The article by Androne et al.[1] describing the improvement in heart
rate recovery after maximal exercise in patients with chronic heart
failure when treated with pyridostigmine, supports the recent concept that
cholinergic stimulation may have a protective role in cardiovascular
disease.[2] We have prompted to investigate this possibility, since
depressed heart rate variability[3] and baroref...
The article by Androne et al.[1] describing the improvement in heart
rate recovery after maximal exercise in patients with chronic heart
failure when treated with pyridostigmine, supports the recent concept that
cholinergic stimulation may have a protective role in cardiovascular
disease.[2] We have prompted to investigate this possibility, since
depressed heart rate variability[3] and baroreflex sensitivity,[4] both
used as indices of parasympathetic function, has been shown to be
independent risk markers for death in chronic heart failure.
We have described previously several aspects of the oral
administration of pyridostigmine bromide, an indirect cholinomimetic
agent, in healthy volunteers, such as the effect on heart rate variability [5] and the response to physical [6] and mental stress.[7,8] Contrary to
the statement by Andone et al,[1] we have demonstrated that
pyridostigmine did blunt the heart rate response to physical exercise, an
effect previous reported by others,[9] and to mental stress. Our
unpublished data with patients with chronic heart failure during exercise
reveal that pyridostigmine causes submaximal bradycardia and increased
oxygen pulse, a variable calculated by the ratio between oxygen uptake and
heart rate that is proportional to stroke volume, suggesting an
improvement in cardiac dynamics during physical effort. Unfortunately, our
findings could not be compared to those by Androne et al.[1] in this
respect, since they did not report data on oxygen pulse.
We have just published [10] results from a ramdomized, double-blind,
cross-over study where pyridostigmine reduced ventricular ectopic activity
and increased heart rate variability in patients with chronic heart
failure. This study together with that of Androne (1) may not contitute
enough evidence to support the proposal for large-scale clinical trials to
test the hypothesis that selective enhancement of parasympathetic activity
will improve outcome,[11] but do certainly point to a new and promising
perspective concening the therapeutic management of patients with chronic
heart failure.
References
(1) Androne AS, Hryniewicz K, Goldsmith R, Arwady A, Katz SD.
Acetylcholinesterase inhibition with pyridostigmine improves heart rate
recovery after maximal exercise in patients with chronic heart failure.
Heart 2003;89(8):854-8.
(2) Nobrega ACL, Castro RRT. Parasympathetic dysfunction as a risk
factor in myocardial infarction: what is the treatment? Am Heart J
2000;140(4):E23
(3) Nolan J, Batin PD, Andrews R, et al. Prospective study of heart
rate variability and mortality in chronic heart failure: results of the
United Kingdom heart failure evaluation and assessment of risk trial (UK-
heart).
Circulation 1998;98(15):1510-6.
(4) Mortara A, La Rovere MT, Pinna GD, et al. Arterial baroreflex
modulation of heart rate in chronic heart failure: clinical and
hemodynamic correlates and prognostic implications. Circulation
1997;96(10):3450-8.
(5) Nobrega AC, dos Reis AF, Moraes RS, Bastos BG, Ferlin EL, Ribeiro
JP. Enhancement of heart rate variability by cholinergic stimulation with
pyridostigmine in healthy subjects. Clin Auton Res 2001;11(1):11-7.
(6) Serra SM, Costa RV, Bastos BG, Santos KB, Ramalho SH, da Nobrega
AC. Exercise stress testing in healthy subjects during cholinergic
stimulation after a single dose of pyridostigmine. Arq Bras Cardiol
2001;76(4):279-84
(7) Nobrega AC, Carvalho AC, Santos KB, Soares PP. Cholinergic
stimulation with pyridostigmine blunts the cardiac responses to mental
stress. Clin Auton Res 1999;9(1):11-6.
(8) Sant'anna ID, Sousa EB, Moraes AV, Loures DL, Mesquita ET,
Nobrega AC. Cardiac function during mental stress: cholinergic modulation
with pyridostigmine in healthy subjects. Clin Sci (Lond) 2003;105(2):161-
5.
