The paper by Souverein et al. has identified oral glucocorticoid
therapy as a risk factor for the development of heart failure [1]. They
noted that the risk was greater in patients with current use and those
receiving higher dosage.
One of the striking findings in their analysis was the greater
incidence of heart failure as compared to ischemic heart disease. This
suggests the possi...
The paper by Souverein et al. has identified oral glucocorticoid
therapy as a risk factor for the development of heart failure [1]. They
noted that the risk was greater in patients with current use and those
receiving higher dosage.
One of the striking findings in their analysis was the greater
incidence of heart failure as compared to ischemic heart disease. This
suggests the possibility that glucocorticoids, in fact, might exert a
suppressive effect on atherosclerosis, a known inflammatory disease [2].
Altering the delicate balance between the pro-inflammatory and anti-
inflammatory factors might retard the development of atherosclerosis but
not be entirely adequate enough to inhibit the other factors that
eventuate in the genesis of heart failure [3]. Additionally, heart failure
is the end result of a complex combination of neurohumoral, inflammatory
and metabolic factors which are controlled by a myriad of interactions, at
the cellular level, that involves many unknown pathways.
Furthermore, the underlying diseases, originally necessitating
corticosteroid treatment, probably requires greater immunosuppression than
does the inflammatory process of atherosclerosis. This fits with the
concept of discordant reciprocal regulation, where levels of adverse
mediators exceed the inhibitors (glucocorticoids), thereby resulting in
myocardial damage [4]. It would also explain the relatively greater
incidence of heart failure versus atherosclerotic vascular disease in the
patients receiving glucocorticoid therapy.
Finally, the article by Souverein and colleagues [1] should increase
the awareness for the potential occurrence of heart failure as a
consequence of glucocorticoid treatment in complicated disease states.
This might allow for measures to be instituted so that the incidence of
heart failure could be minimized or even prevented.
References
(1). Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts ACG,
Leufkens HGM, Walker BR.
Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular
disease in a popul-ation based case-control study. Heart. 2004;90:859-65.
(2). Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis.
Circulation. 2002;105:1135-1143.
(3). Blum A, Miller H. Pathophysiological role of cytokines in
congestive heart failure.
Ann Rev Med. 2001;52:15-27.
(4). Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive
heart disease and the role of hormones. Hypertension. 1994.23:869-77.
Nagaya et al [1] showed that green tea can reverse endothelial
dysfunction in smokers. There is another protective property of green tea
in smokers that is worthy of additional comment.
The polyphenolic catechins in green tea, such as (-)-epigallocatechin
-3-gallate, have been shown to be potent antioxidants in many chemical and
biochemical studies [2,3]. Oxidants, either present in c...
Nagaya et al [1] showed that green tea can reverse endothelial
dysfunction in smokers. There is another protective property of green tea
in smokers that is worthy of additional comment.
The polyphenolic catechins in green tea, such as (-)-epigallocatechin
-3-gallate, have been shown to be potent antioxidants in many chemical and
biochemical studies [2,3]. Oxidants, either present in cigarette smoke
or/and formed in the lungs of cigarette smokers, may trigger oxidative
damage to DNA [4]. Hakim et al [4] studied the effect of decaffeinated
green or black tea on oxidative DNA damage, as measured by urinary 8-
hydroxydeoxyguanosine (8-OHdG), among smokers over a 4-month period.
Plasma and urinary levels of catechins rose significantly in the green tea
group compared with the black tea and control groups. A highly significant
decrease in urinary 8-OHdG was seen after 4 months of drinking green tea,
but there was no change among smokers drinking black tea. Therefore,
Hakim et al [4] concluded that regular green tea drinking might protect
smokers from oxidative damages and could reduce cancer risk or other
diseases caused by free radicals associated with smoking.
More recently Hakim et al [5] reported the effect of green tea on genetic
susceptibility to tobacco smoke, which is thought to be attributable to
genetic polymorphisms in metabolizing enzymes.
Glutathione S-transferase
(GST), a member of the phase II group of xenobiotic metabolizing enzymes,
has been intensively studied at the levels of phenotype and genotype [5].
The GST mu (GSTM1) and GST theta 1 (GSTT1) genes have a null-allele
variant in which the entire gene is absent. By measuring urinary 8-OHdG
levels, Hakim et al [5] demonstrated a significant change from baseline in
both GSTM1-positive and GSTT1-positive green tea groups, but not in the
GSTM1-negative or GSTT1-negative green tea groups, and that black tea
consumption had no effect on urinary 8-OHdG levels among heavy smokers.
Thus Hakim et al [5] showed green tea to be effective in the subgroup of
smokers who are GSTM1- or/and GSTT1-positive.
Green tea may also improve coronary circulation by increasing coronary
flow velocity reserve [6], as black tea using transthoracic Doppler
echocardiography [7]. It has been postulated that improvement in coronary
endothelial function by tea flavonoids, which are more abundant in green
than black tea [8,9], may be a possible mechanism for increased coronary
flow velocity reserve after tea drinking [7].
