I have never seen a satisfactory hypothesis to account for the
occurrence and distribution of atheromatous deposits in arteries but not
veins. One possibility is a Venturi effect, induced by anatomical,
physiological and pathological changes in the geometry in arteries but
not in veins, accounts for the differences. Might such a effect account
for the increased vulnerability of a remodelled vessel...
I have never seen a satisfactory hypothesis to account for the
occurrence and distribution of atheromatous deposits in arteries but not
veins. One possibility is a Venturi effect, induced by anatomical,
physiological and pathological changes in the geometry in arteries but
not in veins, accounts for the differences. Might such a effect account
for the increased vulnerability of a remodelled vessel and the "shoulder"
of a plaque addressed in this study [1].
A differential pressure exists when a flowing fluid passes through a
constricted region or changes direction due to a turn or elbow in a pipe.
The inference is that it also does so in an artery especially at
atherosclotic stenoses and anatomical bifurcations. The relationship
between flow rate and pressure difference in these locations might be
determined by the Bernoulli equation. The low pressure at the point of
highest velocity in these locations may create the possibility for blood
carrying oxygen and carbon dioxide, to partially vaporize; it might
remain partially vaporized after these regions in the arterial wall
(called flashing when applied to flow meters) or it might return to its
liquid state as the pressure increases after the lowest pressure point
(called cavitation again when applied to flow meters) [2].
An atheroscleotic plaque creates in effect a venturi tube. The change
in cross-sectional area in a venturi tube causes a pressure change between
the convergent section and the throat, and the flow rate can be determined
from this pressure drop. Vortices may also be formed by athrosclrotic
plaques. Within these regions of low pressure hypobaric hypoxia and
hypocarbia might exist. Consider the local metabolic implications.
Hypobaric hypoxia might induce a localized lipid shift to accommodate
the accompanying loss in efficiency of ATP resynthesis by oxidative
phosporylation. Any hypocarbia induced might also increase the local rate
of lipid uptake and consumption by increasing the efficiency of oxidative
phosporylation by mass action. If the anaerobic threshold is approached,
intuitively an unlikely event in an artery, oxidative phosporylation will
be inhibited and anaerobic glycolysis stimulated precipitating a fall in
intimal pH but not necessarily free radical release because of the
accompanying hypobaric hypoxia.
In these circumstances free radicals might be responsible for
increasing metabolic rate to accommodate the decrease in efficiency of ATP
resynthesis, by increasing temperature. If so this hypothetical
compensatory mechanism might be compromised and a decline in energy charge
large enough to cause functional impairments induced. If larger apoptosis
and even necrosis with its accompanying inflammatory changes might occur
within the intima and/or media.
One of the functional impairments that might hypothetically be
induced, short of apoptosis or necrosis and inflammation, at bifurations
and in stenotic plaques is the ability of HDL to remove cholesterol from
vessel walls and carry it to the liver where it is can be removed from
blood. In other words a venturi effect might create the metabolic
circumstances in which cholestrol deposition and plaque formation and
growth ate promoted with the passage of time. They might also create
circumstances in which the likelihood of plaque rupture is also increased.
These circumstances should not exist in veins.
References
1. Ramarathnam Krishna Kumar and Komarakshi R. Balakrishnan
Influence of lumen shape and vessel geometry on plaque stresses: possible
role in the increased vulnerability of a remodelled vessel and the
"shoulder" of a plaque
Heart 2005; 0: hrt.2004.049072v1
We read with great interest the scientific letter by Eizawa and
colleagues [1] reporting significant reduction of peripheral blood CD34+
cells in patients with stable coronary artery disease.
They also showed
that, among all common risk factors for atherosclerotic disease, diabetes
mellitus is the only significant predictor of a reduced CD34+ cell count.
However we have some concerns on the...
We read with great interest the scientific letter by Eizawa and
colleagues [1] reporting significant reduction of peripheral blood CD34+
cells in patients with stable coronary artery disease.
They also showed
that, among all common risk factors for atherosclerotic disease, diabetes
mellitus is the only significant predictor of a reduced CD34+ cell count.
However we have some concerns on the definition they provided of EPCs:
both in the title as in the text, peripheral blood CD34-positive cells are
defined as endothelial progenitor cells. It should be noted that
circulating EPCs represent a subset of peripheral blood mononuclear cells
(PBMCs) expressing immature surface markers common to hematopoietic stem
cells and endothelial lineage markers. By contrast CD34 represents a
marker of immature staminal cells that may be used to characterise EPCs
together with other surface antigens, but that identifies not only EPCs.
In fact peripheral blood CD34+ cells form a very heterogeneous pool
containing also CD45+ cells (lymphatic precursors), CD14+ cells
(monocyte/macrophage lineage precursors) and other non-hematopoietic cells
not belonging to the endothelial lineage.