(9) Wenger B, Quigley MD, Kolka MA. Seven-day pyridostigmine
adminstration and thermoregulation during rest and exercise in dry heat.
Aviat Space Environ Med 1993;64(10):905-11.
(10) Behling A, Moraes RS, Rohde LE, Ferlin EL, Nobrega ACL, Ribeiro
JP. Cholinergic stimulation with pyridostigmine reduces ventricular
arrhythmia and enhances heart rate variability in heart failure. Am Heart
J 2003;146(3):494-500.
(11) Sueta CA. Heart rate variability in chronic heart failure:
target for therapy? Am Heart J 2003;146(3):385-7.
Barakat and colleagues' observations are clinically important.
Our work on the performance of the Rose angina questionnaire in a multi-
ethnic study of a community based sample of 1509 adults from European,
Indian, Pakistani and Bangladeshi ethnic groups corroborates and
complements, their observations.[1]
European men and women mostly reported chest pain in Rose
Questionnaire (definite angina c...
Barakat and colleagues' observations are clinically important.
Our work on the performance of the Rose angina questionnaire in a multi-
ethnic study of a community based sample of 1509 adults from European,
Indian, Pakistani and Bangladeshi ethnic groups corroborates and
complements, their observations.[1]
European men and women mostly reported chest pain in Rose
Questionnaire (definite angina criteria) qualifying sites i.e. sternum or
left chest and left arm. In contrast, there were substantial numbers of
South-Asian respondents with left-sided chest pain but without left-sided
arm pain. This pattern was particularly clear in Indians. Right-sided
chest pain was commoner in Pakistanis and the pattern of pain was diffuse
in Bangladeshis of both sexes, in whom left chest pain was never combined
with left arm pain. Our published diagrams on chest pain site illustrate
these points.[1]
The‘classical’ elements of the history were less frequent in South
Asians than in Europeans, while ‘atypical’ features were most common in
Pakistanis and Bangladeshis. Bangladeshis with chest pain mostly failed to
report the other features required for definite angina on the Rose
Questionnaire. Our paper raised the possibility of systematic differences
between ethnic groups in the site of reported chest pain. We wrote that
firm conclusions must await confirmation from further studies. With the
observations of Barakat et al, this area is shown to be epidemiologically
and clinically important. It is likely that Barakat et al's findings
apply not just to Bangladeshis but to other South Asian populations.
With their exceptionally poor knowledge about heart disease and
diabetes,[2] their economic deprivation, the significant clustering of
cardiovascular risk factors,[3] and atypical presentation of pain
associated with coronary heart disease, Bangladeshis are in particular
jeopardy.
References
(1) Fischbacher CM, Bhopal R, Unwin N, White M, Alberti
KG. The performance of the Rose angina questionnaire in South Asian and
European origin populations: a comparative study in Newcastle Int J
Epidemiol 2001;54:786.
(2) Rankin J, Bhopal R. Understanding of heart disease and diabetes
in a South Asian community: cross sectional study testing the `snowball'
sample method. Pub Health 2001;115:253-260.
(3) Bhopal, R S, Unwin N, White M. et al. heterogeneity of coronary
heart disease risk factors in Indian, Pakistani, Bangladeshi and European
origin populations: cross sectional study. BMJ 1999;319:215-220.
We thank Dr Cheung for the interesting observations [1]concerning
our paper.[2]
They suggest - on the basis
of their study,[3] that an arterial
dysfunction (probably due to iron overload) could contribute to the
pathogenesis of the so-called “Thalassemic cardiomyopathy” causing an
increase of arterial stiffness and, consequently, an increase of the
pulsatile pressure if the ventricular systoli...
We thank Dr Cheung for the interesting observations [1]concerning
our paper.[2]
They suggest - on the basis
of their study,[3] that an arterial
dysfunction (probably due to iron overload) could contribute to the
pathogenesis of the so-called “Thalassemic cardiomyopathy” causing an
increase of arterial stiffness and, consequently, an increase of the
pulsatile pressure if the ventricular systolic pump function remains
within normal ranges.