Therefore, although the best advice to cigarette smokers is to stop
smoking, regular drinking of green tea, if the smoker continues to smoke,
may decrease or prevent development of heart disease and cancer.
Furthermore, for most people, drinking tea everyday is not only
pleasurable and easily available but also inexpensive and thus affordable.
References
(1). Nagaya N, Yamamoto H, Uematsu M, Itoh T, Nakagawa K, Miyazawa T,
Kangawa K, Miyatake K: Green tea reverses endothelial dysfunction in
healthy smokers. Heart 2004;90:1485-1486.
(2). Yang CS, Maliakai P, Meng X: Inhibition of carcinogenesis by tea. Annu
Rev Pharmacol Toxicol 2002;42:25-54.
(3). Yang CS, Hong J, Hou Z, Sang S:Green tea polyphenols: antioxidative and
prooxidative effects. J Nutr 2004;134:3181S.
(4). Hakim IA, Harris RB, Brown S, Chow HHS, Wiseman S, Agarwal S, Talbot W:
Effect of increased tea consumption on oxidative DNA damage among smokers:
a randomized controlled study. J Nutr 2003;133:3303S-3309S.
(5). Hakim IS, Harris RB, Chow HHS, Dean M, Brown S, Ali IU: Effect of a 4-
month tea intervention on oxidative DNA damage among heavy smokers: role
of glutathione S-transferase genotypes. Cancer Epidemiol Biomarkers Prev
2004;13:242-249.
(6). Cheng TO: Will green tea be even better than black tea to increase
coronary flow velocity reserve? Am J Cardiol 2004;94:1223.
(7). Hirata K, Shimada K, Watanabe H, Otsuka R, Tokai K, Yoshiyama M, Homma
S, Yoshikawa J: Black tea increases coronary flow velocity reserve in
healthy male subjects. Am J Cardiol 2004;93:1384-1388.
(8). Cheng TO: Antioxidants in Chinese green tea. J Am Coll Cardiol
1998;31:1214.
(9). Cheng TO: Tea is good for the heart. Arch Intern Med 2000;160:2397.
It would seem that the K+(atp) channel opener pinacidil and closer
glibenclamide might exert their effects by deceasing and increasing
respecitively the rates of ATP resynthesis [1,2]. The implication is that
the primary determinants of ATP resynthesis, pH, substrate availability
for oxidative phosphorylation and body temperature, are important
determinants of the degree of H+(atp) channel openess a...
It would seem that the K+(atp) channel opener pinacidil and closer
glibenclamide might exert their effects by deceasing and increasing
respecitively the rates of ATP resynthesis [1,2]. The implication is that
the primary determinants of ATP resynthesis, pH, substrate availability
for oxidative phosphorylation and body temperature, are important
determinants of the degree of H+(atp) channel openess and hence the
effects of pinacidil and glibenclamide. Conceivably the drugs might even
have opposing actions in different myocytes in the same myocardium.
Consider the possibilities in terms of the myocyte buddy hypothesis.
"Dyslipidaema" is the plasma reflection of the heterogeneity of
cellular metabolic needs and their collective mass action effect upon
humoral, hepatic, adrenal and adipocyte modulators of fatty acid
metabolism. In stressed myocardium substrate utilisation by each myocyte
will be primarily determined but its own pH, [AMP], and exposure to
humoral agents such as the "exercise factor" IL-6 and other cytokines[3].
A shift from dependence upon glucose for ATP resynthesis to fatty
acids might be induced in stressed myocytes by inhibition of
phosphofructokinase induced by the fall in pH and/or rise in [AMP] and/or
by inhibiton of the pyruvate dehydrogenase complex by the release of
cytokines. In terms of the myocyte buddy hypothesis that should mean that
some myocytes are more dependent upon fatty acids than others, the greater
the cellular demand the greater the mass action effect in determining the
accompanying plasma lipid profile. The inference is that the avalaility of
ATP, the degree of openess of K+(atp) channels and the potential for
pinacidil and glibenclamide to either open or close them might vary from
myocyte to myocyte especially in stressed myocardium.
Propranalol decrases myocardial uptake of fatty acid nd increases the
uptake of glucose, the reverse of the ompensatory lipid shidt that occurs
with exercise, and causes more myocardial depression in hearts perfused
with fatty acids than in those perfused with glucose [4]. The inference is
that propranalol decreases the efficiency of ATP resynthesis per unit
volume of flowing blood and hence the avalaility of ATP to meet the needs
of stressed myocytes at that moment [5].
The cardioprotective effects of propranalol might well be the product
of an increase in the degree of openess of the K+(atp) channels. In which
case support for the most stressed myocytes by trmsof the myocyte buddy
hypothesis should also be compromised by the propranalol and the
likelihood of developing apoptosis or even necrosis increaed in the most
stressed myocytes, those dependent upon fatty acids for their ATP
resyntheis by residual oxidative phosphorylation. In other words
proprnalol might be cytoprotective in most of the myocardium but could
precipitate the development of confluent areas of myocyte apoptosis and
even necrosis in the most stresed regions of compromised myocardium.