As correctly stated in the editorial by Dr. Francis [2], CD133 is
considered the best surface marker to define, identify and isolate
circulating EPCs [3, 4]. Even if the exact phenotype of EPCs has not been
clearly established, additional markers reflecting endothelial commitment,
including Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2 or KDR),
Platelet-Endothelial Cells Adhesion Molecule-1 (PECAM-1 or CD31), Vascular
Endothelial-Cadherin, von Willebrand Factor, c-kit, Tie-2 and VEGFR-1, are
required. Using flow cytometry less than 0,001% of PBMCs is identified as
EPCs, but two or three markers are needed to avoid unspecific count [5].
Thus minimal requirement to identify EPCs should be the parallel use of
CD34 (or CD133) and KDR expression [6].
Furthermore our experience suggests that the percentage of EPCs among the
CD34+ pool vary widely from patient to patient and, in the same patient,
under different pathophysiological conditions, indicating possible
peripheral differentiation rather than bone-marrow mobilisation.
Taken together these considerations suggest that PBMCs-derived CD34+ cells
may not be used to identify EPCs. On the other hand we also believe that
the major finding included in the paper by Eizawa et al [1]. contributes
to shed light on circulating progenitor cells pathophysiology in chronic
stable coronary artery disease.
The great interest around EPCs arises from their possible use for cell
therapy in cardiac or peripheral critical ischemia. If we believe that
EPCs really have staminal properties and so proliferate and incorporate
into new vessels, there is need for specifically identify them, isolate
and expand. If we consider that EPCs or CD34+ cells stimulate angiogenesis
in a paracrine way by means of producing growth factors [7], it would be
more appropriate to call them “Circulating Angiogenic Cells” (CACs) as
already proposed.
Several clinical conditions characterised by poor endothelial function,
like diabetes mellitus [8], obesity, hypertension, autoimmune disorders
(such as Systemic Lupus Erythematosus), chronic renal diseases, etc., are
likely to be influenced by EPCs reduction and dysfunction.
Circulating cells and vascular wall cells of diabetic patients are exposed
to high oxidative stress, thus increased apoptosis or reduced peripheral
differentiation are likely to explain low EPCs counts.
However studies
must specifically target progenitor cells committed to the endothelial
lineage, in order to avoid identification of unspecific and already known
effects commonly observed in PBMCs derived from diabetic patients [9].
References
(1). Eizawa T, Ikeda U, Matsui K et al. Decrease in circulating
endothelial progenitor cells in patients with stable coronary artery
disease. Heart 2004;90:685-686
(2). Francis S. Endothelial progenitor cells and coronary artery
disease. Heart 2004;90:591-592
(3). Salven P, Mustjoki S, Alitalo R, Alitalo K, Rafii S. VEGFR-3 and
CD133 identify a population of CD34+ lymphatic/vascular endothelial
precursor cells. Blood 2003 Jan 1;101(1):168-72.
(4). Peichev M, Naiyer AJ, Pereira D et al. Expressione of VEGFR-2 and
AC133 by circulating human CD34(+) cells identify a population of
functional endothelial precursors. Blood. 2000 Feb 1;95(3):952-8.
(5). Bompais H, Chagraoui J, Canron X et al. Human endothelial cells
derived from circulating progenitors display specific functional
properties compared with mature vessel wall endothelial cells. Blood. 2004
Apr 1;103(7):2577-84.
(6). Hristov M, Erl W, Weber PC. Endothelial progenitor cells:
isolation and characterization. Trends Cardiovasc Med. 2003 Jul;13(5):201-
6.
(7). Heil M, Ziegelhoeffer T, Mees B, Schaper W. A different outlook on
the role of bone marrow stem cells in vascular growth. Bone marrow
delivers software not hardware. Circ Res. 2004;94:573-74.
(8). Avogaro A, Toffolo G, Kiwanuka E, de Kreutzenberg SV, Tessari P,
Cobelli C. L-arginine-nitric oxide kinetics in normal and type 2 diabetic
subjects: a stable-labelled 15N arginine approach. Diabetes. 2003
Mar;52(3):795-802.
(9). Avogaro A, Pagnin E, Calo L. Monocyte NADPH oxidase subunit
p22(phox) and inducible hemeoxygenase-1 gene expressions are increased in
type II diabetic patients: relationship with oxidative stress. J Clin
Endocrinol Metab. 2003 Apr;88(4):1753-9.
It is well known the relationship between coronary anomalies and
other congenital cardiac abnormalities [1-2]. Indeed, association between
atrial septal defect and coronary anomalies has been previously described
and in this situation compression of the anomalous coronary artery can
occur when septal defects is percutaneously closed [3-4]. We suggest that a transesophageal ecocardiogram should be don...
It is well known the relationship between coronary anomalies and
other congenital cardiac abnormalities [1-2]. Indeed, association between
atrial septal defect and coronary anomalies has been previously described
and in this situation compression of the anomalous coronary artery can
occur when septal defects is percutaneously closed [3-4]. We suggest that a transesophageal ecocardiogram should be done when
percutaneous closure is planned in patients with an atrial septal defect.
It would be useful to identify the ostium and initial course of both
coronary arteries, and will help to avoid possible additional procedure
complications.