We wish to underline that, even in the presence of an increased impedence
of the proximal arterial bed, the systemic vascular resistance (totally
considered) could be reduced in a high cardiac output state due to the
significant chronic anemia. This seems confirmed in our patients, in whom
the afterload was increased because of an unfavourable mass/volume ratio.
Anyway, as suggested by Cheung et al, an increased pulsatile
vascular load might play an additional role in increasing the afterload.
We obviously agree with the multifactorial pathogenesis of this
"cardiomyopathy", but we think that the iron overload play an important
role. Unfortunately, in our group of patients with a quite preserved left
ventricular systolic pump function, we have found only a weak correlation
between ferritin levels and EF% of the left ventricle. Being aware that
the conventional endocardial indexes may overestimate the myocardial fibre
shortening (an effect proportional to wall thickness) we have calculated
(data not published) stress/velocity indexes at midwall level
demonstrating a reduced contractility in 13% of our patients. So, more
detailed information on the myocardial function in thalassemic patients
affected by dilated and hypertrophic ventricles are needed. Doppler tissue
imaging with strain and strain/rate imaging at different stages of the
disease could probably give more information.
References
(1) Cheung YF. Arterial dysfunction contributes to 'beta-thalassaemia cardiomyopathy' [electronic response to Bosi G et al. Left ventricular remodelling, and systolic and diastolic function in young adults with ß thalassaemia major: a Doppler echocardiographic assessment and correlation with haematological data] heartjnl.com 2003
(2) Bosi G, Crepaz R, Gamberini MR, Fortini M, Scarcia S, Bonsante E, Pitscheider W, Vaccari M. Left ventricular remodelling, and systolic and diastolic function in young adults with ß thalassaemia major: a Doppler echocardiographic assessment and correlation with haematological data. Heart 2003;89:762-766.
(3) Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation 2002 Nov 12;106(20):2561-6.
On 24 June the National Institute of Clinical Excellence (NICE)
issued their Appraisal consultation document: coronary artery
stents.[1] With the proviso that ‘the decision to use a bare metal
stent or drug-eluting stent (DES) will depend on the anatomy of
the target vessel for stenting and the severity of the disease’
(presumably reflecting issues of deliverability of the stent
platforms on offer), t...
On 24 June the National Institute of Clinical Excellence (NICE)
issued their Appraisal consultation document: coronary artery
stents.[1] With the proviso that ‘the decision to use a bare metal
stent or drug-eluting stent (DES) will depend on the anatomy of
the target vessel for stenting and the severity of the disease’
(presumably reflecting issues of deliverability of the stent
platforms on offer), the key point was that a ‘DES is
recommended .. [when] .. the target artery is less than 3mm in
diameter or the lesion to be stented is longer than 20mm.’
We applaud the NICE philosophy of selective DES implantation
in a resource-hungry health service. It must be appreciated by
interventional cardiologists, however, that this guideline will
reduce, but not abolish, restenosis. As we recently argued,[2]
there is a law of diminishing returns with DESs; escalating
numbers (and, therefore, costs) would be required to squeeze the
last few % points of restenosis out of the system. Clearly, NICE
have grasped this reality and are endorsing a policy of scientific
rationing, the science providing some targeting of the few DESs
permitted to the lesions most likely to restenose.
What are the implications of the NICE guidelines? Applying
them to our institution reveals that a DES would be used in about
34% of lesions. This would reduce our clinical recurrence (re-
PCI) rate - the only restenosis parameter a centre not performing
routine follow-up angiography can count – from 9% to 5.1%. A
considerable disadvantage of the NICE system would be that no
stents of certain important and commonly used sizes would be
permitted, such as 3 x16mm, 3 x 18mm or any stent of 3.5mm
calibre, even if the target lesion is a long stenosis in the proximal
left anterior descending artery of a diabetic patient. If, instead,
we allotted DES according to our recommended system, based
upon a matrix of restenosis risk,[2] we find that a 34% DES rate
would yield an almost identical overall institutional recurrence
risk (5.2%), with the advantage that we would have DES
available for the sizes and indications mentioned above. Stock
control would also be simpler (important if the DES in question
has a limited shelf life) because rarely used sizes would not be
stocked.
