1. No category

CONTENT
EDITORIAL
Dilated cardiomyopathy
G. Jackson
3
BASIC ARTICLE
Myocardial energy metabolism in dilated cardiomyopathy
W. C. Stanley
5
MAIN CLINICAL ARTICLE
Drugs and/or devices in dilated cardiomyopathy
H. P. Schultheiss and U. Kühl
9
METABOLIC IMAGING
Metabolic imaging in dilated cardiomyopathy
S. Neubauer
13
NEW THERAPEUTIC APPROACHES
Metabolic modulation in dilated cardiomyopathy
H. Tuunanen and J. Knuuti
17
FOCUS ON TRIMETAZIDINE (VASTAREL MR)
The clinical benefits provided by trimetazidine in left ventricular dysfunction patients
G Marazzi, G. Caminiti and M. Voterrani
21
CASE REPORT
Response to cardiac resynchronization therapy resulting from an upgrade to dual-site left
ventricular pacing
M. R. Ginks, S. G. Duckett, G. S. Carr-White and C. A. Rinaldi
25
REFRESHER CORNER
Cardiac amyloidosis
P. Schmidheiny and O. M. Hess
29
HOT TOPICS
Low diagnostic yield of coronary angiography or not catching up with heart disease
pathophysiology?
A Huqi
33
GLOSSARY
G. D. Lopaschuk
37
Editorial
Dilated cardiomyopathy
Graham Jackson
Honorary Consultant Cardiologist, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK
Correspondence: Graham Jackson, Suite 301 Emblem House, London Bridge Hospital, 27 Tooley Street,
London SE1 2PR, UK.
Tel: +44 207 407 5887; e-mail: [email protected]
Dilated cardiomyopathy (DCM) refers to chronic disease of the heart muscle leading to cavity enlargement
and reduced systolic function of the left or both
ventricles. The diagnosis follows on from the exclusion of specific causes including hypertension,
coronary artery disease, rapid supraventricular
arrhythmias, congenital heart disease, pericardial
disease, cor pulmonale, and systemic disease such
as sarcoidosis. In addition, though alcohol excess can
lead to a DCM, abstinence may lead to reversal, so it is
only included if a minimum of six months of complete
abstinence still leaves a DCM at echocardiography.
The prevalence of DCM in the United States
(adjusted for age) is 36 per 100,000 of the population.
The etiology includes genetic transmission (estimated
at 30–40%) indentifying familial DCM, cytotoxic
agents (e.g., anthracycline derivatives), malnutrition
(e.g., protein deficiency), myocarditis (viral etiology),
and autoimmune disease.
The five-year survival averages 30–40% and has
been improved by modern heart failure therapy, but
20% will die within a year of the diagnosis due to
sudden death in most instances (64%) and heart failure deterioration in the remainder. Therefore not
everyone responds and some patients rapidly deteriorate no matter the therapeutic efforts, and for them, if
suitable, heart transplantation is the only option. Beta
blockade and angiotensin-converting enzyme (ACE)
inhibitors or angiotensin II antagonists improve left
ventricular function in 50% of cases, and in 16% it
returns to normal, but the remaining 34% suffer longterm disease progression.
In this issue we focus on DCM, opening up the door
to metabolic mechanisms and potential therapies that
Heart Metab. 2011; 49:3
may improve symptoms and prognosis. Metabolic
agents such as trimetazidine can optimize myocardial
energy metabolism, leading to increased energy from
glucose rather than free fatty acids. The link between
understanding energy metabolism and selecting
therapy using pharmacology or devices is thoroughly
explored and offers therapeutic options that may be
complimentary rather than alternatives. The value of
imaging in diagnosis and monitoring therapy reveals
once more a potential benefit from the metabolic
agent trimetazidine (a partial free fatty acid betaoxidation inhibitor) both symptomatically and potentially prognostically, and the need for large-scale
multicenter outcome studies.
Cardiac amyloidosis is almost certainly under diagnosed so it is timely that it is reviewed as part of this
DCM issue. Though the prognosis is poor, determining the precise etiology can lead to targeted therapy
and improved survival.
Throughout this issue of Heart and Metabolism,
DCM is recognized as a challenging condition. By
combining an understanding of the etiology, metabolic mechanisms, detection and therapeutic options,
we explore the means of rising to the challenge
Further reading
Key references are provided with each article. A
comprehensive review is provided in Hess OM,
McKenna W, Schultheiss H-P (2009) Myocardial Disease. In: Camm AJ, Luscher TF, Serruys PW (eds.) ESC
Textbook of Cardiovascular Medicine. Oxford University Press, Oxford, pp 665–716.
3
Basic article
Myocardial energy metabolism in
dilated cardiomyopathy
William C. Stanley
Division of Cardiology, Department of Medicine, School of Medicine,
University of Maryland, Baltimore, Maryland, USA
Correspondence: Professor William C. Stanley, Division of Cardiology, Department of Medicine, School of
Medicine, University of Maryland, 20 Penn St, HSF-II, Room S022, Baltimore, MD 21201, USA.
Tel: +1 410 706 3585; fax: +1 410 706 3583; e-mail: [email protected]
Abstract
Dilated cardiomyopathy can be broadly defined as heart failure with an enlarged left ventricular
chamber, but with no evidence of ischemic heart disease or myocardial infarction. Recent studies from
patients and animal models show that dilated cardiomyopathy results in a decrease in myocardial
content of adenosine-50 -triphosphate (ATP) and phosphocreatine and a decrease in the capacity for
mitochondrial oxidative metabolism and aerobic ATP production. There is a switch in the source of fuel,
with a decrease in the rate of myocardial fatty acid oxidation and greater glucose oxidation.
Pharmacologically preventing the decrease in fatty acid oxidation with a peroxisome proliferatoractivated receptor-a agonist does not appear to be beneficial. On the other hand, treatment with partial
inhibitors of myocardial fatty acid oxidation has favorable effects on cardiac energy metabolism,
contractile function, and structure.
Heart Metab. 2011;49:5–8.
Keywords: fatty acids, glucose, heart failure, mitochondria
Introduction
Cardiac power generation requires a high rate of
conversion of chemical energy from bloodborne substrates (fatty acids, glucose, and lactate) to contractile
power (Figure 1). Inability to meet the energy requirement results in heart failure, which is most clearly
manifest by an inability to perform physical exercise.
Most forms of heart failure are associated with a
history of cardiac ischemia, myocardial infarction,
hypertension, and/or left ventricular (LV) hypertrophy,
with either a normal or decreased ejection fraction.
Heart failure can also present with a dilated LV and
low ejection fraction, but without the classic history of
ischemia, infarction, or hypertension. This condition
is broadly referred to as dilated cardiomyopathy (or
‘‘idiopathic dilated cardiomyopathy’’); it has no clear
cause, yet a poor prognosis similar to other forms of
heart failure. Dilated cardiomyopathy can be caused
by inherited metabolic defects, specifically those in
Heart Metab. 2011; 49:5–8
mitochondrial oxidative metabolism, or may be
acquired, such as with chronic tachycardia, pregnancy, exposure to toxins, alcoholism, or diabetes.
Several adaptations in myocardial substrate metabolism have been described in response to dilated
cardiomyopathy. This brief overview will highlight
recent findings related to myocardial energy metabolism in dilated cardiomyopathy.
Cardiac energy metabolism in dilated
cardiomyopathy
The energy for cardiac mechanical work and relaxation comes from adenosine-5’-triphosphate (ATP),
which is broken down to adenosine diphosphate
(ADP) and inorganic phosphate to fuel contraction,
and Ca2þ uptake into the sarcoplasmic reticulum
to initiate diastolic relaxation (Figure 1). Oxidative
phosphorylation rapidly resynthesizes ATP in the
5
Basic article
William C. Stanley
Contraction
SR Ca2+ pump
Ion homeostatis
ATPases
CK
ADP + P i
PCr
O2
down of phosphocreatine (PCr) by creatine kinase
(CK) can rapidly synthesize ATP (Figure 1). Hence
ATP content stays relatively constant even with abrupt
increases in LV power output.
Long-chain fatty acids (primarily oleate, palmitate,
and linoleate) are a healthy human heart’s main fuels,
supplying approximately 50% to 80% of the energy
requirement under post-absorptive conditions. The
balance is from pyruvate oxidation, which is derived
in roughly equal proportions from glucose and lactate.
Under normal conditions the myocardium has tremendous metabolic flexibility, and is able to generate
a maximal rate of oxygen consumption, ATP formation, and cardiac power using either fatty acids
or carbohydrates as the sole substrate [1].
Patients with advanced dilated cardiomyopathy
have poor systolic and diastolic function, and switch
the fuel for cardiac metabolism away from fatty acid
oxidation toward greater glucose oxidation [2,3]. This
is illustrated in Figure 2, which shows a reduction in
myocardial free fatty acid oxidation, and greater glucose uptake by the myocardium in patients with
dilated cardiomyopathy. Substrate metabolism was
assessed directly using 3H-oleate to measure fatty acid
oxidation, and arterial and coronary sinus catheterization to assess transmyocardial substrate uptake.
Similar results were found using noninvasive positron
emission tomography [3], and also in the canine
tachycardia model of dilated cardiomyopathy [4–
6]. Moreover, the decline in fatty acid oxidation
was inversely related to the extent of LV dilation
(Figure 3). When the hearts of patients with dilated
cardiomyopathy were stressed by an acute bout of
atrial pacing at 130 beats/min (Figure 2), there was not
the normal increase in myocardial glucose uptake
seen in the controls, suggesting that there is a loss
of ‘‘metabolic flexibility’’ in these patients.
There is growing evidence to suggest that defective
mitochondrial ATP generation contributes to cardiac
Cytosol
ATP
Cr + P i
Oxidative
phosphorylation
NAD +
NADH
Mitochondrial
metabolism
Fatty acids
pyruvate
CO2
Mitochondria
Glucose
lactate
Figure 1. Schematic depiction of cardiac energy metabolism. Adenosine-50 -triphosphate (ATP) is broken down in
the cytosole to fuel the contractile work of systole, Ca2þ
uptake into the sarcoplasmic reticulum, which ends systole
and initiates relaxation and diastolic filling, and for ion
pumps on the sarcolemma. ATP is resynthesized in the
mitochondria by oxidative phosphorylation, which is fueled
by electrons that are transferred to NADH with the
metabolism of fatty acid and pyruvate in the mitochondrial
matrix (ADP adenosine diphosphate, CK creatine kinase, Cr
creatine, PCr phosphocreatine, NADH nicotinamide adenine dinucleotide).
mitochondria. This process is fueled by electrons
generated by metabolism of carbon substrates,
namely fatty acids and pyruvate, in the mitochondrial
matrix, which passes electrons to nicotinamide adenine dinucleotide (NADH) and the electron transport
chain. Here oxygen is consumed and oxidative phosphorylation resynthesizes ATP (Figure 1). Normally
the healthy myocardium sets the blood flow, oxygen
delivery, mitochondrial metabolism, NADH formation, and ATP synthesis to match need for ATP
breakdown. When there is a brief mismatch (i.e.,
during the transition from rest to exercise), the break-
Dilated cardiomyopathy
Control patients
0.20
Free fatty acid
oxidation
0.20
#
#
0.10
0.05
0.05
0.00
*
0.15
Baseline
Pacing
0.00
Lactate uptake
0.20
µmol g −1 min −1
0.10
µmol g −1 min −1
µmol g −1 min −1
#
0.15
0.25
Glucose uptake
0.15
0.10
0.05
Baseline
Pacing
0.00
Baseline
Pacing
Figure 2. Myocardial substrate metabolism in control patients and patients with dilated cardiomyopathy. Figure drawn from
data presented in Neglia et al (2007). Am J Physiol Heart Circ Physiol 293:H3270–H3278 [2].