References
1. Topaz O, DeMarchena EJ, Perin E et al. Anomalous coronary arteries:
angiographic findings in 80 patients. Int J Cardiol 1992;34:129-38.
2. Barriales-Villa R, Morís C, López-Muñiz A et al. Anomalías congénitas de
las arterias coronarias del adulto descritas en 31 años de estudios
coronariográficos en el Principado de Asturias: principales
características angiográficas y clínicas. Rev Esp Cardiol 2001;54:269-281.
3. Maki F, Ohtsuka T, Suzuki M et al. Myocardial ischemia induced by
anomalous aortic origin of the right coronary artery in a patient with
atrial septal defect. Jpn Heart J 2001;42:371-6.
4. Casolo G, Gensini GF, Santoro G et al. Anomalous origin of the
circumflex artery and patent foramen ovale: a rare cause of myocardial
ischaemia after percutaneous closure of the defect. Heart 2003;89:e23.
Dr. O Cheng raises the possibility that some elevations of troponin
we
attribute to pulmonary emboli [1] may be due to paradoxical coronary
emboli
[2].
We cannot, since all of the patients were not cathed acutely,
exclude
this possibility with data although we did not observe in this series
focal
ST segment elevation as one might expect from a paradoxical embolism.
Dr. O Cheng raises the possibility that some elevations of troponin
we
attribute to pulmonary emboli [1] may be due to paradoxical coronary
emboli
[2].
We cannot, since all of the patients were not cathed acutely,
exclude
this possibility with data although we did not observe in this series
focal
ST segment elevation as one might expect from a paradoxical embolism.
We
did angiograms for a few patients who had confusing clinical presentations
(n= 5) and did not find paradoxical emboli. Furthermore, our present
understanding suggests that paradoxical coronary emboli are unusual and
that
most paradoxic emboli do not migrate to the coronary arteries [3,4].
We
did
not observe any systemic emboli. In addition, there is adequate
experimental and clinical data to support the contention that the acute
right heart strain caused by pulmonary emboli can cause RV dysfunction,
ECG
changes and troponin release [5,6].
It is certainly possible that in some
patients there may left ventricular injury due to occult coronary artery
disease and either hypotension, increased cardiac work or both [7]. It
would be difficult for us to advocate coronary angiography in every
patient
with a pulmonary embolism and troponin release or ECG changes until Dr. O
Cheng and others provide more data to suggest that this is a common
occurrence.
Until that time, we and others should be aware of this rare
complication, so that in the unusual case, it can be considered as part of
the differential diagnosis in selected individuals.
References
(1). La Vecchia L, Ottani F, Favero L, Spadaro GL, Rubboli A, Bonanno
C,
Mezzena G, Fontanelli A, Jaffe AS: Increased cardiac troponin I on
admission
predicts in-hospital mortality in acute pulmonary embolism. Heart
2004;90:633-637.
(2). Cheng TO, Paradoxical Coronary Embolism - an Alternative explanation
for
increased cardiac troponin in acutePE. Heart 2004; 90:
(3). Konstantinides S, Geibel A, Kasper W, Olschewski M, Blümel L, Just H:
Patent foramen ovale is an important predictor of adverse outcome in
patients with major pulmonary embolism. Circulation 1998;97:1946-1951.
(4). Wachsman DE, Jacobs AK. Paradoxical coronary embolism: a rare cause
of
acute myocardial infarction. Reviews in Cardiovascular Medicine 2003;
4:107-11.
(5). Goldhaber SZ, Elliot CG: Acute pulmonary embolism. Part 2. Risk
stratification, treatment and prevention. Circulation 2003; 108:2834-2838.
(6). Ammann P, Maggiorini M, Bertel O, Haenseler E, Joller-Jemelka HI,
Oechslin E, Minder EI, Rickli H, Fehr T.Troponin as a risk factor for
mortality in critically ill patients without acute coronary syndromes.Rev
Cardiovasc Med. 2003;4:107-11.
(7). Kiryu S, Raptopoulos V, Baptista J, Hatabu H.Increased prevalence of
coronary artery calcification in patients with suspected pulmonary
embolism.
Am Coll Cardiol. 2003;41:2004-9.
At the outset let me thank Dr. Zhi Young Li for his observations and
the following is my reply:
Li: Firstly, the geometries were used with two sharp angles in the
shoulder regions, which will cause errors for FEA simulation. Special
method needs to use in this regions for correct results, while the authors
didn’t do anything with it.
At the outset let me thank Dr. Zhi Young Li for his observations and
the following is my reply:
Li: Firstly, the geometries were used with two sharp angles in the
shoulder regions, which will cause errors for FEA simulation. Special
method needs to use in this regions for correct results, while the authors
didn’t do anything with it.
Reply: I understand that Dr. Li may want us to use singular
elements? We do not consider that such special elements are required. In
this case there is no crack tip and is a simple bimaterial interface. We
are not studying the effect of sharp bimaterial interface, as the sharp
edge is more mathematical than physical. There is no crack tip singularity
and the bimaterial is assumed to be perfectly bonded. All results are for
far field stresses as seen from the figure itself. We have used a hybrid
element which takes care of incompressibility. Also, we have done a mesh
sensitivity study and the results presented are for the optimized mesh.