That is precisely what happened wit beta blockers in the ISIS-1 trial.
In this large randomised trial of early beta-blockade in acute
myocardial infarction (ISIS-1), almost all the reduction in mortality
associated with the use of atenolol occurred on the day of admission or on
the subsequent day [6]. "Of 217 early deaths adequate records were
available for 193 (79 allocated atenolol and 114 allocated control). In
the atenolol group, necropsy had shown cardiac rupture in 5 patients, and
a further 15 in whom necropsy had not been done had had electro-mechanical
dissociation (total, 20 early deaths from these causes); among control
patients the corresponding numbers were 17 and 37 (total, 54 such deaths).
Electro-mechanical dissociation was probably a manifestation of acute
rupture, and the observed difference in the numbers with this complication
was responsible for much of the difference in early mortality. There was a
slightly higher incidence of fatal ventricular fibrillation and aortic
dissection in the control group, and of bradycardia/asystole in the
atenolol group"[7].
If beta blockers can cause myocardial rupture by precipitating
confluent areas of myocyte apoptosis and necrosis might they might also
cause myocardial fibrosis, ventricular aneurysms and chronic heart failure
as previously proposed [8]. If thy do pinacidil or glibenclamide could
have similar effects.
references
(1). Lembert N, Idahl LA, Ammon HP. K-ATP channel independent effects
of pinacidil on ATP production in isolated cardiomyocyte or pancreatic
beta-cell mitochondria.
Biochem Pharmacol. 2003 Jun 1;65(11):1835-41.
(2). Muller G, Wied S, Wetekam EM, Crecelius A, Unkelbach A, Punter J.
Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in
vitro by the sulphonylureas, glimepiride and , is correlated with
modulations of the cAMP regulatory cascade.
Biochem Pharmacol. 1994 Aug 30;48(5):985-96.
(3). Oxygen supply dependency: has it any clinical relevance?
Richard G Fiddian-Green (8 September 2004) eLetter re: HJ Silverman, J
Abrams, and LJ Rubin
Effects of interleukin-2 on oxygen delivery and consumption in patients
with advanced malignancy
Chest 1988; 94: 816-821
(4). Opie LH, Thomas M. Propranolol and experimental myocardial
infarction: substrate effects. Postgrad Med J. 1976;52 Suppl 4:124-32.
(5). The need for a moratorium on use of beta blockers?
Richard G Fiddian-Green (7 September 2004) eLetter re: P.J. Devereaux,
Salim Yusuf, Homer Yang, Peter T.-L. Choi, and Gordon H. Guyatt
Are the recommendations to use perioperative ß-blocker therapy in patients
undergoing noncardiac surgery based on reliable evidence?
CMAJ 2004; 171: 245-247
(6). Randomised trial of intravenous atenolol among 16 027 cases of
suspected acute myocardial infarction: ISIS-1. First International Study
of Infarct Survival Collaborative Group.
Lancet. 1986 Jul 12;2(8498):57-66.
(7). Mechanisms for the early mortality reduction produced by beta-
blockade started early in acute myocardial infarction: ISIS-1. ISIS-1
(First International Study of Infarct Survival) Collaborative Group.
Lancet. 1988 Apr 23;1(8591):921-3. Erratum in: Lancet 1988 Jul 30;2
(8). The need to manage heart failure from an early age
Richard G Fiddian-Green
bmj.com, 6 Nov 2002 eLettr re: Martin R Cowie and Alex Zaphiriou
Recent developments: Management of chronic heart failure
BMJ 2002; 325: 422-425
I find this a most interesting study for it gets to the nub, what
exactly is it that causes SUD in patients with chronic heart failure.
"During follow up, nine patients died: five patients had a sudden
unexpected death (SUD) and four died of progressive heart failure (PHF).
There were significant intraindividual changes in neutrophil counts (p =
0.02), C reactive protein (p = 0.039), and h...
I find this a most interesting study for it gets to the nub, what
exactly is it that causes SUD in patients with chronic heart failure.
"During follow up, nine patients died: five patients had a sudden
unexpected death (SUD) and four died of progressive heart failure (PHF).
There were significant intraindividual changes in neutrophil counts (p =
0.02), C reactive protein (p = 0.039), and heart rate variability (p
0.018) in those who died of SUD and PHF. SUD "may be preceded by
intraindividual increases in both inflammation and autonomic dysfunction
[presumably meaning heart rate variability]. Both may be causal in genesis
but, even if they are not, intraindividual increases in either may be
convenient markers to identify patients at high risk of impending SUD"[1].
In an earlier electronic communication I concluded that, "metabolic
decompensation in humans will occur when the delivery and uptake of
nutrient can no longer keep pace with the rate of ATP hydrolysis dictated
by the body temperature"[2] as might have occurred with the inflammatory
responses in the patients with SUD in this study. A mechanism, I
suggested, might be the putative "exercise factor, IL-6, produced by
contracting muscles and released into the blood. "IL-6 stimulates cortisol
production, induces lipolysis, and increases temperature presumably by
uncoupling oxidative phosphorylation".