6
Heart Metab. 2011; 49:5–8
Basic article
Myocardial energy metabolism in dilated cardiomyopathy
Free fatty acid uptake
(µmol*min−1*g −1)
0.25
Control patients
Dilated cardiomyopathy
0.20
0.15
0.10
0.05
R = − 0.70
P < 0.01
0.00
45
50
55
60
65
70
75
LV end diastolic diameter (mm)
Figure 3. Myocardial fatty acid uptake plotted as a function
of left ventricular end diastolic diameter. Figure drawn from
data presented in Neglia et al (2007). Am J Physiol Heart
Circ Physiol 293:H3270–H3278 [2].
dysfunction in patients with dilated cardiomyopathy.
In the canine model, there is a decrease in myocardial
ATP, PCr and creatine (Cr) during the progression
to severe dilated end-stage heart failure [7]. Many
studies found that heart failure results in a decrease in
the capacity for mitochondrial ATP generation at the
level of oxidative phosphorylation, particularly seen
in a decline in the electron transport chain’s integrative function [1,8,9]. Unfortunately, it is very difficult
to assess mitochondrial function in samples from
normal humans and patients with dilated cardiomyopathy, thus we do not have a clear understanding of
the precise molecular mechanisms responsible for the
decrease is ATP and impaired oxidative phosphorylation in this condition.
At present, it is not clear whether these alterations
are the cause or consequence of dilated cardiomyopathy. Clearly there are relatively rare inherited
defects in mitochondrial metabolism that present as
dilated cardiomyopathy [10], however this does not
explain the vast majority of cases. In general, it
appears that the mitochondrial defects and the switch
in substrate metabolism are acquired over the course
of the disorder’s development and progression. While
it is clear that it is important to maintain mitochondrial
ATPgenerating capacity in dilated cardiomyopathy, it
is less clear if it is important to maintain the normal
high rate of fatty acid oxidation. Maintaining myocardial fatty acid oxidation over the progression of
tachycardia-induced dilated cardiomyopathy using
fenofibrate, an agonist for peroxisome proliferatoractivated receptor-a, did not improve cardiac function or slow the progression of heart failure [11]. On
the other hand, treatment with oxfenicine, an inhibitor
of myocardial fatty acid oxidation at the level of
carnitine palmitoyl transferase I, prevented LV dilation and delayed decompensated heart failure in this
model [12]. This approach has not been evaluated
specifically in patients with dilated cardiomyopathy,
Heart Metab. 2011; 49:5–8
but small clinical studies in heart-failure patients
have shown promising results with the partial fatty
acid oxidation inhibitors perhexiline [13] or trimetazidine [14–17]. These finding suggest that the
decline in fatty acid oxidation in dilated cardiomyopathy is not detrimental, and inhibition of fatty
acid oxidation has potential as a therapy for this
condition.
In summary, dilated cardiomyopathy results in a
decreased capacity for mitochondrial oxidative
metabolism and aerobic ATP production, and a
decrease in the rate of myocardial fatty acid oxidation
and increased glucose oxidation. Pharmacologically
preventing the decrease in fatty acid oxidation with
peroxisome proliferator-activated receptor-a agonist
does not appear to be beneficial, but treatment with
partial inhibitors of myocardial fatty acid oxidation
has favorable effects on cardiac energy metabolism,
contractile function, and structure.
REFERENCES
1. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev.
2005;85 (3):1093–1129.
2. Neglia D, De CA, Marraccini P, et al. Impaired myocardial
metabolic reserve and substrate selection flexibility during
stress in patients with idiopathic dilated cardiomyopathy.
Am J Physiol Heart Circ Physiol. 2007;293 (6):H3270–H3278.
3. Davila-Roman VG, Vedala G, Herrero P, et al. Altered
myocardial fatty acid and glucose metabolism in idiopathic
dilated cardiomyopathy. J Am Coll Cardiol. 2002;40 (2):271–
277.
4. Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X,
Hintze TH. Reduced nitric oxide production and altered
myocardial metabolism during the decompensation of pacinginduced heart failure in the conscious dog. Circ Res. 1998;83
(10):969–979.
5. Osorio JC, Stanley WC, Linke A, et al. Impaired myocardial
fatty acid oxidation and reduced protein expression of retinoid
X receptor-alpha in pacing-induced heart failure. Circulation.
2002;106 (5):606–612.
6. Lei B, Lionetti V, Young ME, et al. Paradoxical downregulation
of the glucose oxidation pathway despite enhanced flux
in severe heart failure. J Mol Cell Cardiol. 2004;36 (4):567–
576.
7. Shen W, Asai K, Uechi M, et al. Progressive loss of myocardial
ATP due to a loss of total purines during the development of
heart failure in dogs: a compensatory role for the parallel loss
of creatine. Circulation. 1999;100 (20):2113–2118.
8. Rosca MG, Vazquez EC, Kerner J, et al. Cardiac mitochondria
in coronary microembolization-induced heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res. 2008;80:30–39.
9. Sharov VG, Todor AV, Silverman N, Goldstein S, Sabbah HN.
Abnormal mitochondrial respiration in failed human myocardium. J Mol Cell Cardiol. 2000;32 (12):2361–2367.
10. Kelly DP, Strauss AW. Inherited cardiomyopathies. N Engl J
Med. 1994;330 (13):913–919.
11. Labinskyy V, Bellomo M, Chandler MP, et al. Chronic activation of PPAR{alpha} with fenofibrate prevents alterations in
cardiac metabolic phenotype without changing the onset of
decompensation in pacing-induced heart failure. J Pharmacol
Exp Ther. 2007;321 (1):165–171.
12. Lionetti V, Linke A, Chandler MP, et al. Carnitine palmitoyl
transferase-I inhibition prevents ventricular remodeling and
delays decompensation in pacing-induced heart failure. Cardiovasc Res. 2005;66 (3):454–461.
7
Basic article
William C. Stanley
13. Lee L, Campbell R, Scheuermann-Freestone M, et al.
Metabolic modulation with perhexiline in chronic heart
failure: a randomized, controlled trial of short-term use
of a novel treatment. Circulation. 2005;112 (21):3280–3288.
14. Belardinelli R, Purcaro A. Effects of trimetazidine on the
contractile response of chronically dysfunctional myocardium
to low-dose dobutamine in ischaemic cardiomyopathy.
Eur Heart J. 2001;22 (23):2164–2170.
15. Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic patients
8
with coronary artery disease: a double-blind placebocontrolled study. Cardiovasc Diabetol. 2003;2 (1):16.
16. Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine
improves left ventricular function and quality of life in elderly
patients with coronary artery disease. Eur Heart J. 2004;25
(20):1814–1821.
17. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical
trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol.
2006;48 (5):992–998.
Heart Metab. 2011; 49:5–8
Main clinical article
Drugs and/or devices in
dilated cardiomyopathy
Heinz-Peter Schultheiss and Uwe Kühl
Medizinische Klinik für Kardiologie und Pulmologie, Charité – Universitätsmedizin Berlin,
Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany
Correspondence: Dr Uwe Kühl, Medizinische Klinik II, Cardiology and Pneumonology, Charité –
Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30 D-12200 Berlin, Germany.
Tel: +49 30 8445 4219; fax: +49 30 8445 4219; e-mail: [email protected]
Abstract
Dilated cardiomyopathy (DCM) is the most common type of nonischemic heart muscle disease, with a
prevalence of 36 cases per 100,000 people. In contrast to other heart diseases it often affects the young
and presents with reduced systolic function and ventricular dilatation due to infectious, toxic, metabolic,
or genetic causes. Regardless of the underlying cause, patients are given standard medication for heart
failure in order to improve cardiac function, treat symptoms, and prevent complications. Subgroups of
patients with acquired infectious or postinfectious autoimmune diseases can be treated successfully if
underlying causes have been characterized carefully.
Heart Metab. 2011;49:9–12.
Keywords: Anti-viral or immunomodulatory treatment, autoimmunity, dilated cardiomyopathy,
heart failure therapy, ICD, immunosuppression, myocarditis
Introduction
Dilated cardiomyopathy (DCM) is a cardiac muscle
disease characterized by reduced contractile function
and dilatation of the left or both ventricular chambers
[1]. Aside from genetic inheritance and etiologically
undefined ‘‘idiopathic’’ cases, DCM is often acquired
and caused by infections or toxic agents (e.g., alcoholic cardiomyopathies), or associated with autoimmune diseases, pregnancy, systemic, and other
cardiovascular disorders. Since the acquired causes
constitute a sizeable proportion of DCM, the observed
frequency of the undefined so-called ‘‘idiopathic’’
entities, last but not least, depends on the effort and
technical means applied to come to a specific and
reliable diagnosis [2,3]. This important issue notably
concerns immune, autoimmune and infectious causes
due to the fact that subgroups of patients may gain
benefit from specific treatment strategies [4]. Uncovering such treatable causes of DCM demands, however, direct analysis of tissue samples obtained by
biopsy, because non-invasive clinical tools do not
Heart Metab. 2011; 49:9–12
usually provide the required diagnostic accuracy to
allow successful intervention (Fig. 1) [5,6].
Symptomatic treatment of heart failure
Although conventional pharmacotherapy does not
influence specific causes of acquired diseases of viral
or immune origin, it remains the hallmark of any heart
failure therapy [7]. It does not depend on the disease’s
etiology and remains primarily supportive. Despite
routine use of angiotensin-converting enzyme (ACE)
inhibitors or angiotensine II receptor (ABR) blockers,
beta blockers, diuretics, and spironolactone in
patients with heart failure due to DCM, these patients
still have a considerable annual mortality rate of 5–
10%. A survival benefit has been demonstrated for
ACEinhibitors, beta blockers, and spironolactone,
which should be administered routinely starting
with low doses in all patients with New York Heart
Association (NYHA) class II to IV heart failure [8].
Diuretics may improve heart failure symptoms without
9
Main clinical article
Heinz-Peter Schultheiss and Uwe Kühl
Figure 1. Histology of acute and chronic dilated cardiomyopathy (DCM)/inflammatory cardiomyopathy (DCMi) influencing
treatment decisions. (a) Regular myocardial tissue without infiltrating inflammatory cells, fibroses or scars. (b) Active
myocarditis. (c) Chronic DCMi without relevant fibrosis or scars. (d) DCM with myocyte hypertrophy and replacement
fibrosis (scars). A significant number of patients without irreversible myocardial injury may improve spontaneously (a) or
upon immunosuppressive treatment (b, c) if ventricular dysfunction is caused by an acute or chronic inflammatory process.