Li: Secondly, in figure 4a and figure 4b, the results showed maximal
stress actually in the opposite side of the plaque, which is in grey. This
is not in the shoulder region which is in red. This is due to the very
thin fibrous in that region.
Reply: Yes, the observation is true and we agree. But our interest is
only to find the maximum stress in proximal regions to the lipid since the
rupture of the cap is the main interest.
Li: Thirdly, figure 4c doesn’t prove anything, and it possibly is
wrong. Thin fibrous cap does result in high stress concentration in the
thin fibrous region. The result shows the stress only increases in the
other parts of the fibrous cap but not in the shoulders, which seems
incorrect.
Reply: It may be noted that the graph is plotted from 0 deg. to 90
deg. which is the major axis of the elliptical lumen. What is reported is
for the variation of lipid thickness at the minor axis. The stresses do
increase with lipid thickness as seen from the figure in this region. As
one moves to the shoulder the lipd increase in terms of thickness is low.
In other words, the increase in lipid increases the stresses only locally
and is one of the major emphasis of the paper. This is clearly brought out
in 6c and 6d.
Li: Fourthly, in figure 5a, maximal stress decreases when degree of
stenosis increases. This is due to the lumen is decreased with large
stenosis, and this results in less loading (pressure) applied on the lumen
wall. This certainly decreases the maximal stress on the fibrous cap. The
same lumen areas should be chosen when comparing the stenosis effect.
Reply: What Dr. Li states is the essence of Laplace law
which we have quoted. Engineers konw this for pressure vessels where
stress is directly proportional to radius of curvature for a given
internal pressure. We have not varied the area as the idea is to compare
stresses for the same pressure. Also in a given artery one cannot choose
the same area and vary the stenosis!
Li: Finally, the finite element method needs to be refined for this
model. The FEM actually affected the results (including figure 7), and
resulted incorrect conclusion.
Reply: As we have stated before what we have reported is for the
optimized mesh. Also the mesh density is retained for all the study and
hence will not enter into the major conclusions. The increase in stress
for the same pressure is again due to Law of Laplace as stated before and
in the text.
Staniforth et al provide interesting data relating to a sex bias in
favour of men with regard to implantable cardioverter defibrillator (ICD)
use,[1] concluding that the reason for this discrepancy is unclear.
Previous work has suggested that women are less likely to be referred for
ICD implantation, even when clinically appropriate.[2] This is surprising
given that survival rates in w...
Staniforth et al provide interesting data relating to a sex bias in
favour of men with regard to implantable cardioverter defibrillator (ICD)
use,[1] concluding that the reason for this discrepancy is unclear.
Previous work has suggested that women are less likely to be referred for
ICD implantation, even when clinically appropriate.[2] This is surprising
given that survival rates in women after ICD use are similar to their male
counterparts.[3] The long-held notion of male gender as a risk factor in
patients with coronary artery disease probably favours more male
referrals, which mirrors the TIMI III Registry findings,[4] where women
were less likely to undergo coronary angiography as well as referral for
revascularisation after acute coronary syndromes.
In addition, a large
cross-sectional study across 91 intensive care units in Great Britain
showed that there was inequity of female referrals to such units after
sustaining a myocardial infarct compared to age-adjusted males.[5] Can
this gender disparity in ICD take-up be explained by greater co-morbidity
in females, bearing in mind they present at a slightly older age compared
to men, as the authors postulate? This is unlikely, as evidenced by large
studies where even after adjustment for comorbid conditions, female sex
remained an independent predictor of reduced cardiac interventions in
coronary artery disease.[6,7] All these findings imply we are adopting a
less aggressive approach in our treatment of females with coronary artery
disease, despite mortality risks being broadly similar to that of males.
What about gender differences in survival outcomes in patients at
risk of sudden cardiac death? Perers et al reported that female gender was
associated with a higher chance of reaching hospital alive after suffering
an out of hospital cardiac arrest.[8] Herlitz et al also showed that
females were more likely to survive to hospital discharge following an in-
hospital cardiac arrest.[9] However, the aetiology of the cardiac arrest
in less than half of these patients was specifically due to coronary
ischaemia, so one cannot argue that women are less deserving of an ICD.
If one of the reasons for this gender discrepancy turns out that
women are indeed declining the procedure more often, then we need to focus
our attention on how to better educate them as to the risks and benefits
of intervening. As for physicians’ preferences in referral rates, we need
to re-evaluate our practice and keep in mind that Venus is not so far away
from Mars after all.
References
(1). Staniforth AD, Sporton SC, Robinson NM, et al. Is there a sex bias
in implantable cardioverter-defibrillator referral and prescription? Heart
2004;90:937-8.
(2). Beauregard LA. Incidence and management of arrhythmias in women. J
Gend Specif Med 2002;5:38-48.