We were interested to read the recent scientific letter from Pollard et al published in Heart.[1]
The authors evaluated the safety of a
protocol for earlier sit up and mobilisation after routine transfemoral
cardiac catheterisation in contemporary practice. Patients were
randomised to be mobilised after 2½ hours or 4½ hours bed rest. The
authors report that a significant reduction in...
We were interested to read the recent scientific letter from Pollard et al published in Heart.[1]
The authors evaluated the safety of a
protocol for earlier sit up and mobilisation after routine transfemoral
cardiac catheterisation in contemporary practice. Patients were
randomised to be mobilised after 2½ hours or 4½ hours bed rest. The
authors report that a significant reduction in the duration of bed rest
was achieved in the early mobilisation protocol group with no adverse
effect on vascular complications. They also report that early
mobilisation was associated with a reduction in pain and discomfort,
although this data is not presented. On this basis, the authors call into
question the role of alternative arterial access sites for diagnostic
cardiac catheterisation.
The published data does not support this viewpoint. Firstly, the
early mobilisation protocol still required 2½ hours of bed rest. There is
extensive published evidence that bed rest after medical procedures has
few benefits and a wide range of adverse effects.[2] The combination of
back pain related to bed rest and groin pain related to femoral puncture
and pressure haemostasis delays mobilisation and return to normal activity
after discharge in at least one third of patients.[3] Secondly, despite
studying only a selected low risk group of patients (only some elective
patients with chest pain undergoing diagnostic angiography were eligible
for the study. Patients with a difficult femoral puncture, those
undergoing percutaneous revascularisation, receiving adjunctive
antithrombotic therapy or with previously treated peripheral vascular
disease were excluded) haematomas re-bleeding and vaso-vagal reactions
were common. Indeed this study suggests that these problems occur in 15-
20% of these low risk patients. In contrast to this, we have recently
reported on a series of 1000 consecutive transradial cases, in which a
third of the study subjects had major risk factors for vascular
complications.[4] Patients undergoing diagnostic angiography or
percutaneous intervention were mobilised immediately, removing the
potential for adverse effects from bed rest. Avoiding a groin puncture
will facilitate a rapid return to normal activity after discharge. In
this high risk population the incidence of both major and minor vascular
complications was less than 1%. The data from the North Staffordshire
series is entirely compatible with other published case series and
randomised trials, which consistently show that use of the transradial
access site is associated with short mobilisation and discharge times, a
reduction in procedure costs and vascular complications, and a consistent
improvement in patient quality of life when compared to the femoral access
site.[5-7]
In our view the data presented (a 2½ hour period of bed rest and 15-
20% incidence of access site problems) strengthens the case for selecting
the radial artery (no bed rest and less than 1% incidence of access site
problems) in the majority of patients undergoing routine diagnostic
cardiac catheterisation.
References
(1) Pollard SD, Munks K, Wales C, Crossman DC, Cumberland DC, Oakley
GDG, Gunn J. Position and mobilisation post-angiography study. (PAMAS): a
comparison of 4.5 hours and 2.5 hours bed rest. Heart 2003;89:447-448.
(2) Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful
treatment needing more careful evaluation. Lancet 1999;354:1229-1233.
(3) Foulger V. Patients’ views of day-case cardiac catheterisation.
Professional Nurse 1997;12:478-480.
(4) Eccleshall SC, Banks M, Carroll R, Jaumdally R, Fraser D, Nolan J.
Implementation of a diagnostic and interventional transradial programme:
resource and organisational implications. Heart 2003;89:561-562.
(5) Eccleshall S, Muthusamy T, Nolan J. The transradial access site
for cardiac procedures: a clinical perspective. Stent 1999;2(3):74-9.
(6) Al-Allaf K, Eccleshall S, Kaba R, et al. Arterial access for
cardiac procedures utilising the percutaneous transradial approach. Br J
Cardiol 2000;7:548-52.