In the later stage of DCM (d) specific treatment at best can prevent inflammation-associated progression of heart failure, but
ventricular function will not recover.
significant effect on long-term outcome. Despite
improvements in the treatment of heart failure in the
last 15 years, clinical outcome following the onset of
symptoms has not substantially changed.
Cardiac transplantation has been considered the last
treatment for end-stage heart failure, with DCM as one
of the leading causes diagnosed at the time of the
operation. Since the necessary number of organs is
stagnating or has even declined in some countries
over the past years, mechanical left ventricular assist
device (LVAD) has been introduced as one promising
option to improve prognosis until recovery from acute
fulminant disease or to bridge to transplantation in
end-stage disease (Fig. 1).
Antiarrhythmic treatment
Due to their negative inotropic effects, most antiarrhythmic drugs, including newer substances such as
dronedarone should be avoided in patients with
severe systolic heart failure and an ejection fraction
below 35% and acute or worsened heart failure
(NYHA IV), respectively. Beta blockers or amiodarone can be used but have to be handled with care in
these patients and may prevent sinus tachycardia and
different forms of supraventricular or ventricular
arrhythmias, respectively. In the long run, however,
10
drugs do not significantly reduce increased mortality
due to sudden cardiac death (SCD) caused by
tachyarrhythmias, ventricular tachycardia (VT), or
ventricular fibrillation (VF). An implantable cardioverter-defibrillator (ICD) is established as the
most reliable therapeutic tool and indicated for documented VT/VF or aborted SCD for secondary prevention. If patients with irreversibly impaired ventricles
and left ventricular branch block are supplied with an
ICD, it can be combined with cardiac resynchronization therapy (CRT) e.g., by biventricular chamber
pacing. In early stages of acute disease or DCM
due to acquired causes, a wearable defibrillator (LifeVest1) rather than a permanent device is a rational
choice for patients with a temporary risk of sudden
cardiac arrest to bridge the first critical period if
spontaneous or treatment-associated recovery is
expected.
Biopsy-based specific treatment of acquired
disease
The gold standard of diagnosing the underlying causes
of infectious myocarditis and inflammatory cardiomyopathy (DCMi) is the histological, immunohistological
and polymerase chain reaction (PCR)-based analysis of
endomyocardial biopsies if its time-dependent and
Heart Metab. 2011; 49:9–12
Main clinical article
Drugs and/or devices in dilated cardiomyopathy
methodological limitations are kept in mind [9]. Both
persistent viral infections and infection-associated or
postinfectious inflammatory processes of the myocardium have been recognized as independent prognostic parameters—in addition to left and right ventricular dysfunction—in myocarditis and DCM [3,10].
Therefore, in addition to conventional pharmacotherapy specific treatment options are required that directly
address the underlying viral or inflammatory causes of
the disease (Fig. 1).
Immunoadsorption
Persisting virus infections and postinfectious myocardial injury may produce antibodies that crossreact
with myocardial antigens and the myocyte Fc-receptors thereby contributing to impairment of cardiac
contractility [11,12]. Long-term reduction of such
cardio-depressive antibodies from sera of patients
with refractory heart failure as a result of DCM by
immunoadsorption significantly improves ventricular
function in many but not all patients [13,14]. The
effect of immunoadsorption on longterm outcome is
not currently known; a controlled treatment trial is
currently being performed.
Immunomodulatory treatment
Myocardial inflammatory processes or autoimmunity
may survive myocardial virus elimination and warrant
immunosuppressive treatment in order to prevent later
immune-mediated myocardial injury, particularly in
the aggressive forms of myocarditis such as giant cell
granulomatous myocarditis (Table 1). Frequently
administered anti-inflammatory drugs are immunoglobulins, corticosteroids, azathioprine and cyclosporine, which are administered on top of regular
heart-failure medication. a-Methylprednisolone is
generally given, at a rate of 1 mg/kg body weight,
initially for 4 weeks. Depending on the body weight,
100 to 150 mg azathioprine daily can be administered
in addition to the steroid medication. The steroid
dosage is titrated biweekly in increments of 10 mg
until a maintenance dose of 10 mg is reached. The
treatment should last for 3 to 6 months. Current data
from initial randomized trials confirm efficacy of
those treatment regimens in carefully selected patients
[15–17].
Both treatment of early disease with frequent spontaneous recovery and the lack of information on the
actual virus state due to incomplete diagnostic
accuracy have blurred the results of the initial
randomized trials [18–20]. More recent studies with
exactly characterized cohorts of patients have confirmed earlier data that patients with inflammatory
cardiomyopathy respond well to immunosuppression
if persistent viral infection is excluded before treatment [15–17].
Anti-infectious treatment
Interferons (IFNs) serve as a natural defense against
many viral infections. Their innate production is
associated with clinical recovery from viral infection
and subsequent sequelae while exogenous administration is protective. Type I interferons therefore constitute a promising choice for treatment for selected
infectious agents.
Data from an IFN-b phase II study provided first
evidence that antiviral IFN-b 1a therapy effectively
clears cardiac enterovirus and adenovirus infections
in patients with chronic heart failure when given
subcutaneously every other day in addition to constant heart failure medication [21]. The dosage
4 106 IU and 6 106 IU IFN-b was well tolerated.
After 24 weeks of treatment complete elimination of
the viral genome was proven in follow-up biopsies in
Table 1. Immunosuppressive treatment of patients with myocarditis and inflammatory cardiomyopathy.
Muromonab (anti-CD3-antibodies)1
Methylprednisolon
Pantoprazole
5 mg/day iv for 7 days
10 mg/kg bw (first 3 days) than
1 mg/kg bw (see below)
Trough level: 100–150 mg
50–150 mg/day5
1 mg/kg bw (4 weeks), tapering
10 mg for 6 to 12 months
20 mg/day
Calcimagon D31
1 1/day
Ciclosporin2
Azathioprine4 (optional)
Methylprednisolon3
GCM
GCM,
Myocarditis: lymphocytic (auto-)immune
eosinophilic granulomateous
Patients with giant cell myocarditis (GCM) should be treated with anti-CD3-antibodies, cortisone, and ciclosporin immediately after
established diagnosis. Virusnegative DCMi or autoimmune myocardites, eosinophilic myocarditis, and granulomatous myocarditis such
as sarcoidosis often respond to cortisone alone. Cortisone treatment may have to be replaced by other immunosuppressive drugs in case
of side effects or may be extended by azathioprine, if necessary. In every case, therapy should be dispensed for about 6 months. 1Attend
initial hypotension and allergic reactions; 2Control liver and kidney parameters; 3Control blood count, glucose; 4Control blood count,
liver and kidney parameters; 5Reduce or terminate if leukocyte counts <1000/nl or liver enzymes >3-fold normal value.
Heart Metab. 2011; 49:9–12
11
Main clinical article
Heinz-Peter Schultheiss and Uwe Kühl
all patients. This was paralleled by a significant
improvement in left ventricular function and ventricular size and amelioration of heart failure symptoms.
None of the patients deteriorated. While entero- and
adenoviruses seem to respond well to the interferon-b
treatment, subsequent open-labeled studies have
shown that other viruses such as erythroviruses,
including parvovirus B19, respond less well in terms
of virus clearance, although erythrovirus load
decreased and patients improved clinically. These
data were confirmed by a first recently presented
randomized IFN-b treatment study (BICC-trial) [22].
The other viruses might respond in a better way to
distinct anti-viral treatment regimens, but optimal
treatment conditions for viruses other than enterovirus
and adenovirus have not yet been defined. At present,
antiviral therapy is still a matter of clinical trials in
specialized centers.
Conclusion
In acute DCM or DCMi, management is first of all
supportive and does not aim at the causative
agent. Rapid aggressive support of cardiac function
including inotropic therapy, mechanical circulatory
support, and arrhythmia management may be lifesaving by bridging the interval for return to improved
or native ventricular function or providing a
bridge to transplantation. Generally a biopsy-based
diagnosis is mandatory to initiate any specific treatment, in addition to standard heart failure therapy,
in order to improve prognosis in patients with
acute and chronic infectious and/or inflammatory
disease.
REFERENCES
1. Richardson P, McKenna W, Bristow M, et al. Report of the
1995 World Health Organization/International Society and
Federation of Cardiology Task Force on the definition and
classification of cardiomyopathies. Circulation. 1996;93:841–
842.
2. Mangnani JW, Suk Danik HJ, Dec GW, DiSalvo TG. Survival
in biopsy-proven myocarditis: A long-term retrospective analysis of the histopathological, clinical, and hemodynamic
predictors. Am Heart J. 2006;151:463–470.
3. Caforio AL, Calabrese F, Angelini A, et al. A prospective study
of biopsy-proven myocarditis: prognostic relevance of clinical
and aetiopathogenetic features at diagnosis. Eur Heart J.
2007;28:1326–1333.
4. Kuhl U, Schultheiss HP. Viral myocarditis: diagnosis, aetiology and management. Drugs. 2009;69:1287–1302.
12
5. Liu PP, Schultheiss HP. Myocarditis. In: Baunwald, ed. Heart
Disease. 8 ed. Philadelphia: WB Saunders Co; 2008.
pp. 1775–1792.
6. Mangnani JW, Dec GW. Myocarditis: current trends in diagnosis and treatment. Circulation. 2006;113:876–890.
7. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005
Guideline Update for the Diagnosis and Management of
Chronic Heart Failure in the Adult: a report of the American
College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Writing Committee to Update the
2001 Guidelines for the Evaluation and Management of Heart
Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart
and Lung Transplantation: endorsed by the Heart Rhythm
Society. Circulation. 2005;112:e154–e235.
8. Felker GM, Thompson RE, Hare JM, et al. Underlying causes
and long-term survival in patients with initially unexplained
cardiomyopathy. N Engl J Med. 2000;342:1077–1084.
9. Schultheiss HP, Kuehl U. Cardiovascular Viral Infections. In:
Lennette’s Laboratory Diagnosis of Viral Infections, 4 ed. Edited
by Lennette . New York: Informa Healthcare USA Inc; 2010.
pp. 304–318.
10. Kühl U, Pauschinger M, Seeberg B, et al. Viral persistence in
the myocardium is associated with progressive cardiac dysfunction. Circulation. 2005;112:1965–1970.
11. Caforio AL, Tona F, Bottaro S, et al. Clinical implications of
anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. Autoimmunity. 2008;41:35–45.
12. Staudt A, Eichler P, Trimpert C, Felix SB, Greinacher A.
Fc(gamma) receptors IIa on cardiomyocytes and their potential functional relevance in dilated cardiomyopathy. J Am Coll
Cardiol. 2007;49:1684–1692.
13. Staudt A, Hummel A, Ruppert J, et al. Immunoadsorption in
dilated cardiomyopathy: 6-month results from a randomized
study. Am Heart J. 2006;152:712.e1–712.e6.
14. Trimpert C, Herda LR, Eckerle LG, et al. Immunoadsorption in
DCM: long-term reduction of cardiodepressant antibodies. Eur
J Clin Invest. 2010;40:685–691.