(3). Pires LA, Sethuraman B, Guduguntla VD, et al. Outcome of women
versus men with ventricular tachyarrhythmias treated with the implantable
cardioverter defibrillator. J Cardiovasc Electrophysiol 2002;13:563-8.
(4). Stone PH, Thompson B, Anderson HV, et al. Influence of race, sex,
and age on management of unstable angina and non-Q-wave myocardial
infarction: The TIMI III registry. Jama 1996;275:1104-12.
(5). Raine R, Goldfrad C, Rowan K, et al. Influence of patient gender
on admission to intensive care. J Epidemiol Community Health 2002;56:418-
23.
(6). Bearden D, Allman R, McDonald R, et al. Age, race, and gender
variation in the utilization of coronary artery bypass surgery and
angioplasty in SHEP. SHEP Cooperative Research Group. Systolic
Hypertension in the Elderly Program. J Am Geriatr Soc 1994;42:1143-9.
(7). Raine RA, Crayford TJ, Chan KL, et al. Gender differences in the
treatment of patients with acute myocardial ischemia and infarction in
England. Int J Technol Assess Health Care 1999;15:136-46.
(8). Perers E, Abrahamsson P, Bang A, et al. There is a difference in
characteristics and outcome between women and men who suffer out of
hospital cardiac arrest. Resuscitation 1999;40:133-40.
(9). Herlitz J, Rundqvist S, Bang A, et al. Is there a difference
between women and men in characteristics and outcome after in hospital
cardiac arrest? Resuscitation 2001;49:15-23.
We thank Dr Kelion for his helpful comments regarding our recent
review on stress echocardiography in Heart [1]. We entirely agree with Dr
Kelion that both British Society of Echocardiography and British Nuclear
Cardiac Society need to raise awareness of the utility of functional tests
for the assessment of coronary artery disease and not squabble about which
technique is superior. Given the fact tha...
We thank Dr Kelion for his helpful comments regarding our recent
review on stress echocardiography in Heart [1]. We entirely agree with Dr
Kelion that both British Society of Echocardiography and British Nuclear
Cardiac Society need to raise awareness of the utility of functional tests
for the assessment of coronary artery disease and not squabble about which
technique is superior. Given the fact that both stress echocardiography
and SPECT imaging have similar diagnostic accuracy, either technique may
be used to perform functional testing.
The decision to proceed to
echocardiography or SPECT will depend on local availability and local
expertise. When both techniques are accessible with equal availability of
expertise, the choice of test will largely depend on the shorter waiting
time of the tests. It is time the National Institute of Excellence (NICE)
incorporated stress echocardiography alongside SPECT for the assessment of
CAD, not least, because the current guidelines by American College of
Cardiology (ACC) and American Heart Association recommend use of either
imaging technique for the assessment of CAD.
Yours sincerely,
R Senior
M Monaghan
H Becher
J Mayet
P Nihoyannopoulos
References
1. Senior R, Monaghan M, Becher H, Mayet J, Nihoyannopoulos P. Stress
echocardiography for the diagnosis and risk stratification of patients
with supected or known coronary artery disease: a critical appraisal.
Heart 2005; 91: 427-436.
We appreciate the comments made by Kasikcioglu and Dickerman
concerning our published study. [1] The assumption of “hypertrophic
cardiomyopathy”-like myocardial changes and the difficulty of assessment
of these changes is also supported by our recent findings pointing to a
reduced diastolic function in bodybuilders with anabolic steroid abuse by
using cardiac tissue doppler imaging, while conventio...
We appreciate the comments made by Kasikcioglu and Dickerman
concerning our published study. [1] The assumption of “hypertrophic
cardiomyopathy”-like myocardial changes and the difficulty of assessment
of these changes is also supported by our recent findings pointing to a
reduced diastolic function in bodybuilders with anabolic steroid abuse by
using cardiac tissue doppler imaging, while conventional echocardiographic
methods (M-Mode, blood doppler) showed no significant changes in
comparison to anabolic-free controls or endurance-athletes [2].
Concerning the points raised by Dickerman, we are well aware of the
intrinsic limitations of such a study as already mentioned in the
discussion of our results. However, our left ventricular dimensions
correspond to the results found by other authors in anabolic-free strength
athletes [3-5] and we do not share the opinion that differences in
measurements of wall thicknesses of approximately 1 mm between authors are
significant. The echocardiographic measurements in our cross-sectional
study were made by the same experienced investigator. Nonetheless we
certainly do not exclude wall thicknesses of approximately 13 mm in
anabolic-free athletes, especially in athletes with higher body dimensions
or from strength-endurance disciplines. [6]
Also, we did not state that
the training regimen would be the same in bodybuilders as in
weightlifters, but indeed we discussed that these differences would lead
to the opposite changes than the one observed by inducing a more eccentric
type of left ventricular hypertrophy in the bodybuilders. Finally we do
not share the opinion of Dickerman that our data show a lower
cardiovascular performance in the weightlifters because of the different
level of exhaustion and the similar indicator of submaximal ergometric
performance in comparison with the group of bodybuilders.