The variable which I have since considered in greater depth [3] is
the tissue pH which I have proposed might modulate fluid distribution and
balance, partly by modulating renal tubular energetics, and hence
myocardial workload. In short a fall in tissue pH might protect the heart
by increasing intracellular fluid (ICF)volume, decreasing extracellular
fluid (ECF) volume [which should decrease the area of the ventricular
pressure-volume loop (P-VL]), and opening the K+(atp) channels [which
should also decrease the area of the P-VL further]. Should the
cytoprotective effect of cytosolic acidification be compromised, either
because a impairment of the residual ATP pool size and/or the resynthesis
upon which it it depends, the cytosolic pH should rise and/or not fall as
much as it should and the likelihood that the demand for ATP outstripping
the capacity for ATP resynthesis increased. Indeed in limiting the opening
or inducing the closing of the K+ (atp) channels myocardial workload might
also be inappropriately increased.
Cardiac behaviour is classically defined in terms of the Frank-
Starling law which states that "the force of contraction of the cardiac
muscle is proportional to its initial length. The energy set free at each
contraction is a simple function of cardiac filling. When the diastolic
filling of the heart is increased or decreased with a given volume, the
displacement of the heart increases or decreases with this volume". A rise
in systemic tissue pH might, therefore, be expected to "improve" the Frank
-Starling curve or shift it to the left both by limiting the opening of
the K+(atp) channels and by increasing ECF volume. Conversely a fall in
systemic tissue pH might be expected to have the opposite effect and make
the curve "worse" by opening K+(atp) channels and decreasing ECF volume.
Is not this conventional interpretation back-to-front? In other words
is it not better to have to have a low pH, low ECF volume and open
K+(atp) channels, the physiological responses to haemorrhagic shock, than
a high pH, high ECF volume and closed K+(atp) channels? But
hyperkalaemia, which should accompany a fall in tissue pH because of the
H+/K+ exchange, increases the risk of developing cardiac arrhythmias and
may be cardioprotective if contraction ceases as is well known from the
use of potassium cardioplegia. Cardiopulmonary bypass is obviouly needed
to maintain peripheral tissue energetics in these circumstances.
Sympathetic stimulation and/or catecholamine release has in effect
the same myocardial actions as a rise in systemic tissue pH in so far as
cardiac output is concerned. That is it increases myocardial contractility
and cardiac output. If excessive, however, a rise in tissue pH could
precipitate tissue eneregtic failure by inhibitng oxidative
phosphorylation, stimulating anaerobic glycolysis, and increasing the
demand for nutrient dispatch from the heart to sustain a constant level of
ATP resynthesis. This could overwhelm the hearts capacity and precipitate
an acute fall in availability of the substrate needed to maintain
myocardial tissue energetics [5]. The state is analogous to that induced
in anaesthetised dogs by a progressive decrease in their FiO2. Cardiac
arrest occurred before a gut mucosal intramucosal acidosis developed in
these circumstances, but a preterminal fall could have been missed for
measurements were only made very 20 minutes[6].
To what degree then might the effects of autonomic stimulation or an
inflammatory response be modulated by or even induced by changes in tissue
pH?
Might the metabolic effects of sympathetic stimulation oppose those
of an abnormal fall in tissue pH and parasympathetic stimulation oppose
those of an abnormal elevation in tissue pH? A rise in temperature caused
by an inflammatory response, which appears to be a feature of anaerobic
glycolysis rather than oxidative phosphorylation, can be expected to
upregulate oxidative phosphorylation by increasing the protonmotive force,
downregulate anaerobic glycolysis certainly if stimulated by an abnormal
elevation in tissue pH, and increase ATP output unless limited by
substrate dispatch from the heart. What of the possibility of sympathetic
stimulation, or rather catecholamine release being induced by an abnormal
fall in pH and parasympathtic stimulation being induced by an abnormal
rise?
What then of the relevance of inflammation and autonomic dysfunction
to the onset of SUD in heart failure? If by autonomic dysfunction is meant
variability in heart rate it might be a reflection of a increase in
amplitude of the normal fluctuations in tissue pH and, therefore,
indicative of metabolic stress.
The fluctuation in temperature seen an inflammatory response are very
similar and indeed can be expected to be inversely related to any
fluctuations in tissue pH solely because of their physical
relationship [8]. The degree of any leukocytosis present might even change
in parallel be they cause or effect. As these are likely to be accompanied
by equally rapid and relatively large fluctuations in serum [K+] and
degree of K+(atp) opening the stage is clearly set for SUD.
References
(1). A M A Shehab, R J MacFadyen, M McLaren, R Tavendale, J J F Belch,
and A D Struthers
Sudden unexpected death in heart failure may be preceded by short term,
intraindividual increases in inflammation and in autonomic dysfunction: a
pilot study
Heart 2004; 90: 1263-1268
(2). Oxygen supply dependency: has it any clinical relevance?
Richard G Fiddian-Green (8 September 2004) eLetter re: HJ Silverman, J
Abrams, and LJ Rubin
Effects of interleukin-2 on oxygen delivery and consumption in patients
with advanced malignancy
Chest 1988; 94: 816-821
(3). pH-guided management of fluid distribution and balance and
myocardial workload..