15. Frustaci A, Russo MA, Chimenti C. Randomized study on the
efficacy of immunosuppressive therapy in patients with virusnegative inflammatory cardiomyopathy: the TIMIC study. Eur
Heart J. 2009; doi: 10.1093/eurheartj/ehp249.
16. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, et al.
Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: twoyear follow-up results. Circulation. 2001;104:39–45.
17. Kühl U, Strauer BE, Schultheiss HP. Methylprednisolone in
chronic myocarditis. Postgrad Med J. 1994;70 (Suppl 1):S35–
S42.
18. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of
immunosuppressive therapy for myocarditis. The Myocarditis
Treatment Trial Investigators. N Engl J Med. 1995;333:269–
275.
19. Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G,
Maseri A. Immunosuppressive therapy for active lymphocytic
myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation. 2003;107:857–863.
20. Stanton C, Mookadam F, Cha S, et al. Greater symptom
duration predicts response to immunomodulatory therapy in
dilated cardiomyopathy. Int J Cardiol. 2008;128:38–41.
21. Kühl U, Pauschinger M, Schwimmbeck PL, et al. Interferonbeta treatment eliminates cardiotropic viruses and improves
left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation. 2003;107:2793–2798.
22. Schultheiss HP, Piper C, Sowade K, et al. The effect of
subcutaneous treatment with interferon-beta-1b over 24
weeks on safety, virus elimination and clinical outcome in
patients with chronic viral cardiomyopathy. Circulation.
2008;(118):Abstract 3322.
Heart Metab. 2011; 49:9–12
Metabolic imaging
Metabolic imaging in
dilated cardiomyopathy
Stefan Neubauer
University of Oxford Centre for Clinical Magnetic Resonance Research, Department of Cardiovascular
Medicine, John Radcliffe Hospital, Oxford, United Kingdom
Correspondence: Professor Stefan Neubauer, Department of Cardiovascular Medicine, John Radcliffe Hospital,
Oxford OX3 9DU, UK.
Tel: +44 0 1865 851085; fax: +44 0 1865 222077; e-mail: [email protected]
Sponsorship: The author is funded by the British Heart Foundation, the Medical Research Council, the
Wellcome Trust, and the National Institute for Health Research Biomedical Research Centre Programme.
Abstract
Cardiac metabolism is deranged in dilated cardiomyopathy (DCM). Phosphorus-31 (31P) and hydrogen1 (1H) magnetic resonance spectroscopy (MRS) allow for the non-invasive assessment of various aspects
of cardiac metabolism, showing deranged cardiac energetics and lipid accumulation in DCM. In the
future, MRS may become an important biomarker tool for monitoring the effects of novel heart-failure
treatments in DCM.
Heart Metab. 2011;49:13–16.
Keywords: Dilated cardiomyopathy, energetics, magnetic resonance spectroscopy, metabolism,
steatosis
Introduction
Dilated cardiomyopathy (DCM) is a common cause of
heart failure, and may be due to many different
etiologies (genetic, post myocarditis, toxic, etc.). A
common feature of DCM is a derangement of cardiac
metabolism. As reviewed elsewhere, metabolic
alterations are likely to be a key factor in the pathophysiology of contractile dysfunction [1]. Accordingly, metabolic modulation currently appears as
one of the most promising new strategies for chronic
drug therapy with the potential to further improve
long-term prognosis, as an additive to established
therapy with angiotensin-converting enzyme (ACE)
inhibitors, beta blockers, and diuretics.
In light of this, non-invasive assessment of the
metabolic state of the myocardium in DCM has been
an important goal in cardiology for many decades. In
principle, two techniques allow for this: magnetic
resonance spectroscopy (MRS) and positron emission
tomography (PET). The largest number of studies has
Heart Metab. 2011; 49:13–16
been performed with MRS [2], and early proofofprinciple investigations point to the value of metabolic MRS parameters as biomarkers of disease and
prognosis, and for monitoring therapy.
Methodological considerations
MRS can be performed on the same magnetic resonance systems used for imaging, typically at a field
strength of 1.5–3 tesla (T). There are, however,
additional hardware and software requirements, such
as a phosphorus-31 (31P) surface coil, a broadband
radiofrequency transmitter, spectroscopy pulse
sequences, and post-processing software [2,3]. After
shimming the magnetic field, an MR spectrum is
obtained using a spectral localization technique,
which makes it possible to obtain signal from a voxel
element within the heart [2]. Because of the inherent
low resolution of MRS, a large number of acquisitions
have to be signal averaged in order to obtain a
13
Metabolic imaging
Stefan Neubauer
Figure 1. In vivo human cardiac phosphorus-31 (31P) magnetic resonance spectroscopy, 3-dimensional chemical shift
imaging sequence. Left: Short-axis hydrogen-1 (1H) magnetic resonance image of the heart with a superimposed grid of
spectroscopic voxels. The interrogated cardiac voxel (blue square) is placed in the interventricular septum to avoid
contamination from skeletal muscle. Saturation bands are placed over the chest wall skeletal muscle to suppress further any
skeletal muscle signal. Right: Example of a cardiac 31P magnetic resonance spectrum in a healthy individual. Resonances for
2,3-diphosphoglycerate (2,3-DGP), phosphodiesters (PDE), phosphocreatine (PCr), and the three phosphorus atoms of
adenosine-50 -triphosphate (ATP) (from left to right: g, a, and b ATP) are detectable. 3T Siemens TIM-Trio system.
Acquisition matrix size 16x16x8 voxels, field of view 240 240 200 mm. Reprinted from [16].
magnetic resonance spectrum with an acceptable
signal-to-noise ratio. A typical 31P spectrum from a
normal individual is shown in Figure 1 (Figure 1).
Resonances are shown for the three phosphorus atoms
of adenosine-50 -triphosphate (ATP) (a, b and g ATP),
phosphocreatine (PCr), and also 2,3-diphosphoglycerate (2,3-DPG) from blood and phosphodiesters (PDE)
from phospholipids. The PCr to ATP ratio is an exqui-
sitely sensitive index of the energetic state of the heart
[4]. Figure 2 shows a hydrogen-1 (1H) MR spectrum
from the heart (Figure 2). While 1H spectra show many
metabolites, quantification has so far been limited to
lipids (triglycerides), which provide a measure of
myocardial steatosis (another key factor in the development of contractile dysfunction), and to the total
creatine peak [5].
Figure 2. In vivo human cardiac hydrogen-1 (1H) magnetic resonance spectroscopy. Spectrum consisting of 35 averages (TR
2800 ms, TE/TM ¼ 10/7 ms), from a 12.6 cm3 voxel positioned in the interventricular septum of a healthy volunteer as
shown in (B) and (C). Resonance assignment: (1) residual water, 4.7 ppm; (2) total creatine CH2, 3.9 ppm; (3) Ntrimethyl groups, 3.2 ppm; (4) total creatine CH3, 3 ppm; (5) unsaturated fat, 2.0–2.3 ppm; (6) fat (CH2)n, 1.3 ppm; (7)
fat terminal methyl, 0.9 ppm. Spectrum acquired by Dr. Belen Rial, Oxford Centre for Clinical Magnetic Resonance
Research.
14
Heart Metab. 2011; 49:13–16
Metabolic imaging
Metabolic imaging in dilated cardiomyopathy
There are only two previous studies on 1H-MRS in
DCM. In a mixed group of patients with non-ischemic
heart failure (15 patients, 11 of whom had DCM),
Nakae et al. [10] found a nearly 50% decrease in total
creatine content, which also correlated inversely with
plasma brain natriuretic peptide (BNP) levels. Apart
from an early proof-of-principle study [11], there are
no data on 1H-MRS-measured myocardial lipid levels
in patients with DCM, and these studies are urgently
needed.
Findings in DCM
Deranged cardiac energy metabolism is a hallmark of
the failing heart [1], regardless of the etiology. In
DCM, PCr to ATP ratios are reduced, correlating with
the New York Heart Association (NYHA) functional
class [4] and left ventricular ejection fraction [6]. Most
importantly, they are a strong predictor of prognosis,
and in one study the PCr to ATP ratio was a better
predictor of long-term survival than NYHA class or left
ventricular ejection fraction (Figure 3) [7]. Although
PCr to ATP ratios are powerful indicators of the extent
of energetic derangement in DCM, they still underestimate the true extent of metabolic derangement.
Recent spectroscopy techniques have made the
absolute quantification of ATP and PCr possible,
showing approximately 50% reduction in PCr and
35% reduction in ATP, with a concomitant 25%
decrease in the PCr to ATP ratio, in heart failure
[8]. An even more sensitive indicator of deranged
energetics may be the dynamic rate of turnover of
ATP. Recently, ATP turnover (ATP flux through the
creatine kinase reaction) was measured in volunteers
and patients with heart failure; for an 18% reduction
in PCr concentrations, a 50% reduction in the rate of
turnover of ATP was demonstrated [9]. Thus, the
measurement of ATP turnover rates holds promise
as a highly sensitive indicator of energetic derangement in heart failure.
Treatment studies
An important area is the use of MRS for monitoring
energetic changes in the heart after novel forms of
treatment of DCM. We showed that conventional
treatment of DCM with beta blockers, ACE inhibitors
and diuretics for 3 months significantly improved the
PCr to ATP ratio, together with clinical improvement
[12]. Most recently, a study of the use of the investigational drug trimetazidine in patients with heart
failure of mixed etiology revealed that trimetazidine
was associated with a 33% increase in the PCr to ATP
ratio, concomitant with improvements in NYHA
class and left ventricular ejection fraction (EF) [13].
In a recent study, we investigated the effects of
chronic exercise on DCM, and found an improvement on EF after 8 months of therapy, achievable
DCM patient died 7 days
after MR examination
DCM, PCr/ATP < 1.6
DCM, PCr/ATP > 1.6
PCr
γ
PDE
Volumeer
α
β-ATP
Total mortality (%)
2,3 DPG
50
40
p = 0.036
30
PCr/ATP < 1.60
20
PCr/ATP > 1.60
10
0
0
10
0
−10
−20 ppm
500
1000
1500
Days of follow-up
Figure 3. Phosphorus-31 (31P) magnetic resonance spectroscopy in dilated cardiomyopathy. Left: 31P magnetic resonance
spectra in, from bottom upward: a healthy volunteer, a patient with mild dilated cardiomyopathy (DCM), a patient with
severe DCM with reduced phosphocreatine (PCr) to adenosine-50 -triphosphate (ATP) ratio, and a patient who died 7 days
after the magnetic resonance examination, showing a massive reduction in the PCr to ATP ratio. Right: Kaplan–Meyer curve
analysis of total mortality in DCM. Patients were subdivided according to the initial PCr to ATP ratio (greater or less than
1.60). Substantially increased mortality was observed in patients with an initially reduced PCr to ATP ratio. Modified from
Beer M et al. [8]. ß2002 American College of Cardiology Foundation.