(7) Kiemeneij F, Laarman GJ, Odekerken D et al. A randomised
comparison of percutaneous transluminal coronary angioplasty by the
radial, brachial and femoral approaches: the Access study. J Am Coll
Cardiol 1997;29(6):1269-75.
I read the article by Barrera-Ramirez et al. with interest and have some comments.
I think this case is an extensive myocardial stunning induced by emotional stress. Some stunning occured with emotional stress, cerebrovascular attack,
and surgery. Symathetic denervation is involved in such cases. Prolonged T
wave inversion would indicate the change in repolarization related to the
sympathetic...
I read the article by Barrera-Ramirez et al. with interest and have some comments.
I think this case is an extensive myocardial stunning induced by emotional stress. Some stunning occured with emotional stress, cerebrovascular attack,
and surgery. Symathetic denervation is involved in such cases. Prolonged T
wave inversion would indicate the change in repolarization related to the
sympathetic activation. The discrepancy between remarkable ST elevation and
mild elevation of myocardial enzymes would indicate myocardial stunning with
sympathetic denervation. Although some Japanese docotrs call such a clinical
state ampulla cardiomyopathy, it is contoversial. Apical thrombus has
firstly described all over the world.[2]
References
(1) Barrera-Ramirez CF, Jimenez-Mazuecos JM, Alfonso F. Apical thrombus associated with left ventricular apical ballooning. Heart 2003;89:927.
(2) Tetsuya Sato et al. Extensive myocardial stunning showing transient regression of prolonged T wave inversion and prolonged sympathetic
denervation. Internal Med 2001;40:312-319.
We read the review paper by Tousoulis et al. with great interest. We applaud their thoroughness in describing the molecular and cellular
mechanisms involved in the inflammatory mechanisms and haemostatic factors
leading to coronary atherosclerosis. They also describe the role of
chronic infection in this process.[1] However, they omit an important
factor that is common to the majority of patients su...
We read the review paper by Tousoulis et al. with great interest. We applaud their thoroughness in describing the molecular and cellular
mechanisms involved in the inflammatory mechanisms and haemostatic factors
leading to coronary atherosclerosis. They also describe the role of
chronic infection in this process.[1] However, they omit an important
factor that is common to the majority of patients suffering from this
condition – current or previous cigarette smoking.
We have undertaken an investigation into the relationship between
smoking habit, notably quantitative measurement of nicotine intake and
factors involved in the formation of the plaque and the inflammatory
process. Due to ‘social desirability bias’ associated with smoking
patients frequently under-report or deny their smoking habit. It would
seem therefore that the greater the clinical impact of smoking the greater
the patient guilt enhancing the likelihood of denial.
To improve the accuracy of information about smoking a 6-minute point
-of-care test to detect nicotine metabolites (including cotinine), called
SmokeScreen® was developed.[2] The easy to use colorimetric urine test
can provide qualitative, semi-quantitative and quantitative measurements
of nicotine intake. With this test we undertook an audit of smoking habits
of 154 new patients attending a large inner-city hospital cardiology
outpatient clinic, comparing the test identification of smoking with self-
completed questionnaire of current smoking habit. The results identified
112 (72.7%) as non-smokers, 30 (19.5%) as confessed smokers and 12 (7.8%)
as ‘smoking deceivers’.
We followed this with another study of the same population (n=85, 33
smokers and 52 never-smokers) to examine the interaction of smoking with
risk factors associated coronary artery disease, as assessed by a
biochemical screen and a blood count. Interestingly, none of the
parameters measured in the biochemical screen, such as cholesterol, HDL
and triglycerides; urea and electrolytes and liver function tests were
associated with smoking habit or quantitative assessment of nicotine
intake. Whereas white blood cell count (WBC) was significantly higher in
smokers (p=0.002), in particular neutrophils (p=0.01) and eosinophils
(p=0.02). Lymphocytes, monocytes and basophiles were higher but failed to
reach significance. Quantitative assessment of nicotine intake of the
smokers further revealed a positive correlation with WBC (p<_0.0001 neutrophils="neutrophils" p0.001="p0.001" eosinophils="eosinophils" p0.004="p0.004" and="and" lymphocytes="lymphocytes" p0.02="p0.02" with="with" monocytes="monocytes" approaching="approaching" significance="significance" p="p"/> It would seem from this pilot study that smoking or the amount of
tobacco consumed doesn’t influence the biochemical risk factors for
coronary artery disease, such as cholesterol and HDL, but does increase
many of the cellular factors which Tousoulis et al. identified as
contributors to the inflammatory response and to the formation and
instability of the atheromatous plaque.[1]
We suggest that identification of smokers, feedback from the point-of-care
test and subsequent advice on smoking cessation could have a significant
impact on reducing many of the risk factors associated with coronary
atherosclerosis and lower cardiovascular events and mortality.