Richard G Fiddian-Green (4 November 2004) eLetter re: Shehan
Hettiaratchy and Remo Papini
Initial management of a major burn: II—assessment and resuscitation
BMJ 2004; 329: 101-103
(4). Frank-Starling law of the heart
www.whonamedit.com/synd.cfm/1242.html
(5). Successful evolutionary adaptation to environmental stress?
Richard G Fiddian-Green
Heart Online, 14 Jul 2004 eLetter re: D A Lawlor, G Davey Smith, R
Mitchell, and S Ebrahim
Temperature at birth, coronary heart disease, and insulin resistance:
cross sectional analyses of the British women’s heart and health study
Heart 2004; 90: 381-388
(6). Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED,
Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine.
J Appl Physiol. 1984 Apr;56(4):1065-9.
(7). Reciprocal pH-dependence of myocardial protection and dysfunction.
Richard G Fiddian-Green (2 August 2004) eLetter re: Satoshi Ohki, Fumio
Kunimoto, Yukitaka Isa, Hiroshi Tsukagoshi, Susumu Ishikawa, Akio Ohtaki,
Toru Takahashi, Tetsuya Koyano, Noboru Oriuchi, and Yasuo Morishita
Changes in gastric intramucosal pH and circulating blood volume following
coronary artery bypass grafting
Can J Anesth 2000; 47: 516-521
(8). Severinghaus JW, Astrup P, Murray JF Blood gas analysis and
critical care medicine.
Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 2):S114-22.
I wish to echo the excellent points made by Seiler [1] in his editorial on
the echocardiographic assessment of patent foramen ovale (PFO).
First, although contrast transesophageal echocardiogrpahy is said to be
the gold standard for diagnosing PFO [1], very often the sedated state of
the patient necessary for the transesophageal examination often prevents
the patient from performing an effective...
I wish to echo the excellent points made by Seiler [1] in his editorial on
the echocardiographic assessment of patent foramen ovale (PFO).
First, although contrast transesophageal echocardiogrpahy is said to be
the gold standard for diagnosing PFO [1], very often the sedated state of
the patient necessary for the transesophageal examination often prevents
the patient from performing an effective or adequate Valsalva maneuver
which is the essential part of the examination [1-3].
Second, the patient needs to practise the Valsalva maneuver before the
actual start of the examination [1].
Third, it is the release phase of the Valsalva maneuver, rather than the
straining phase, that is the crucial time for echocardiographic detection
of the right to left shunt across the PFO [1-5].
Fourth, and the most important of all, it is essential for the referring
physician to put on the requisition form to the echocardiographic
laboratory that the reason for the study is to ‘rule out paradoxical
embolism’ rather than ‘to rule out cardiogenic emboli’ [2,5]. In the
latter case, what the echocardiographic technician or even the
echocardiographer usually does is concentrating on ruling out a left
atrial thrombus, a left atrial myxoma, mitral valve prolapse, vegetations
on the mitral or aortic valve, a left ventricular thrombus or ventricular
aneurysm, dilated cardiomyopathy, or atherosclerotic plaques in the
ascending aorta [3].
Performance of contrast study with Valsalva maneuver
is not a part of routine echocardiography.
I have seen many false negative studies reported from echocardiographic
laboratories, because of failure to follow the 7 steps outlined by Seiler
[1]. This is particularly true in echocardiographic laboratories that are
very busy with routine studies of which careful and time-consuming
performance of contrast echocardiography with Valsalva maneuver is not a
routine part.
References
(1). Seiler C: How should we assess patent foramen ovale? Heart
2004;90:1245-1247.
(2). Cheng TO: The proper conduct of Valsalva maneuver in the detection of
patent foramen ovale. J Am Coll Cardiol, in press.
(3). Cheng TO: Paradoxical embolism. A diagnostic challenge and its
detection during life. Circulation 1976;53:565-568.
(4). Cheng TO: Mechanism of ST elevation in acute pulmonary embolism. Int J
Cardiol, in press.
(5). Cheng TO: Paradoxical embolism: diagnosis and management. J Emerg Med
2001;20:416-417.
In his elegant review of aldosterone blockade (Heart 2004; 90:1229-
1234), Dr. Struthers has failed to mention the diuretic properties of
spironolactone.
Spironolactone in itself may be a weak diuretic but in combination with
frusemide it provides excellent diuresis, which improves quality of life
and exercise capacity in elderly patients with end stage congestive
cardiac failure [1]. Spirono...
In his elegant review of aldosterone blockade (Heart 2004; 90:1229-
1234), Dr. Struthers has failed to mention the diuretic properties of
spironolactone.
Spironolactone in itself may be a weak diuretic but in combination with
frusemide it provides excellent diuresis, which improves quality of life
and exercise capacity in elderly patients with end stage congestive
cardiac failure [1]. Spironolactone in low doses as used in Rales study
[2], is said to have no apparent diuretic effect, but causes significant
reduction in mortality. We believe that in the very elderly Spironolactone
can also be used in combination with loop diuretics primarily for
improvement of exercise capacity and quality of life, for the overriding
issue for these patients in the quality of the last years of their life.