Heart Metab. 2011; 49:13–16
15
Metabolic imaging
Stefan Neubauer
without extra energetic cost to the myocardium, as
estimated by similar PCr to ATP ratios [14]. Although
currently available studies on this subject are clearly
limited by their small size, the concept of monitoring
novel drug therapy for heart failure with regards to
its effects on cardiac energetics is an extremely
appealing one.
Future perspective
The main challenge for MRS is the improvement of the
method’s low signal to noise. Promising techniques on
the horizon to achieve this are higher field strength (7T
and more) and hyperpolarisation methods (for carbon13 [13C] MRS) [15], which can boost the signal by
several orders of magnitude, but require intravenous
application of external hyperpolarized 13C metabolites. These are exciting novel directions for future
research.
Summary
MRS allows for the non-invasive assessment of various
aspects of cardiac metabolism in DCM, and has the
potential to become an important biomarker tool for
diagnostic and prognostic assessment as well as for
the monitoring of therapy.
REFERENCES
1. Neubauer S. The failing heart—an engine out of fuel. N Engl J
Med. 2007;356:1140–1151.
2. Bottomley PA. MR spectroscopy of the human heart: the status
and the challenges. Radiology. 1994;191:593–612.
3. Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy
in myocardial disease. JACC Cardiovasc Imaging. 2009;2:87–
96.
16
4. Clarke K, O’Connor AJ, Willis RJ. Temporal relation between
energy metabolism and myocardial function during ischemia
and reperfusion. Am J Physiol. 1987;253:H412–H421.
5. van der Meer RW, Doornbos J, Kozerke S, Schär M, Bax JJ,
Hammer S, Smit JW, Romijn JA, Diamant M, Rijzewijk LJ, de
Roos A, Lamb HJ. Metabolic imaging of myocardial triglyceride content: reproducibility of 1H MR spectroscopy with
respiratory navigator gating in volunteers. Radiology.
2007;245 (1):251–257.
6. Neubauer S, Horn M, Pabst T, et al. Contributions of 31P
magnetic resonance spectroscopy to the understanding of
dilated heart muscle disease. Eur Heart J. 1995;16 (Suppl
O):115–118.
7. Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with
dilated cardiomyopathy. Circulation. 1997;96:2190–2196.
8. Beer M, Seyfarth T, Sandstede J, et al. Absolute concentrations
of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with P-SLOOP magnetic resonance spectroscopy. J Am
Coll Cardiol. 2002;40:1267–1274.
9. Smith CS, Bottomley PA, Schulman SP, Gerstenblith G, Weiss
RG. Altered creatine kinase adenosine triphosphate kinetics in
failing hypertrophied human myocardium. Circulation.
2006;114:1151–1158.
10. Nakae I, Mitsunami K, Matsuo S, Matsumoto T, Morikawa S,
Inubushi T, Koh T, Horie M. Assessment of myocardial creatine concentration in dysfunctional human heart by proton
magnetic resonance spectroscopy. MRM. 2004;3:19–25.
11. Walecki J, Michalak MJ, Michalak E, Bilinska ZT, Ruzyllo W.
Usefulness of 1H MR spectroscopy in the evaluation of myocardial metabolism in patients with dilated idiopathic cardiomyopathy: pilot study. Acad Radiol. 2003;10 (10):1187–1192.
12. Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary
artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation. 1992;86:1810–1818.
13. Fragasso G, Perseghin G, De Cobelli F, et al. Effects of
metabolic modulation by trimetazidine on left ventricular
function and phosphocreatine/adenosine triphosphate ratio
in patients with heart failure. Eur Heart J. 2006;27:942–948.
14. Beer M, Wagner D, Myers J, Sandstede J, Köstler H, Hahn D,
Neubauer S, Dubach P. Effects of exercise training on myocardial energy metabolism and ventricular function assessed
by quantitative phosphorus-31 magnetic resonance spectroscopy and magnetic resonance imaging in dilated cardiomyopathy. J Am Coll Cardiol. 2008;51 (19):1883–1891.
15. Schroeder MA, Cochlin LE, Heather LC, Clarke K, Radda GK,
Tyler DJ. In vivo assessment of pyruvate dehydrogenase flux in
the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci U S A. 2008;105:12051–12056.
16. Neubauer, Stefan. Metabolic imaging with cardiac magnetic
resonance spectroscopy. Heart Metab. 2009;44:17–20.
Heart Metab. 2011; 49:13–16
New therapeutic approaches
Metabolic modulation in
dilated cardiomyopathy
Helena Tuunanen and Juhani Knuuti
Turku PET Centre, University of Turku, Finland, Department of Medicine, Turku University Hospital,
Turku, Finland
Correspondence to Correspondence: Helena Tuunanen, Department of Medicine, Turku University Hospital,
PO Box 51, 20521 Turku, Finland.
Tel: 358 2 313 0000; e-mail: [email protected]
Management of patients with dilated cardiomyopathy (DCM) and chronic heart failure (HF) remains
challenging. There is a need for novel medical therapies independent of the neurohormonal axis that
improve cardiac performance. Experimental and preliminary clinical studies have demonstrated that
metabolic modulators enhancing myocardial glucose metabolism directly or indirectly by limiting free
fatty acid (FFA) metabolism, may improve left ventricular (LV) function in HF. This paper reviews the
literature on the effects of metabolic modulators on human HF (both ischemic and idiopathic). The
effects of acute metabolic modulation (mainly by manipulating circulating substrate levels) and longterm metabolic modulation (trimetazidine, perhexiline, etomoxir) are discussed.
Heart Metab. 2011;49:17–19.
Keywords: etomoxir, Heart failure, metabolism, perhexiline, trimetazidine
Introduction
Metabolic modulation is linked to glucose being a
more energy-efficient fuel than free fatty acids (FFAs).
Cardiac FFA and glucose metabolism are tightly
coupled, which means that inhibition of one results
in an increment in another. Several different agents
can achieve a myocardial metabolic switch from
oxidation of FFAs towards that of glucose. In this
paper we focus on metabolic shift achieved by 1)
manipulating circulating substrate levels (nicotinic
acid and its derivatives, glucose-insulin-potassium
infusion), 2) FFA betaoxidation inhibitors (trimetazidine, ranolazine), 3) carnitine palmitoyltransferase
(CPT)-1 blockers (perhexiline, etomoxir), and 4)
dichloroacetate (direct carbohydrate oxidation activator).
Acute metabolic modulation
In small groups of patients with heart failure (HF),
intravenous infusion of dichloroacetate [1] or glucoseinsulin-potassium [2] and intracoronary infusion of
Heart Metab. 2011; 49:17–19
pyruvate [3,4] has been associated with improved
cardiac function. Compared with double-blind
placebo, three-day treatment with trimetazidine
improved ejection fraction (EF) and enhanced myocardial perfusion in patients with prior myocardial
infarction and ischemic HF [5]. However, the positive
effects of trimetazidine were lost in patients with
severe left ventricular (LV) dysfunction, possibly
due to large, metabolically inactive scar tissue in these
patients. In contrast, Wiggers et al. [6] demonstrated
that acute substrate availability modulation does not
influence cardiac function in hibernating myocardium either at rest or after exercise. The study
included substrate modulation either with insulinglucose (high insulin, low FFA) and somatostatinheparin (high FFA, low insulin). Furthermore, a
previous study demonstrated that acute FFA deprivation in patients with idiopathic dilated cardio-myopathy (DCM), in contrast to healthy controls, uncouples cardiac contractile function from oxidative
metabolism so that myocardial efficiency deteriorates
further [7]. Thus, these preliminary studies suggest
that acute manipulation of substrate levels may not be
a promising form of therapy in HF.
17
New therapeutic approaches
Helena Tuunanen and Juhani Knuuti
18
Baseline
Follow-up
9
8
FFA uptake (umol/100g/min)
A first study in the early 1990 s showed that compared
with double-blind placebo, six-month treatment with
trimetazidine improves EF in patients with ischemic
HF medicated with digoxin and diuretics only [8].
Thereafter, trimetazidine has been shown to improve
not only EF in both ischemic [9–15] and non-ischemic
HF [11,16], but also regional myocardial wall motion
both at rest and during dobutamine-induced stress
[9,13] as well as to enhance LV diastolic function
[15] and to reverse LV remodeling [10,11,15,17] in
patients with ischemic HF. The clinical effects of
trimetazidine include improvement in exercise tolerance, New York Heart Association (NYHA) class and
quality of life [10,12,15,17,18] in patients with
ischemic HF. Interestingly, the largest study [18],
involving 200 patients with multivessel coronary
artery disease and mildly impaired LV function (EF
<50%), demonstrated surprisingly pronounced
improvement in survival rates after two years of treatment with trimetazidine (92% with trimetazidine versus 62% with placebo, p < 0.0001).
The metabolic effects of trimetazidine include
improvement in whole-body insulin sensitivity in
patients with ischemic HF and type II diabetes treated
with diet only [17]. Furthermore, Monti et al. [19]
showed that improvement in whole-body insulin sensitivity by trimetazidine is accompanied by a metabolic shift from FFA to glucose oxidation in skeletal
muscle during euglycemic hyperinsulinemia in diabetic HF patients. Trimetazidine also improved
metabolism at the myocardial level, as evidenced
by increased myocardial phosphocreatine (PCr)-adenosine-5’-triphosphate (ATP) ratio in non-diabetic
patients with ischemic HF [12]. Additionally, there
is some evidence that trimetazidine limits inflammatory response [10] and improves endothelial function
[20] in HF patients.
Our recent positron emission tomography (PET)
study including non-diabetic patients with idiopathic
DCM demonstrated improvement in EF after three
months of treatment with trimetazidine as compared
with placebo (Fig. 1) [16]. Trimetazidine had no effect
on myocardial FFA uptake and only minor inhibitory
effects on myocardial FFA oxidation (Fig. 2),
suggesting another major mechanism contributing
to the benefit in the study. Rather, our data showed
increased whole-body insulin sensitivity in idiopathic DCM, as also found by Fragasso et al. in
diabetic ischemic HF patients [17], thus hypothetically countering the myocardial damage of insulin
resistance. Furthermore, the positive effects of trimetazidine on LV function were especially evident in
patients with a high degree of beta-blockade, strongly
suggesting an additive effect of these two modalities
of therapy.
(a)
7
6
5
4
3
2
1
0
TMZ
placebo
(b)
0.07
Beta-oxidation rate constant (1/min)
Long-term metabolic modulation
0.06
Baseline
Follow-up
−10%
P < 0.05
0.05
0.04
0.03
0.02
0.01
0
TMZ
placebo
Figure 1. Myocardial A) free fatty acid (FFA) uptake and B)
betaoxidation rate constant at baseline (blue bars) and after
three months of treatment with trimetazidine (TMZ) or
placebo (red bars) in patients with idiopathic dilated
cardiomyopathy and heart failure. Reprinted with permission from Tuunanen et al. [16].