References
(1) Tousoulis D, Davies G, Stefanadis, Toutouzas P, Ambrose JA.
Inflammatory and thrombotic mechanisms in coronary atherosclerosis. Heart 2003;89:993-997.
(2) Cope GF, Nayyar P, Holder R, Gibbons J, Bunce R. A simple near-patient
test for nicotine and its metabolites in urine to assess smoking habit. Clin Chim Acta 1996;256:135-149.
Bosi and colleagues [1] suggested that significant volume
load of the heart as a result of chronic anaemia in young adults with beta
thalassaemia major is the main culprit of the so-called 'beta thalassaemic
cardiomyopathy'. Their findings, based on echocardiographic assessment of
left ventricular function, were similar to those reported
previously.[2,3] Nonetheless, the role of arterial dysfunction in th...
Bosi and colleagues [1] suggested that significant volume
load of the heart as a result of chronic anaemia in young adults with beta
thalassaemia major is the main culprit of the so-called 'beta thalassaemic
cardiomyopathy'. Their findings, based on echocardiographic assessment of
left ventricular function, were similar to those reported
previously.[2,3] Nonetheless, the role of arterial dysfunction in the
pathogenesis of myocardial contractile dysfunction has likewise been
ignored.
The fact that both the end systolic meridional and circumferential
wall stress were increased in their patients would suggest an elevated
left ventricular afterload. The importance of optimal ventriculo-arterial
interaction in enhancing mechanical efficiency of the heart cannot be
overemphasized. Unexpectedly, the systemic vascular resistance, which
reflects the static vascular load, was significantly lower in their
patients than controls. Furthermore, the significance of the pulsatile
vascular load has not been discussed.
We have previously shown that teenagers and young adults with beta-
thalassaemia major have arterial endothelial dysfunction and increased
arterial stiffness.[4] The increase in arterial stiffness, relating
probably to structural alteration as a result of iron overload and
endothelial dysfunction, and increased wave reflection as a result of a
faster pulse wave velocity increase the pulsatile afterload. Interaction
between left ventricular ejection and systemic arterial impedance may thus
render less favorable as the impedance modulus may no longer be the least
at where the flow harmonics are highest.[5]
Our previous findings support the view of a multi-factorial etiology
of LV failure in patients with beta-thalassaemia major.[6] Apart from
myocardial iron deposition, myocarditis and immunogenetic profile,
arterial dysfunction is also contributory.
References
(1) Bosi G, Crepaz R, Gamberini MR, et al. Left ventricular
remodelling, and systolic and diastolic function in young adults with b
thalassaemia major: a Doppler echocardiographic assessment and correlation
with haematological data. Heart 2003;89:762-766.
(2) Lewis SB, Rachmilewitz AE, Amitai N, et al. Left ventricular function
in b-thalassemia and the effect of multiple transfusion. Am Heart J 1978;96:636-645.
(3) Kremastinos DT, Tsiapras DP, Tsetos GA, et al. Left ventricular
diastolic Doppler characteristics in beta-thalassemia major. Circulation 1993;88:1127-1135.
(4) Cheung YF, Chan GCF, Ha SY. Arterial stiffness and endothelial function
in patients with beta-thalassaemia major. Circulation 2002;106;2561-2566.