References
(1). Yusuf SW, Mishra RM. Use of Spironolactone in severe end stage
congestive cardiac failure in elderly patients; a pilot study. Cardiol in
the Elderly 1996; 4:105-109.
(2). Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. Randomized
aldactone evaluation study investigators. N Engl J Med 1999; 341:709–17.
Yousef et al concluded in a recent publication that
long-term anticoagulation in non-valvular atrial
fibrillation is effective and safe in general clinical
practice as evidenced by comparable rates of stroke and
major complications to those obtained from clinical trials.
[1]
However, results are misinterpreted in this study. First,
this is not a long-term study, because that 739 pati...
Yousef et al concluded in a recent publication that
long-term anticoagulation in non-valvular atrial
fibrillation is effective and safe in general clinical
practice as evidenced by comparable rates of stroke and
major complications to those obtained from clinical trials.
[1]
However, results are misinterpreted in this study. First,
this is not a long-term study, because that 739 patients
enrolled during 5 years were treated for a total of 1484
patients-years indicates a mean follow-up of only 2 years,
a comparable duration to that followed up in clinical
trials.[2] Although anticoagulation is a life-long
treatment in patients with atrial fibrillation, there is
uncertainty as to the long-term safety of anticoagulation,
particularly in very elderly patients who are prone to
bleeding complications, because clinical trials were
analyzed at short duration of follow-up of 1 to 2 years.[3]
Secondly, annual events rates should be corrected according
to numbers of events occurred during 1484 patients-years,
and so annual major bleeding, thromboembolic, and stroke
rates are 1.9%, 0.9%, and 2.1%, respectively. These rates
are slightly higher than those in pooled data of clinical
trials (1.3%, 0.3%, and 1.4%, respectively),[2] possibly
because of a difference of patient selection between actual
clinical practice and clinical trials. Patients enrolled
in clinical trials were more strictly selected to be at low
risk of bleeding and younger than those in community
setting.[4] Therefore, there remains uncertainty as to
efficacy and safety of long-term anticoagulation in
patients with atrial fibrillation in general clinical
practice.
References
(1). Yousef ZR, Tandy SC, Tudor V, et al. Warfarin for non-
rheumatic atrial fibrillation: five year experience in a
district general hospital. Heart 2004; 90: 1259-1262.
(2). Atrial Fibrillation Investigators. Risk factors for
stroke and efficacy of antithrombotic therapy in atrial
fibrillation. Analysis of pooled data from five randomized
controlled trials. Arch Intern Med 1994;154:1449-1457.
(3). Albers GW. Atrial fibrillation and stroke. Three new
studies, three remaining questions. Arch Intern Med 1994;
154: 1443-1448.
(4). Sudlow M, Thomson R, Thwaites B, et al. Prevalence of
atrial fibrillation and eligibility for anticoagulants in
the community. Lancet 1998; 352: 1167-1171.
We would like to congratulate Struthers and colleagues on their
recent paper showing that sudden unexpected death in a small group of
patients with heart failure is preceded by changes in both cardiac
autonomic nervous control and markers of inflammation. [1]
Their findings
lend support to the hypothesis that changes in inflammatory or autonomic
status, might determine on which particular da...
We would like to congratulate Struthers and colleagues on their
recent paper showing that sudden unexpected death in a small group of
patients with heart failure is preceded by changes in both cardiac
autonomic nervous control and markers of inflammation. [1]
Their findings
lend support to the hypothesis that changes in inflammatory or autonomic
status, might determine on which particular day a person with seemingly
stable (or even unrecognized) heart disease dies. Factors such as
emotional stress, infection, physical activity and ambient temperature may
all be important. In addition, strong recent evidence implicates ambient
air pollution. Cardiovascular mortality rates increase during episodes of
high air pollution and it is postulated that this association is
attributable to either a systemic inflammatory response or an influence of
inhaled pollutants on the cardiac autonomic nervous system. [2,3]
Until now, these hypotheses have been open to the criticism that the
supporting information is derived from long term studies showing that
baseline measures of cardiac autonomic control and inflammation are of
prognostic value over succeeding years. [4,5,6] Struthers has
provided important preliminary evidence that these influences may indeed
exert short term effects.
A much larger multi-centre study is required, perhaps with even more
frequent sampling, to further examine temporal relationships between
markers of cardiac autonomic control and inflammation and cardiovascular
mortality and morbidity. Simultaneous collection of data on a range of
influences, including environmental data such as temperature and ambient
air pollution, might allow another more proximal stage in the process
culminating in sudden cardiac death to be identified.
Thus, we might
begin to determine the relative importance of those factors, intrinsic or
extrinsic, that by determining day to day levels of inflammation and
cardiac autonomic control, increase the immediate risk of sudden cardiac
death. This is of more than academic interest; factors such as air
pollution are eminently modifiable and for those that are not such as
infection or seasonal changes in temperature, treatment could be altered.