The other agents reported in long-term metabolic
interventions are the carnitine palmitoyltransferase
(CPT)-1 blockers etomoxir and perhexiline. A small
open-label study without a control group demonstrated that three months of treatment with etomoxir
might improve EF both at rest and after maximal
exercise in patients with chronic HF [21]. However,
due to the liver toxicity of etomoxir revealed in the
Etomoxir for the Recovery of Glucose Oxidation
(ERGO) study [22], it was judged not to be a candidate
for further development for treatment of patients with
HF. A double-blind placebo-controlled study demonstrated that eight weeks of administration of perhexiline improves EF, resting and peak dobutamine stress
regional myocardial function, peak exercise oxygen
consumption, and quality of life, as well as normalizes
skeletal muscle phosphocreatine recovery after exercise in both ischemic and non-ischemic HF patients
Heart Metab. 2011; 49:17–19
New therapeutic approaches
Metabolic modulation in dilated cardiomyopathy
60
P < 0.03
Ejection fraction (%)
50
Baseline
Follow-up
40
30
20
10
0
TMZ
Placebo
Figure 2. Ejection fraction at baseline (blue bars) and after
three months treatment (red bars) with trimetazidine (TMZ)
or placebo in patients with idiopathic dilated cardiomyopathy and heart failure. Reprinted with permission from
Tuunanen et al. [16].
[23]. Furthermore, a retrospective multi-center database analysis in the United Kingdom revealed that
perhexiline therapy is well tolerated and provides
symptomatic relief in approximately 59% of patients
with chronic HF and/ or refractory angina [24]. In
contrast, a recent study [25] including 36 patients with
post-infarction HF showed that one-year administration of perhexiline has no impact on exercise
capacity and does not improve the deformation of
abnormal myocardial segments in these patients.
Summary
The concept that metabolic agents may optimize
myo-cardial energy metabolism and allow more efficient production of energy from glucose than from
FFAs is appealing. However, studies on of the effects
of metabolic modulation on patients with HF have
yielded conflicting results. At present trimetazidine, a
partial FFA betaoxidation inhibitor, appears to be the
most promising agent for the metabolic approach.
Larger clinical randomized multi-center studies are
warranted to confirm the effects of these agents on
patients with HF.
REFERENCES
1. Bersin, et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 1994; 23(7):1617–1624.
2. Cottin, et al. Glucose insulin potassium infusion improves
systolic function in patients with chronic ischemic cardiomyopathy. Eur J Heart Fail 2002; 4(2):181–184.
3. Hermann, et al. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: An open study.
Lancet 1999; 353(9161):1321–1323.
Heart Metab. 2011; 49:17–19
4. Hermann, et al. Improved systolic and diastolic myocar- dial
function with intracoronary pyruvate in patients with congestive heart failure. Eur J Heart Fail 2004; 6(2):213–218.
5. Feola, et al. The acute administration of trimetazidine modified myocardial perfusion and left ventricular function in 31
patients with ischaemic ventricular dysfunction. Int J Cardiovasc Imaging 2004; 20(4):315–320.
6. Wiggers, et al. Influence of insulin and free fatty acids on
contractile function in patients with chronically stunned and
hibernating myocardium. Am J Physiol Heart Circ Physiol
2005; 289(2):H938–H946.
7. Tuunanen, et al. Free fatty acid depletion acutely decreases
cardiac work and efficiency in cardiomyopathic heart failure.
Circulation 2006; 114(20):2130–2137.
8. Brottier, et al. Therapeutic value of a cardioprotective agent in
patients with severe ischaemic cardiomyopathy. Eur Heart J
1990; 11(3):207–212.
9. Belardinelli, et al. Effects of trimetazidine on the contrac tile
response of chronically dysfunctional myocardium to lowdose dobutamine in ischaemic cardiomyopathy. Eur Heart J
2001; 22(23):2164–2170.
10. Di Napoli, et al. Long-term cardioprotective action of trimetazidine and potential effect on the inflammatory process in
patients with ischaemic dilated cardiomyopathy. Heart 2005;
91 (2):161–165.
11. Fragasso, et al. A randomized clinical trial of trimetazi dine, a
partial free fatty acid oxidation inhibitor, in patients with heart
failure. J Am Coll Cardiol 2006; 48(5):992–998.
12. Fragasso, et al. Effects of metabolic modulation by tri metazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur
Heart J 2006; 27(8):942–948.
13. Lu, et al. Effects of trimetazidine on ischemic left ventric ular
dysfunction in patients with coronary artery disease. Am J
Cardiol 1998; 82(7):898–901.
14. Rosano, et al. Trimetazidine improves left ventricular function
in diabetic patients with coronary artery disease: A doubleblind placebo-controlled study. Cardiovasc Diabetol 2003;
2(16):1–9.
15. Vitale, et al. Trimetazidine improves left ventricular func tion
and quality of life in elderly patients with coronary artery
disease. Eur Heart J 2004; 25(20):1814–1821.
16. Tuunanen, et al. Trimetazidine, a metabolic modulator, has
cardiac and extracardiac benefits in idiopathic dilated car
diomyopathy. Circulation 2008; 118(12): 1250–1258.
17. Fragasso, et al. Short- and long-term beneficial effects of
trimetazidine in patients with diabetes and ischemic cardio
myopathy. Am Heart J 2003; 146(5):E18.
18. El-Kady, et al. Effects of trimetazidine on myocardial per
fusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: A 24-month
study. Am J Cardiovasc Drugs 2005; 5(4):271–278.
19. Monti, et al. Metabolic and endothelial effects of trimeta
zidine on forearm skeletal muscle in patients with type 2
dia betes and ischemic cardiomyopathy. Am J Physiol Endocr
Metab 2006; 290(1):E54–E59.
20. Belardinelli, et al. Trimetazidine improves endothelial function in chronic heart failure: an antioxidant effect. Eur Heart J
2007; 28:1102–1108.
21. Schmidt-Schweda, et al. First clinical trial with etomoxir in
patients with chronic congestive heart failure. Clin Sci 2000;
99(1): 27–35.
22. Holubarsh, et al. A double-blind randomized multicentre
clinical trial to evaluate the efficacy and safety of two doses
of etomoxir in comparison with placebo in patients with
moderate congestive heart failure: the ERGO (Etomoxir for
the Recovery of Glucose Oxidation) study. Clin Sci (Lond)
2007; 113(4):205–212.
23. Lee, et al. Metabolic modulation with perhexiline in chronic
heart failure: A randomized, controlled trial of short- term use
of a novel treatment. Circulation 2005; 112(21):3280–3288.
24. Phan, et al. Multi-centre experience on the use of perhexiline
in chronic heart failure and refractory angina: old drug, new
hope. Eur J Heart Fail 2009; 11(9):881–886.
25. Bansal, et al. Effects of perhexiline on myocardial defor mation
in patients with ischaemic left ventricular dysfunction. Int J
Cardiol 2010; 139(2): 107–112.
19
Focus on vastarelW mr
The clinical benefits provided by
trimetazidine (VastarelW MR) in left
ventricular dysfunction patients
Giuseppe Marazzi, Giuseppe Caminiti and Maurizio Volterrani
Center for Clinical and Basic Researc, Cardiovascular Research Unit, Department of Medical Sciences,
IRCCS San Raffaele Roma, Rome, Italy
Correspondence: Giuseppe Marazzi, Centre for Clinical and Basic Research, Cardiovascular Research Unit,
Department of Medical Sciences, IRCCS San Raffaele Roma, Rome, Italy.
E-mail: [email protected]
Abstract
Metabolic treatment involves the use of drugs that improve cardiomyocyte function. Trimetazidine
(Vastarel1 MR) is the most investigated drug in this group with a well-established role in the treatment of
chronic angina. The available data suggest that therapy combining trimetazidine and hemodynamic
drugs is effective in patients with chronic heart failure, leading to additional benefits such as
improvement in left ventricular function, exercise tolerance and quality of life. However, while
trimetazidine has shown beneficial effects on surrogate endpoints in several small trials, its effect on
cardiovascular events in chronic heart failure subjects needs to be confirmed in further large randomized
studies.
Heart Metab. 2011;49:21–24.
Keywords: Chronic heart failure, left ventricular function, metabolic therapy, trimetazidine
Introduction
Despite treatment with conventional agents, a high
proportion of patients with chronic heart failure (CHF)
and left ventricular (LV) dysfunction continue to have
symptoms and poor quality of life (QOL). Emerging
evidence suggests that chronic heart failure is an
‘‘energy-deprived’’ state in which alterations in substrate metabolism of myocardial cells contribute to the
development and maintenance of LV dysfunction [1].
Trimetazidine (TMZ) (Vastarel1 MR) belong to a
group of drugs called ‘‘metabolic modulators’’ that
benefit CHF patients by modulating cardiac metabolism without altering hemodynamics. TMZ selectively inhibits the activity of long-chain 3-ketoacyl
coenzyme A thiolase (3-KAT), the final enzyme of the
fatty acid b-oxidation path.
This leads to a change in substrate energy, partially
inhibiting b-oxidation of fatty acids and increasing
glucose oxidation, which is more efficient with
regards to adenosine- 5’-triphosphate (ATP) proHeart Metab. 2011; 49:21–24
duction per molecule of oxygen consumed. This prevents intracellular acidosis and electrolyte disorders
[2] and preserves energy necessary to sustain contractile function.
Effects on left ventricular function
Several studies published in the last decade have
demonstrated significant improvements of LV function during long-term administration of TMZ [3–8].
First observations were made in diabetic patients with
ischemic CHF. In a small crossover trial an increase of
LV ejection fraction from 36% to 45% was observed in
the TMZ group compared with placebo, while exercise time did not change between the two groups [3].
In a similar population, Rosano et al. [4] observed a
significant reduction of LV diastolic and systolic
diameters (from 63 mm to 58 mm and from 41 mm
to 34 mm respectively) and a significant increase of LV
ejection fraction (þ5.4% U) in the TMZ group, while
21
Focus on vastarelW mr
Giuseppe Marazzi, Giuseppe Caminiti and Maurizio Volterrani
no significant changes were detected in the placebo
group.
These results have been confirmed and amplified by
a larger study reporting improvements in LV volumes,
LV ejection fraction, and diastolic function in elderly
subjects with post-ischemic CHF, most of whom had
multi-vessel coronary disease and large areas of hibernating myocardium, with and without diabetes [5].
According to these data, it has been hypothesized that
benefits of TMZ on LV function are related to its
metabolic action leading to improved glucose utilization and optimization of myocardial energy metabolism even in the presence of chronic reduction of
blood flow. Consequently, the structural and metabolic
alterations of myocardial cells related to chronic ischemiamay be reversed by TMZ, with a resulting improvement of the mechanical efficiency of areas of viable
myocardium. Several studies have been published
supporting this hypothesis. In 38 patients with ischemic
LV dysfunction, Belardinelli et al. [6] evaluated the
contractile response to low-dose infusions of dobutamine at baseline and after 2 months of treatment with
TMZ or placebo. At the end of the follow-up period,
TMZ significantly improved the rest and peak systolic
wall thickening score index, LV ejection fraction, and
peak oxygen uptake. The investigators concluded that
the improvement in LV contractility was due to the
recruitment of stunned or hibernating cells after
optimal oxygen utilization by these cells. El-Kady
et al. [7] obtained a similar result using gated single
photon emission computerized tomography. In this
study, there was a significant improvement of summed
stress and rest scores, systolic wall thickness, and wall
motion score index with TMZ compared with placebo.