(5) Nichols WW, O'Rourke MF. Vascular impedance. In McDonalds's Blood
Flow in Arteries: Theoretical, Experimental and Clinical Principles. 4th
ed. London: Edward Arnold; 1998:54-97, 243-293.
(6) Jessup M, Manno CS. Diagnosis and management iron-induced heart disease
in Cooley's anemia. Ann N Y Acad Sci 1998;850:242-250.
In the report by Palka et al,[1] and in previous such reports [2,3]
the phenotypic variation seen in supposedly genetically identical
monozygotic (MZ) twins with hypertrophic cardiomyopathy (HCM) is
interpreted as a measure of the importance of environmental influences.
However, although environmental factors undoubtedly contribute to the
phenotype in HCM, there is substantial evidence that d...
In the report by Palka et al,[1] and in previous such reports [2,3]
the phenotypic variation seen in supposedly genetically identical
monozygotic (MZ) twins with hypertrophic cardiomyopathy (HCM) is
interpreted as a measure of the importance of environmental influences.
However, although environmental factors undoubtedly contribute to the
phenotype in HCM, there is substantial evidence that discordance between
MZ twins in fact has a genetic component. MZ twins develop from a
separation of the embryonic cells at any point from the two-cell stage up
until as late as day 8 when the primordial streak has already started to
form.[4] The timing of the separation has consequences for the genetic
composition of each twin, as the cells become more heterogeneous with time
with respect to the mitochondria they carry [5] and the pattern of
methylation, and hence potential gene expression, they display.[6]
Mitochondria are inherited through the maternal line only and contain
their own genome which encodes a subset of mitochondrial proteins. During
mitosis mitochondria can segregate unequally between the daughter cells.
Where the oocyte contains a mixed population of mitochondrial DNA variants
somatic mosaicism can arise, one consequence of which is that one MZ twin
may inherit a different complement of mitochondrial DNA than the other.
While such a difference in mitochondrial DNA is often of only theoretical
relevance, it would be of particular importance in HCM. Not only do many
of the mitochondrial DNA mutation syndromes display HCM-like features, but
common variants in mtDNA are associated with susceptibility to
cardiomyopathy [7] and co-inheritance of mitochondrial variants with
sarcomeric mutations produces a much more extreme phenotype .[8] These
findings can be explained by the recent recognition that perturbations of
myocardial energetics play a central role in HCM pathogenesis.[9]
DNA methylation plays a recognised role in regulation of gene
expression, and important changes in the methylation of genes occur during
embryogenesis. In particular the male gametic genome is first demethylated
[10] and then selectively re-methylated in a step wise fashion up to the
stage of the blastocyst.[5] Hence, some of the observed discordance
between MZ twins can also be due to separation of a heterogeneously
methylated group of cells, with discordant patterns of gene expression.
It is through these epigenetic modifying phenomena that we may begin
to explain the differences in phenotypic expression of HCM, not only in MZ
twins but also that seen within and between pedigrees containing the same
causal mutant gene.
References
(1) Palka P, A Lange, DJ Burstow. Different presentation of
hypertrophic cardiomyopathy in monozygotic twins. Heart 2003;89(7):751.
(2) Reid JM, AB Houston, E Lundmark. Hypertrophic
cardiomyopathy in identical twins. Br Heart J 1989;62(5):384-8.
(3) Ko YL et al. Idiopathic hypertrophic cardiomyopathy in
identical twins. Morphological heterogeneity of the left ventricle. Chest1992;102(3):783-5.
(4) Gringras, P. and W. Chen, Mechanisms for differences in monozygous
twins. Early Hum Dev 2001;64(2):105-17.
(5) Youssoufian H, RE Pyeritz. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet 2002;3(10):748-58.
(6) Singh SM, B Murphy, R O'Reilly. Epigenetic contributors
to the discordance of monozygotic twins. Clin Genet 2002;62(2):97-103.
(7) Khogali SS et al. A common mitochondrial DNA variant
associated with susceptibility to dilated cardiomyopathy in two different
populations. Lancet 2001;357(9264):1265-7.