The claimed concentrations of testosterone were not described in this
publication but reported elsewhere. [7] As already suggested by the normal
concentrations of luteinizing hormone and follicle-stimulating hormone no
abnormally increased testosterone concentrations were found in the ex-
users, but 2 ex-users showed testosterone levels below the normal range.
We agree with Dickerman that this publication as well as the current
comments are fruitful by stimulating a more critical approach for future
studies.
References
(1). Urhausen A, Albers T, Kindermann W. Are the cardiac effects of
anabolic steroid abuse in strength athletes reversible? Heart 2004;90:496-
501
(2). Urhausen A, Krieg A, Scharhag J, Kindermann W. Tissue velocity
imaging in the assessment of left ventricular function in endurance
athletes vs. strength athletes abusing anabolic steroids. Med Sci Sports
Exerc 2003;35(Suppl):S318
(3). Snoeckx LHEH, Abeling HFM, Lambregts JAC, Schmitz JJF, Verstappen
FTJ, Renemann RS: Echocardiographic dimensions in athletes in relation to
their training program. Med Sci Sports Exerc 1982;14:428-434
(4). George KP, Wolfe LA, Burggraf GW: The athletic heart syndrome: a
critical review. Sports Med 1991;11;300-331
(5). Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P: The upper
limit of physiologic cardiac hypertrophy in highly trained elite athletes.
N Engl J Med 1991;324:295-301
(6). Urhausen A, Monz T, Kindermann W. Echocardiographic criteria of
physiological left ventricular hypertrophy in combined strength- and
endurance-trained athletes. Int J Card Imaging 1997;13:43-52
(7). Urhausen A, Albers T, Kindermann W. Reversibility of the effects on
blood cells, lipids, liver function and hormones in former anabolic-
androgenic steroid abusers. J Steroid Biochem Mol Biol 2003;84:369-375
We refer to the article by Prasad and Pennell in Heart (2004;90:1241-
1244), Safety of cardiovascular magnetic resonance in patients with
cardiovascular implants and devices. We applaud the authors’ efforts to
identify and summarise the problems and solutions associated with magnetic
resonance imaging (MRI) in patients with biomedical implants and devices.
We refer to the article by Prasad and Pennell in Heart (2004;90:1241-
1244), Safety of cardiovascular magnetic resonance in patients with
cardiovascular implants and devices. We applaud the authors’ efforts to
identify and summarise the problems and solutions associated with magnetic
resonance imaging (MRI) in patients with biomedical implants and devices.
Our experience confirms the need expressed by clinicians for a greater
accessibility to information regarding the effects, whether potential or
actual, of MRI on biomedical implants and devices. In 2003, the UK Heart
Valve Registry (UKHVR), which is responsible for registering all heart
valve replacement prostheses and annuloplasty rings implanted in the UK,
received nearly 500 telephone enquiries requesting information relating to
the identification of heart valve prostheses and annuloplasty rings for
patients referred for MRI.
In 2004 the number of similar requests had
risen by 58% overall and, in the first three months of 2005 this figure
had already increased by 55%. Whilst we cannot confirm that these
increases are the result of increases in the numbers of cardiac implant
patients referred for MRI rather than an increased awareness of the
service offered by the UKHVR, we have no reason to doubt that a
significant number of such patients are, and will continue to be referred
for MRI. Thus, it is essential that information is not only made
available and accessible but that it is based on empirical evidence and
not on assumption.
The UKHVR has so far tested over 100 different heart valves and
annuloplasty rings for interactions with magnetic field induced forces
under MRI at both low and high field strengths.[1-3] Whilst we acknowledge
that the majority of heart valve prostheses have been tested for
magnetic field interactions, there are some valves which, to date, have
not.
Therefore, it concerns us that Prasad and Pennell make the following
statement “ at 1.5 T all heart valve prostheses and annuloplasty rings are
CMR compatible” (Edwards MB, Taylor KM & Shellock FG (J Magn Reson
Imaging 2000). A recent study undertaken by the UKHVR which evaluated
magnetically induced forces at higher field strengths found that a
previously considered MR safe heart valve prosthesis was found to interact
with the magnetic field and appeared to become increasingly magnetised
with each re-insertion into the MR system.[3]
The valve in question has
often been quoted as being safe to undergo MRI because it is a
bioprosthesis (i.e. animal tissue valve) and there is an assumption that
all bioprostheses are safe. A similar assumption is regularly applied to
annuloplasty rings, one of which also contains the alloy in question.
Although this study was conducted at a high field strength, we feel it has
indicated that it is unsafe to assume certain biomedical materials found
in implants will behave in a similar fashion at any given field strength.
As a result of these findings we believe it is necessary to conduct ex
vivo testing of all implants and devices in all MR environments.
Finally, we would like to confirm that whenever the UKHVR receives a
request for information relating to the safety or compatibility of a heart
valve prosthesis we are always very careful to identify the individual
prosthesis with the patient and confirm its safety/compatibility status.
If we find a prosthesis has not been tested we advise the clinician as
such and never recommend it is safe to expose a patient to an MR
procedure.