On the other hand the benefits of TMZ on LV function
seem not to be limited to the group of CHF of ischemic
origin. In a study by Fragasso et al. [8], ejection fraction
significantly increased in patients treated with TMZ,
regardless of the etiology of CHF. Tuunanen et al. [9]
evaluated 19 patients with idiopathic dilated cardiomyopathy randomized to single-blind TMZ or placebo
for 3 months. Interestingly in the TMZ group, EF was
increased by 15% during the treatment, whereas in the
placebo group, it decreased by 17%.
Exercise tolerance
The usefulness of TMZ to improve the functional
status and the exercise capacity of patients with
ischemic cardiomyopathy has been assessed in several studies [7,9–12]. Improvements in exercise
capacity have been evaluated by a six-minute walking
test, change in New York Heart Association (NYHA)
functional class, or an ergometric test.
In the study of Brottier et al. [3], 20 patients were
randomized to either placebo or TMZ. At 6-month
22
follow-up, all patients on TMZ reported a considerable clinical improvement in symptoms such as
angina and dyspnea, together with a 9% increase of
LV ejection fraction. More recently, an Italian study
obtained a similar result [5], with a reduced incidence
of angina episodes and improvement in NYHA class
after 6 month in the TMZ group compared with
placebo.
Another trial enlisted 61 patients with a past history
of myocardial infarction, a depressed LV ejection
fraction (<40%), and coronary anatomy unsuitable
for revascularization [10]. The authors demonstrated a
significant improvement in functional status (evaluated by NYHA functional class) after 18 months of
treatment with TMZ administered at standard doses.
El-Kady et al. further confirmed these findings [7] in a
larger study involving 200 patients with multi-vessel
coronary artery disease and impaired LV function (LV
ejection fraction <50%). Patients were randomized to
TMZ or placebo in an open-label design, and after 24
months of treatment, the patients receiving TMZ had a
significant reduction in the frequency of anginal episodes per week, a reduction in the weekly consumption of nitrate tablets, and a significant increase in
treadmill exercise test duration (þ75 s with TMZ versus þ25 s with placebo, p < 0.01).
In the study by Fragasso et al. [8], TMZ was associated with significant improvements in functional
capacity assessed by ergometric test. The authors
demonstrated a significant increase of peak metabolic
equivalent system (from 7.4 to 8.8, p ¼ 0.04) and total
exercise time (from 314 s to 402 s, p ¼ 0.04) in the
TMZ group. Conversely, these parameters remained
stable in the conventional therapy group. At the same
time in the TMZ group there was a significant
reduction in plasma natriuretic peptide levels compared with conventional therapy. Interestingly these
improvements were equally apparent in patients with
non-ischemic and ischemic cardiomyopathy. In
another study [11], conducted in patients with stable
ischemic CHF, the distance walked in 6 minutes
significantly improved in the TMZ group, from 355
m at baseline to 417 m at the end of follow-up.
Conversely, the distance walked decreased in the
placebo group.
The improvement in exercise tolerance with TMZ
may be secondary to its effects on LV systolic and
diastolic performance. However, in the study of Di
Napoli et al. [11], there was no significant change on
LV diastolic and systolic diameter after 6 months of
treatment in the TMZ group compared to placebo.
Therefore, an additional mechanism of action such as
a direct effect of TMZ on skeletal muscle should be
taken into account. A recent study by Monti et al. [12]
demonstrated that TMZ treatment in diabetic patients
with ischemic cardiomyopathy improves forearm
skeletal muscle metabolism.
Heart Metab. 2011; 49:21–24
Focus on vastarelW mr
The clinical benefits provided by trimetazidine (Vastarel j MR) in left ventricular dysfunction patients
8
Baseline
Visual analog scale
7
6 months
6
5
4
3
2
1
0
Trimetazidine
Placebo
Figure 1. Changes (6 months vs. baseline) in visual analog
scale observed in the TMZ and placebo groups.
Quality of life
Currently, few data are available on the impact of
TMZ on QOL. In the study of Vitale et al. [5], QOL,
assessed by the visual analogue scale, significantly
improved in all patients treated with TMZ, while it
remained unchanged in those allocated to placebo.
Fragasso et al. [8] assessed QOL with two tests: a
visual analogue scale measuring the general wellbeing and an LV dysfunction questionnaire (LVD36) in order to measure the impact of LV dysfunction
on daily life. The authors showed a significant
decrease in LVD-36 score (from 18 to 15,
p ¼ 0.038) and no significant increase of visual
analogue scale, which went from 63% to 71%
( p ¼ 0.07). More recently, we investigated the effects
of TMZ on different areas of QOL in elderly patients
with ischemic dilated cardiomyopathy by using a selfadministered questionnaire, the MacNew Quality of
Life After Myocardial Infarction. We showed a significant improvement in physical and social areas in
patients randomized to TMZ, but not in those allocated to placebo (Fig. 1) [13]. Benefits of TMZ on QOL
could be related to several factors. First, in patients
with ischemic CHF and recurrent angina, the
increased well-being could be a consequence of its
anti-angina effects. Moreover, the improvement in
exercise tolerance and a direct action on skeletal
muscle mass could play a role [14].
Additional benefits
According to some recent studies, TMZ seems to have
a broader spectrum of action at cardiac level than
previously thought. TMZ improves several parameters
related with the outcome of CHF patients. Gunes et al.
[15] demonstrated that the addition of TMZ to optimal
medical therapy in patients with CHF of ischemic
Heart Metab. 2011; 49:21–24
origin might improve heart-rate variability that is
related to the improvement of LV ejection fraction.
Cera et al. [16] showed that long-term treatment with
TMZ can yield a significant reduction of Tpeak–
Tend-d index, a noninvasive marker of dispersion of
ventricular repolarization in post-ischemic CHF
patients. A study by Belardinelli et al. [17] demonstrated that TMZ improved endothelium-dependent
relaxation (EDR) in patients with ischemic cardiomyopathy. The authors postulated that EDR improvement
was significantly related to an antioxidant effect of
TMZ because they observed a concomitant reduction
in plasma levels of some malondialdehyde and lipid
hydroperoxides. Taken together these studies suggest
that TMZ has additional mechanisms of action in
CHF subjects.
Conclusion
The available data suggest that therapy combining
TMZ and hemodynamic drugs is effective in patients
with CHF, leading to additional benefits such as
improvement in LV function, exercise tolerance,
and QOL. TMZ has shown beneficial effects on surrogate endpoints in several small trials. However,
further large randomized studies are needed to answer
the question of whether these effects could translate
into decreased morbidity and mortality.
REFERENCES
1. Stanley WC, Recchi FA, Lopaschuk GD. Myocardial substrate
metabolism in the normal and failing heart. Physiol Rev.
2005;85:1093–1129.
2. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal
drug trimetazidine shifts cardiac energy metabolism from fatty
acid oxidation to glucose oxidation by inhibiting mitochondrial longchain 3-ketoacyl coenzyme A thiolase. Circ Res.
2000;86:580–588.
3. Brottier L, Barat JL, Combe C, Boussens B, Bonnet J, Bricaud H.
Therapeutic value of a cardioprotective agent in patients with
severe ischemic cardiomyopathy. Eur Heart J. 1990;11:207–
212.
4. Rosano GM, Vitale C, Sposato B, et al. Trimetazidine improves
left ventricular function in diabetic patients with coronary
artery disease. A double-blind, placebo-controlled study. Cardiovasc Diabetol. 2003;2:1–9.
5. Vitale C, Wajngaten M, Sposato B, Gebara O, Rossini P,
Fini M, Volterrani M, Rosano GM. Trimetazidine improves
left ventricular function and quality of life in elderly patients
with coronary artery disease. Eur Heart J. 2004;25:1814–
1821.
6. Belardinelli R, Cianci G, Gigli M, et al. Effects of trimetazidine
on myocardial perfusion and left ventricular systolic function
in type 2 diabetic patients with ischemic cardiomyopathy.
Cardiovasc Pharmacol. 2008;51:611–615.
7. El-Kady T, El Sabban K, Gabali M, et al. Effects of trimetazidine
on myocardial perfusion and the contractile response of
chronically dysfunctional myocardium in ischemic cardiomyopathy: a 24-month study. Am J Cardiovasc Drugs.
2005;5:271–278.
8. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical
trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with systolic dysfunction heart failure. J Am
Coll Cardiol. 2006;48:992–998.
23
Focus on vastarelW mr
Giuseppe Marazzi, Giuseppe Caminiti and Maurizio Volterrani
9. Tuunanen H, Engblom E, Naum A, et al. Trimetazidine, a
metabolic modulator, has cardiac and extracardiac benefits in
idiopathic dilated cardiomyopathy. Circulation. 2008;118:
1250–1258.
10. Di Napoli P, Taccardi AA, Barsotti A. Long-term cardioprotective action of trimetazidine and potential effect on the
inflammatory process in patients with ischaemic dilated
cardiomyopathy. Heart. 2005;91:161–165.
11. Di Napoli P, Di Giovanni P, Gaeta MA, D’Apolito G, Barsotti
A. Beneficial effects of trimetazidine treatment on exercise
tolerance and B-type natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy.
Am Heart J. 2007;154:602e1–602e5.
12. Monti LD, Setola E, Fragasso G, et al. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in
patients with type 2 diabetes and ischemic cardiomyopathy.
Am J Physiol Endocrinol Metab. 2006;290:E54–E59.
24
13. Marazzi G, Gebara O, Vitale C, Caminiti G, Wajngarten M,
Volterrani M, Ramires JA, Rosano G, Fini M. Effect of trimetazidine on quality of life in elderly patients with ischemic
dilated cardiomyopathy. Adv Ther. 2009;26:455–461.
14. Emre M, Karayaylali I, San M, Demirkazik A, Kavak S. The
acute effect of trimetazidine on the high frequency fatigue in
the isolated rat diaphragm muscle. Arch Pharm Res. 2004;27:
646–652.
15. Gunes Y, Guntekin U, Tuncer M, Sahin M. The effects of
trimetazidine on heart rate variability in patients with heart
failure. Arq Bras Cardiol. 2009;93:154–158.
16. Cera M, Salerno A, Fragasso G, et al. Beneficial electrophysiological effects of trimetazidine in patients with post-ischemic
chronic heart failure. J Cardiovasc Pharm Ther. 2010;15:24–30.
17. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine
improves endothelial dysfunction in chronic heart failure: an
antioxidant effect. Eur Heart J. 2007;28 (9):1102–1108.
Heart Metab. 2011; 49:21–24
Case report
Response to cardiac
resynchronization therapy resulting
from an upgrade to dual-site left
ventricular pacing
M.R. Ginks, S.G. Duckett, G.S. Carr-White and C.A. Rinaldi
Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK
Correspondence: Dr. C.A. Rinaldi, Cardiac Department, St Thomas’ Hospital, London SE1 7EH, UK.