(8) Arbustini E. et al. Coexistence of mitochondrial DNA and beta
myosin heavy chain mutations in hypertrophic cardiomyopathy with late
congestive heart failure. Heart 1998;80(6):548-58.
(9) Blair E. et al. Mutations in the gamma(2) subunit of AMP-
activated protein kinase cause familial hypertrophic cardiomyopathy:
evidence for the central role of energy compromise in disease
pathogenesis. Hum Mol Genet 2001;10(11):1215-20.
(10) Mayer W et al. Demethylation of the zygotic paternal genome. Nature 2000;403(6769):501-2.
We do not agree that our study population was highly selected. The
only exclusion criteria in our study were severe psychiatric problems
and/or dementia, planned admission to a nursing home, not taking care of
their own medication (e.g. filled or administered by relatives or district
nurses) and/or life expectancy of less than 3 months.
We feel that we sufficiently described the characteristics of our...
We do not agree that our study population was highly selected. The
only exclusion criteria in our study were severe psychiatric problems
and/or dementia, planned admission to a nursing home, not taking care of
their own medication (e.g. filled or administered by relatives or district
nurses) and/or life expectancy of less than 3 months.
We feel that we sufficiently described the characteristics of our
population (co-morbidity, physical examination and medication that
describe our population). We choose not to report cardio thoracic ratio
and echocardiography data, because although they were available on the
majority of patients, there were many differences in the way these data
were reported between the participating hospitals. More objective
assesments of cardiac function such as ejection fraction or fractional
shortening were mostly missing.
Once more we want to emphasise that the major aim of our study was to
develop a comprehensive and easily applicable prognostic model predicting
the risk of death in patients with heart failure, based on information
that is readily available in daily care. In their study Kearney et al.[1] did
not include co-morbidity and relatively easy to obtain characteristics
from physical examination such as weight, ankle oedema and blood pressure.
In addition patients with diabetes were excluded in their study.[2] In
our opinion it is very important to first study whether these relatively
easily obtainable characteristics are predictive, before assessing the
additional value of more difficult to obtain data from cardiovascular
imaging. We also want to emphasise that several similarities between
Kearney’s and our study are noticeable. Both studies find renal function
as an important predictor. We used a history of renal insufficiency as a
binomial value, but inclusion of the continuous variables serum creatinine
or creatinine clearance (calculated with Cockroft and Gault’s formula) led
to similar findings. Kearney et al find a predictive value of low sodium
levels. We also found low sodium levels to be predictive, although
slightly less than other variables and therefore not included in the
model.
Mean frusemide dose (or bumetanide equivalent) in our study was 124
mg/day. We did not include dose in the model, but high frusemide dose and
low ACE-inhibitor dose could also be important and readily available
predictors of mortality and might be subject of future studies.
Although not reported bootstrapping was performed and yielded similar
results.
References
(1) Kearney MT, Fox KA, Lee AJ et al. Predicting death due to progressive
heart failure in patients with mild-to-moderate chronic heart failure. J
Am Coll Cardiol 2002;40:1801-8.
(2)
Bouvy ML, Heerdink ER, Leufkens HGM, Hoes AW. Predicting mortality
in patients with heart failure: a pragmatic approach. Heart 2003;89:605-609.
Dear Editor
The article by Androne et al.[1] describing the improvement in heart rate recovery after maximal exercise in patients with chronic heart failure when treated with pyridostigmine, supports the recent concept that cholinergic stimulation may have a protective role in cardiovascular disease.[2] We have prompted to investigate this possibility, since depressed heart rate variability[3] and baroref...
Dear Editor
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European men and women mostly reported chest pain in Rose Questionnaire (definite angina c...
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We thank Dr Cheung for the interesting observations [1]concerning our paper.[2]
They suggest - on the basis of their study,[3] that an arterial dysfunction (probably due to iron overload) could contribute to the pathogenesis of the so-called “Thalassemic cardiomyopathy” causing an increase of arterial stiffness and, consequently, an increase of the pulsatile pressure if the ventricular systoli...
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We were interested to read the recent scientific letter from Pollard et al published in Heart.[1]
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Dear Editor
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