Maria-Benedicta Edwards
UK Heart Valve Registry
Department of Cardiothoracic Surgery
Hammersmith Hospital
Du Cane Road
London W12 0NN
1. Edwards MB, Taylor KM, Shellock FG. Prosthetic heart valves:
evaluation of magnetic field interactions, heating, and artifacts at 1.5
T. J. Magn Reson Imaging 200012:33-369.
2. Edwards MB, Ordidge RJ, Thomas DL, Hand JW, Taylor KM. Translational
and rotational forces on heart valve prostheses subjected ex vivo to a 4.7
T MR system. J.Magn.Reson.Imaging 2002;16:653-659 (Corrigendum J.Magn.
Reson. Imaging 2003;17:386-387).
3. Edwards MB, Ordidge RJ, Hand JW, Taylor KM, Young IR. Assessment of
magnetic field (4.7 T) induced forces on prosthetic heart valves and
annuloplasty rings. J.Magn.Reson.Imaging 2005 (in press).
4. Edwards MB. Heart valves and annuloplasty ring implants in the United
Kingdom 1974 – 2004. A guide to types, models and MRI safety. A UK Heart
Valve Registry publication, London 2005 (in press).
The article by Day et al [1]. raises some issues about platelet
activation, heparin therapy and acute restenosis after percutaneous
coronary intervention that merit further discussion. When compared to
other anticoagulants heparin not only has the disadvantage of providing a
variable (and unpredictable) anticoagulant response as Day et al. have
stated but also has little or no effect on clot...
The article by Day et al [1]. raises some issues about platelet
activation, heparin therapy and acute restenosis after percutaneous
coronary intervention that merit further discussion. When compared to
other anticoagulants heparin not only has the disadvantage of providing a
variable (and unpredictable) anticoagulant response as Day et al. have
stated but also has little or no effect on clot bound thrombin[2].
However, in clinical practice, when prescribed to prevent acute restenosis
after percutaneous intervention, heparin has been more reliable and
effective than these other anticoagulants and is now the drug of choice
during percutaneous and other vascular intervention [3].
This suggests that
the principal benefits conferred by heparin when used for this indication
may not be related to its effects on the coagulation cascades. It is
therefore possible that the principal mode of action of heparin in this
situation is by its effects on platelet activation. This is also suggested
by work on the Folts coronary thrombosis model in which cyclic flow
reductions due to platelet thrombosis were unaffected by the selective
thrombin inhibitor recombinant hirudin [4].
Platelet activation is a tightly regulated series of events that are
initiated by the binding of an agonist to a platelet membrane and
culminate in platelet secretion and platelet aggregation. This process can
be divided into three phases: (1) shape change, (2) microaggregation
(primary aggregation) and (3) macroaggregation (secondary aggregation)[5].
During primary haemostasis macroaggregation is a crucial step as it gives
the initial strength to a platelet plug; later, during secondary
haemostasis, the platelet plug is reinforced by being consolidated within
an enveloping fibrin mesh. It is therefore conceivable that similar events
occur during pathological thrombosis.
Heparin affects platelet activation in at least four ways:
(i) Heparin stimulates platelets, probably by a direct action, inducing
shape change and microaggregation. [6-7]
(ii) In predisposed individuals who have had prior exposure to heparin an
immune mediated response may cause intense platelet aggregation.[8-9]
(iii) Heparin, in concentrations that vastly exceed those targeted
clinically, possibly by a direct action, is a mild inhibitor of platelet
macroaggregation.[10-11]
(iv) Intravenous heparin even in very low doses causes an almost complete
inhibition of platelet macroaggregation.[10-11]
The inhibitory action of heparin that is of clinical benefit is
unlikely to be that observed by Day et al. who used washed platelets which
were heparinised in vitro; we state this because several workers,
including ourselves, have demonstrated that while intravenous
heparinisation, even in low doses, almost completely inhibits platelet
macroaggregation, little or no inhibition of platelet macroaggregation is
detected even when blood is heparinised in vitro even with much higher
doses.[10-13]
When we studied the relationship between heparin dosage and the
inhibition of platelet macroaggregation after intravenous heparinisation,
we found that the inhibition of platelet macroaggregation caused by
administering 30 U Kg-1 of heparin was almost complete and therefore
increasing the dose to 300 U Kg-1 had no additional effect [13]. This
suggests that, at all doses currently used in clinical practice, heparin
exerts an almost complete inhibition of platelet macroaggregation. We have
further demonstrated that the indirect inhibition of platelet
macroaggregation is mediated by heparin-releasable endothelial enzymes
such as lipoprotein lipase and hepatic lipase;[14] it has also been shown
that release of endothelium-anchored lipase does not depend on the
molecular weight of the heparin.[15]
Most interventionalists currently administer heparin as a single dose
just before uncomplicated percutaneous intervention; additional post-
procedural doses have been associated with a higher risk of bleeding
complications while conferring no further reduction in the rate of
restenosis [3]. This suggests that heparin may provide better prophylaxis
against acute restenosis than it does against later occlusion.
