretation of the North American Vasovagal Pacemaker Study (VPS).[2] This was not a randomised study of cardiac pacing, but rather a randomised trial...
Dear Editor,
We share many of the reservations that Morley-Davies and Byrne have regarding the North American Vasovagal Pacemaker Study (VPS).[1] However, this study should be considered in the context of the other available data supporting the role of pacing in selected patients. We also are interested in the study by Di Girolamo et al[2] suggesting a benefit for orthostatic training in those with neurocardio...
Iemura et al's hypothesis that endothelial dysfunction is associated with coronary aneurysms which have regressed after Kawasaki disease (KD) is interesting[1]; however, there are two issues with respect to their study design that need to be considered, in addition to the issues reported before.[2, 3]
(1) Is endothelial dysfunction associated with regressed coronary aneurysms per se late after KD?
...Dear Editor:
We appreciate the kind comments of Dr Mitani regarding our article in the March 2000 issue of Heart and for sharing their experiences with us.[1]
In group 1 and 2 patients who had regressed coronary aneurysm after Kawasaki disease, there was significantly more vascular constriction with acetylcholine and poorer dilatation with isosorbide dinitrate at the regressed site, than in group 3 patient...
We read with interest the article by Kubler et al[1] concerning 3 patients with platypnoea-orthodeoxia syndrome. As reported, this syndrome is infrequent and the diagnosis can be difficult. It is characterised by dyspnoea and arterial hypoxaemia induced by upright position that resolved by recumbency. This is usually the consequence of right-to-left shunt at the atrial level. Such shunting is frequent in...
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