References
(1). Shehab AM, RJ.. McLaren, M. Tavendale, R. Belch, JJF. Struthers,
AD. Sudden unexpected death in heart failure may be preceded by short
term, intraindividual increases in inflammation and in autonomic
dysfunction: a pilot study. Heart 2004; 90:1263-1268.
(2). Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, et
al. Air pollution and cardiovascular disease: a statement for healthcare
professionals from the Expert Panel on Population and Prevention Science
of the American Heart Association. Circulation 2004; 109:2655-2671.
(3). Routledge HC, Ayres JG, Townend JN. Why cardiologists should be
interested in air pollution. Heart 2003; 89:1383-1388.
(4). La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ.
Baroreflex sensitivity and heart-rate variability in prediction of total
cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and
Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478-
484.
(5). Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, 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; 98:1510-1516.
(6). Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective
study of C-reactive protein, homocysteine, and plasma lipid levels as
predictors of sudden cardiac death. Circulation 2002; 105:2595-2599.
La Vecchia et al [1] considered increased cardiac troponin on
admission to be the strongest independent predictor of mortality in acute
pulmonary embolism. They attributed the increased troponin to right
ventricular involvement, because they excluded patients with known or
prior coronary artery disease in their study. The criteria they used for
exclusion were documented angina, previous my...
La Vecchia et al [1] considered increased cardiac troponin on
admission to be the strongest independent predictor of mortality in acute
pulmonary embolism. They attributed the increased troponin to right
ventricular involvement, because they excluded patients with known or
prior coronary artery disease in their study. The criteria they used for
exclusion were documented angina, previous myocardial infarction, coronary
angioplasty or bypass surgery.
But they have not excluded coronary embolism which can occur in
patients without prior, known coronary artery disease. As a matter of
fact, paradoxical coronary embolism has been reported in patients with
increased pulmonary artery pressure, e.g., pulmonary embolism [2,3] or
increased right atrial pressure, e.g. Valsalva maneuver or cough [2-4].
It also accounts for ST segment elevation in right precordial leads on ECG
in patients with acute pulmonary embolism [5,6]. Paradoxical coronary
embolism may contribute to the increased mortality in patients with acute
pulmonary embolism [7,8].
Finally, the diagnosis of paradoxical embolism
in acute pulmonary embolism carries an important therapeutic implication,
because patent foramen ovale, the commonest cause of paradoxical embolism,
can now be closed nonsurgically [9].
References
(1). La Vecchia L, Ottani F, Favero L, Spadaro GL, Rubboli A, Boanno 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 embolism. A diagnostic challenge and its
detection during life. Circulation 1976;53:565-568.
(3). Cheng, TO: Paradoxic embolism. Am Heart J 1996;131:1238.
(4). Cheng TO: Paradoxical embolism: diagnosis and management. J Emerg Med
2001;20:416-417.
(5). Cheng TO: Right-sided chest-lead abnormalities on EKG in acute
pulmonary embolism. J Nat Med Assoc 2003;95:862.
(6). Cheng TO: Brugada syndrome vs pulmonary embolism vs paradoxical
embolism. What are we to believe? Int J Cardiol 2004;94:119.
(7). Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser
KD, Rauber K, Iversen S, Redecker M, Kienast J: Management strategies and
determinants of outcome in acute major pulmonary embolism: results of a
multicenter registry. J Am Coll Cardiol 1997;30:1165-1171.
(8). 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.
(9). Cheng TO: Percutaneous closure of patent foramen ovale is the procedure
of choice for paradoxical embolism. Circulation 2003;108:e126.
In the editorial "Is informed consent possible in acute myocardial
infarction?" published in the November issue of Heart, Dr. Foëx argues that
clinicians must learn to empower their patients to make autonomous
decisions when they can. According to Dr. Foëx, the empirical studies on
informed consent in acute myocardial infarction (AMI) that he cites
suggest that some patients are competent and consider...
In the editorial "Is informed consent possible in acute myocardial
infarction?" published in the November issue of Heart, Dr. Foëx argues that
clinicians must learn to empower their patients to make autonomous
decisions when they can. According to Dr. Foëx, the empirical studies on
informed consent in acute myocardial infarction (AMI) that he cites
suggest that some patients are competent and consider themselves competent
to make a decision.
This is in contrast to the impression of the vast majority (86%) of
cardiologists, surveyed in the study by Ågård and colleagues, who felt
that patients in interventional trials in AMI were unable to understand
all the information given to them [1]. In Ågård et al’s study of patients’
perception of the informed consent process in an AMI trial, most of the
patients ”were willing to allow, or even wanted, their physician to decide
for them – at least if they were to be too ill to be asked about
participation in research” [2].
In our recent study, published in the October issue of Heart, we
analyse to what extent patients in the DANAMI-2 trial felt able to make
the decision, and to what extent they found the consent process
acceptable [3]. We found that the majority (76% of the trial participants
and 63% of the non-participants) agreed or almost agreed that they felt
able to make the decision, and 50% of the trial participants and 34% of
the non-participants found it acceptable that patients in their situation
have to make such a decision. We conclude that informed consent should be
sought in AMI trials, and we further argue that patients’ self-assessed
ability to make a decision should be explicitly addressed during the
informed consent process to avoid that patients who do not feel competent
are pressurised into decision-making.