Regarding the role of the platelet in restenosis: as the authors
point out, restenosis results from a combination of smooth muscle
proliferation, recoil and incorporation of thrombus; platelets are thought
to play significant roles in all three processes. It is however likely
that acute restenosis, both after percutaneous intervention and coronary
artery bypass grafting, is largely the result of thrombosis [16].
On the basis of the above arguments we propose that the principal way
in which heparin retards thrombosis, and hence acute restenosis, is by its
lipase mediated actions that prevent the formation of the platelet plug,
upon which fibrin would be laid, rather than by its antithrombin III-
mediated inhibition of thrombin.
The observations by previous workers that increased bleeding times
after intravenous heparin correlate with lipase release [17], but are
independent of heparin’s effect on plasma coagulation [12], raise the
possibility that the bleeding diathesis associated with heparin therapy
may also be more closely linked to heparin’s effects on platelet
activation than they are to heparin’s anticoagulant properties.
Refernces
(1). Day JRS, Malik IS, Weerasinghe A, et al. Distinct yet
complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors
on platelet activation and aggregation: implications for restenosis during
percutaneous coronary intervention Heart 2004;90:794-799.
(2). Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is
protected from inhibition by heparin-antithrombin III but is susceptible
to inactivation by antithrombin III-independent inhibitors. J Clin Invest
1990;86:385-91.
(3). Smith SCJr, Dove JT, Jacobs AK, et al. ACC/AHA Guidelines for
Percutaneous Coronary Intervention (Revision of the 1993 PTCA Guidelines)
A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines
for Percutaneous Transluminal Coronary Angioplasty) Endorsed by the
Society for Cardiac Angiography and Interventions. J Am Coll Cardiol
2001;37:2239i-lxvi
(4). Belcher PR, Drake-Holland AJ, Hynd JW, et al. Failure of
recombinant hirudin to influence intracoronary thrombosis in the dog. Clin
Sci (London) 1996;90:363-8
(5). Pedvis LG, Wong T, Frojmovic MM. Differential inhibition of the
platelet activation sequence: shape change, micro- and macro-aggregation,
by a stable prostacyclin analogue (Iloprost). Thromb Haemost 1988;59:323-
328.
(6). Thomson C, Forbes CD, Prentice CR. The potentiation of platelet
aggregation and adhesion by heparin in vitro and in vivo. Clin Sci Mol Med
1973;45:485-94.
(7). Kappa JR, Fisher CA, Addonizio VPJ. Heparin-induced platelet
activation: the role of thromboxane A2 synthesis and the extent of
platelet granule release in two patients. J Vasc Surg 1989;9:574-579
(8). Chong BH, Fawaz I, Chesterman, CN et al. Heparin-induced
thrombocytopenia: mechanism of interaction of the heparin-dependent
antibody with platelets. Br J Haematol 1989:73:235-240.
(9). Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced
thrombocytopenia in patients treated with low-molecular- weight heparin or
unfractionated heparin. N Engl J Med 1995;332:1330-1335.
(10). Besterman EM and Gillett MP. Heparin effects on plasma
lysolecithin formation and platelet aggregation. Atherosclerosis
1973;17:503-13.
(11). Belcher PR, Muriithi EW, Milne EM et al. Heparin, Platelet
Aggregation, Neutrophils And Cardiopulmonary Bypass. Thromb Res
2000;98:249-56.
(12). Heiden D, Mielke, CHJ Rodvien R. Impairment by heparin of primary
haemostasis and platelet [14C]5- hydroxytryptamine release. Br J Haematol
1977;36:427-436.
(13). Muriithi EW, Belcher PR, Day SP et al. Heparin induced platelet
dysfunction and cardiopulmonary bypass. Ann Thorac Surg 2000;69:1827-32.
(14). Muriithi EW, Belcher PR, Day SP et al. Lipolysis generates
platelet dysfunction after in vivo heparin administration. Clin Sci (Lond)
2002;103:433-40.
(15). Nasstrom B, Stegmayr BG, Olivecrona G et al. Lower plasma levels
of lipoprotein lipase after infusion of low molecular weight heparin than
after administration of conventional heparin indicate more rapid
catabolism of the enzyme. J Lab Clin Med 2003;142:90-9.
(16). Schoen FJ, Padera RF Jr. Cardiac Surgical Pathology. In: Cohn LH,
Edmunds LH Jr, eds. Cardiac Surgery in the Adult. 2nd Edition New York:
McGraw-Hill, 2003:119-185.
(17). Barrowcliffe TW, Merton RE, Gray E et al. Heparin and bleeding:
an association with lipase release. Thromb Haemost 1988;60:434-436.
Dear Editor,
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Dear Editor,
The article by Day et al [1]. raises some issues about platelet activation, heparin therapy and acute restenosis after percutaneous coronary intervention that merit further discussion. When compared to other anticoagulants heparin not only has the disadvantage of providing a variable (and unpredictable) anticoagulant response as Day et al. have stated but also has little or no effect on clot...
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