Arguably, few patients are able to reach a deliberate autonomous
decision - in the strictly limited sense of reaching a well-informed
decision after due deliberation - under acute circumstances. What, then,
is the specific aim of an informed consent process in AMI trials? In her
book, Autonomy and trust in bioethics, O’Neill argues that the requirement
of informed consent should not be grounded in some conception of
individual autonomy [4]. Instead, she argues that informed consent
requirements are justified because they have the potential to prevent and
limit deception and coercion of patients, and to preserve a basis of trust
in the relationship between patients and physicians. This modest, but
nevertheless important, role of informed consent makes sense particularly
in the context of AMI trials. Likewise, Ågård et al. suggest that what
really seems to matter is not that patients are fully informed, but that
their right to say yes or no is respected.
References
(1). Ågård A, Herlitz J, Hermeren G. Obtaining informed consent from
patients in the early phase of acute myocardial infarction: physicians'
experiences and attitudes. Heart 2004;90:208-10.
(2). Ågård A, Hermeren G, Herlitz J. Patients' experiences of
intervention trials on the treatment of myocardial infarction: is it time
to adjust the informed consent procedure to the patient's capacity? Heart
2001;86:632-7.
(3). Gammelgaard A, Mortensen OS, Rossel P. Patients' perceptions of
informed consent in acute myocardial infarction research: a questionnaire
based survey of the consent process in the DANAMI-2 trial. Heart
2004;90:1124-8.
(4). O'Neill O. Autonomy and trust in bioethics. Cambridge: Cambridge
University Press, 2002.
Dear Editor,
The paper by Souverein et al. has identified oral glucocorticoid therapy as a risk factor for the development of heart failure [1]. They noted that the risk was greater in patients with current use and those receiving higher dosage.
One of the striking findings in their analysis was the greater incidence of heart failure as compared to ischemic heart disease. This suggests the possi...
Dear Editor,
Nagaya et al [1] showed that green tea can reverse endothelial dysfunction in smokers. There is another protective property of green tea in smokers that is worthy of additional comment.
The polyphenolic catechins in green tea, such as (-)-epigallocatechin -3-gallate, have been shown to be potent antioxidants in many chemical and biochemical studies [2,3]. Oxidants, either present in c...
Dear Editor,
It would seem that the K+(atp) channel opener pinacidil and closer glibenclamide might exert their effects by deceasing and increasing respecitively the rates of ATP resynthesis [1,2]. The implication is that the primary determinants of ATP resynthesis, pH, substrate availability for oxidative phosphorylation and body temperature, are important determinants of the degree of H+(atp) channel openess a...
Dear Editor,
I find this a most interesting study for it gets to the nub, what exactly is it that causes SUD in patients with chronic heart failure.
"During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and h...
Dear Editor,
I wish to echo the excellent points made by Seiler [1] in his editorial on the echocardiographic assessment of patent foramen ovale (PFO).
First, although contrast transesophageal echocardiogrpahy is said to be the gold standard for diagnosing PFO [1], very often the sedated state of the patient necessary for the transesophageal examination often prevents the patient from performing an effective...
Dear Editor,
In his elegant review of aldosterone blockade (Heart 2004; 90:1229- 1234), Dr. Struthers has failed to mention the diuretic properties of spironolactone.
Spironolactone in itself may be a weak diuretic but in combination with frusemide it provides excellent diuresis, which improves quality of life and exercise capacity in elderly patients with end stage congestive cardiac failure [1]. Spirono...
Dear Editor,
Yousef et al concluded in a recent publication that long-term anticoagulation in non-valvular atrial fibrillation is effective and safe in general clinical practice as evidenced by comparable rates of stroke and major complications to those obtained from clinical trials. [1]
However, results are misinterpreted in this study. First, this is not a long-term study, because that 739 pati...
Dear Editor,
We would like to congratulate Struthers and colleagues on their recent paper showing that sudden unexpected death in a small group of patients with heart failure is preceded by changes in both cardiac autonomic nervous control and markers of inflammation. [1]
Their findings lend support to the hypothesis that changes in inflammatory or autonomic status, might determine on which particular da...
Dear Editor,
La Vecchia et al [1] considered increased cardiac troponin on admission to be the strongest independent predictor of mortality in acute pulmonary embolism. They attributed the increased troponin to right ventricular involvement, because they excluded patients with known or prior coronary artery disease in their study. The criteria they used for exclusion were documented angina, previous my...
Dear Editor,
In the editorial "Is informed consent possible in acute myocardial infarction?" published in the November issue of Heart, Dr. Foëx argues that clinicians must learn to empower their patients to make autonomous decisions when they can. According to Dr. Foëx, the empirical studies on informed consent in acute myocardial infarction (AMI) that he cites suggest that some patients are competent and consider...
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