Tel: +44 207 188 9257;
fax: +44 207 188 2354; e-mail: [email protected]
Abstract
A 56-year-old man with ischemic dilated cardiomyopathy underwent a secondary prevention biventricular implantable cardioverter defibrillator (ICD) implant. He did not respond symptomatically despite a
good radiographic position of the left ventricular (LV) lead. On the basis of an acute hemodynamic study,
a second LV lead was implanted, resulting in a good clinical response from dual-site LV pacing.
Heart Metab. 2011;49:25–28.
Keywords: Cardiac resynchronization therapy, multi-site pacing, non-responder
Introduction
Cardiac resynchronization therapy (CRT) has been
shown in large randomized trials to confer benefit
in both symptoms and prognosis in selected patients
with heart failure [1–5]. However, approximately one
third of patients do not derive clear clinical benefit
(while a similar proportion of matched controls
improve without CRT [1]). One reason for this is
positioning of the left ventricular (LV) lead in a region
of myocardial scar [6–8]. Here we present a case of a
patient who did not respond to CRT initially but who
improved symptomatically following the implantation
of a second LV lead and multi-site LV pacing.
History
A 56-year-old male presented with a non-ST segment
elevation myocardial infarction. Coronary angiography showed occlusions in the left anterior descending
and circumflex coronary arteries and a patent right
Heart Metab. 2011; 49:25–28
coronary artery. A delayed enhancement cardiac
magnetic resonance imaging (MRI) scan showed significant LV systolic impairment and a complex pattern
of largely subendocardial infarction (Figure 1).
Left ventricular ejection fraction (LVEF) was 16%.
He underwent coronary artery bypass grafting with
three saphenous vein grafts. Following a cardiac arrest
secondary to ventricular fibrillation one month postoperatively, he received a biventricular implantable
cardioverter defi-brillator (ICD). When seen in the
outpatient clinic two months later, he remained short
of breath with minimal exertion, with no improvement since device implantation. He remained on
maximal tolerated doses of appropriate heart failure
medication. Echocardiographic optimization of atrioventricular (AV) and inter-ventricular (VV) delays was
performed at one and three months.
At this point the device was delivering biventricular
pacing 98% of the time. LVEF was noted to be 18%.
However, he remained in New York Heart Association (NYHA) class III. He went on to have assessment
with three-dimensional echocardiography, which
25
Case report
Ginks et al.
Figure 1. Short axis stack of delayed enhancement cardiac magnetic resonance images from apex (top left) to base (bottom
right).
(ii) exclusion of other conditions that may be underlying symptoms, (iii) optimization of device settings
has been performed, and (iv) that a high percentage of
biventricular pacing is being delivered.
This case raises several interesting questions. First,
why did this patient not respond to CRT? What is the
mechanism of benefit from the implantation of a
second LV lead? Is this a function of multi-site pacing
or has the second lead better avoided the subendocardial scar? Should this approach be considered at
the initial procedure? Should it be applied to all non-
20
15
% Change dP/dt from intrinsic
gave a systolic dyssynchrony index of 11%, with basal
infero-posterior and lateral LV segments showing the
latest volume change. Cardio-pulmonary exercise
testing (CPET) was performed and the maximal myocardial oxygen consumption (MVO2) was 9.6 ml/kg/
minute (41 % predicted). The decision was made to
perform an acute hemodynamic assessment with LV
stimulation at different sites within the coronary veins,
with a view to implant a second LV lead should this
give rise to significant acute hemodynamic improvement. This was performed 10 months after the initial
CRT defibrillator implant. A RadiTM wire (Radi
Medical Systems, Uppsala, Sweden) was passed to
the LV cavity using a 5 French femoral arterial sheath.
The acute hemodynamic response to different pacing
modes is shown in Figure 2.
On the basis of these findings, a second LV lead was
implanted in a posterior vein and was connected to a
new device along with the existing LV lead using a
bifurcating adapter to the LV port (Figure 3).
At six-month review he had improved symptomatically, from NYHA class III to NYHA class II. CPET was
repeated with improvement in MVO2 to 49% predicted. LVEF had improved to 23%.
10
5
0
−5
−10
−15
−20
−25
Discussion
We have presented a case of a clinical non-responder
to CRT who improved following the addition of a
second LVlead, in line with the findings of acute
hemodynamic assessment. The optimal strategy for
clinical non-responders is not clear. Initial steps
should ensure: (i) compliance with appropriate heart
failure medications and optimization of fluid status,
26
−30
RV
LV old
BIV old
LV new
BIV new
2 site LV
Pacing configuration
Figure 2. Percentage change in acute hemodynamics from
intrinsic rhythm in different pacing configurations. RV right
ventricular pacing, LV old pre-existing left ventricular (LV)
lead, BIV old conventional cardiac resynchronization
therapy (CRT) using previously implanted leads, LV new
newly sited LV lead, BIV new conventional CRT using newly
sited LV lead, 2 site LV dual-site pacing using old and new
LV leads together. All modes used DDD pacing.
Heart Metab. 2011; 49:25–28
Case report
Response to cardiac resynchronization therapy resulting from an upgrade to dual-site left ventricular
pacing
Figure 3. Upper images: Posterior anterior (PA) and lateral chest X-rays of lead positions following initial implant procedure.
Lower images: PA and lateral chest X-rays following upgrade with addition of second left ventricular lead.
responders? What is the role of acute hemodynamic
assessment?
In this case it appears that the initial LV lead may
have been overlying a region of subendocardial scar
in the postero-lateral wall. This may not be apparent at
the time of the implant procedure, as capture
threshold may still be normal. If a lead is overlying
an area of subendocardial scar, it may capture but give
rise to a lesser degree of clinical benefit. Overlay
techniques and image-guided implant technologies
are in development and may have a role in the future,
to facilitate LV lead delivery away from areas of
myocardial scar.
Intuitively, a second LV lead is more likely to be
beneficial if the initial lead was not optimally positioned [9]. Multi-site pacing may enable us to pace
more effectively around areas of scar. Furthermore, in
a dilated left ventricle, it may be that pacing from
several different loci will facilitate greater reversal of
dyssyn-chrony. However, studies examining the acute
hemo-dynamic response to single versus dual-site LV
pacing in CRT patients have given conflicting results
Heart Metab. 2011; 49:25–28
[9,10]. Furthermore, despite the fact that acute hemodynamic response has been widely used as a marker
of response to CRT, the evidence that this correlates
with long-term response is very limited [11].
Two groups have published data regarding longterm response to dual-site LV pacing in CRT. The
TRIP-HF study assessed the effects of dual-site LV
pacing in patients with atrial fibrillation, diminished
LVEF and a bradycardia-related pacing indication
[12]. In this cohort, dual-site LV pacing in conjunction
with CRT gave rise to significant improvements over
conventional CRT in reverse LV remodeling, albeit not
in symptomatic response or exercise capacity. Lenarczyk et al. have also shown higher response rates to
multi-site LV pacing, but this was not in the form of a
randomized trial [13]. The implantation of two LV
leads is feasible but technically challenging, and in
the case of patients in sinus rhythm necessitates the
use of a bifurcating adapter, which leads to elevated
capture thresholds [14] and hence reduced device
longevity. However, dual-site pacing represents
an alternative approach in the context of clinical
27
Case report
Ginks et al.
non-response to CRT. Alternative strategies include
the surgical implantation of an epicardial LV lead via
mini-thoracotomy [15], or endocardial LV stimulation via a trans-septal [16,17] or apical approach
[18].
Conclusion
In this case, an upgrade from single-site to dual-site LV
pacing resulted in improved clinical response to CRT.
This represents one approach to CRT non-responders.
Randomized studies are needed to establish the best
approach to this challenge.
REFERENCES
1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR,
Loh E, Kocovic DZ, et al. Cardiac resynchronization in chronic
heart failure. N Engl J Med. 2002;346 (24):1845–1853.
2. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De
Marco T, Carson P, et al. Cardiac-resynchronization therapy
with or without an implantable defibrillator in advanced
chronic heart failure. N Engl J Med. 2004;350 (21):2140–
2150.
3. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R,
Wilkoff B, Canby RC, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced
chronic heart failure: the MIRACLE ICD trial. JAMA. 2003;289
(20):2685–2694.
4. Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Tavazzi L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N
Engl J Med. 2005;352 (15):1539–1549.
5. Linde C, Abraham WT, Gold MR, John Sutton St, Ghio M,
Daubert C S. Randomized trial of cardiac resynchronization in
mildly symptomatic heart failure patients and in asymptomatic
patients with left ventricular dysfunction and previous heart
failure symptoms. J Am Coll Cardiol. 2008;52 (23):1834–1843.
6. White JA, Yee R, Yuan X, Krahn A, Skanes A, Parker M, Klein
G, et al. Delayed enhancement magnetic resonance imaging
predicts response to cardiac resynchronization therapy in
patients with intraventricular dyssynchrony. J Am Coll Cardiol.
2006;48 (10):1953–1960.
28
7. Chalil S, Stegemann B, Muhyaldeen SA, Khadjooi K, Foley
PW, Smith RE, Leyva F. Effect of posterolateral left ventricular
scar on mortality and morbidity following cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2007;30
(10):1201–1209.
8. Bleeker GB, Kaandorp TAM, Lamb HJ, Boersma E, Steendijk P,
de Roos A, van der Wall EE, et al. Effect of posterolateral scar
tissue on clinical and echocardiographic improvement after
cardiac resynchronization therapy. Circulation. 2006;113
(7):969–976.
9. Padeletti L, Colella A, Michelucci A, Pieragnoli P, Ricciardi G,
Porciani MC, Tronconi F, et al. Dual-site left ventricular
cardiac resynchronization therapy. Am J Cardiol. 2008;102
(12):1687–1692.
10. Pappone C, Rosanio S, Oreto G, Tocchi M, Gulletta S, Salvati
A, Dicandia C, et al. Cardiac pacing in heart failure patients
with left bundle branch block: impact of pacing site for
optimizing left ventricular resynchronization. Ital Heart J.
2000;1 (7):464–469.
11. Tournoux FB, Alabiad C, Fan D, Chen AA, Chaput M, Heist
EK, Mela T, et al. Echocardiographic measures of acute
haemodynamic response after cardiac resynchroniza-tion
therapy predict long-term clinical outcome. Eur Heart J.
2007;28 (9):1143–1148.
12. Leclercq C, Gadler F, Kranig W, Ellery S, Gras D, Lazarus A,
Clémenty J, et al. A randomized comparison of triple-site versus
dual-site ventricular stimulation in patients with congestive
heart failure. J Am Coll Cardiol. 2008;51 (15):1455–1462.
13. Lenarczyk R, Kowalski O, Kukulski T, Pruszkowska-Skrzep P,
Sokal A, Szulik M, Zielinska T, et al. Mid-term outcomes of
triple-site vs. conventional cardiac resynchronization therapy:
A preliminary study. Int J Cardiol. 2009;133 (1):87–94.
14. Rho RW, Patel VV, Gerstenfeld EP, Dixit S, Poku JW, Ross HM,
Callans D, et al. Elevations in ventricular pacing threshold
with the use of the y adaptor. Pacing Clin Electrophysiol.
2003;26 (3):747–751.
15. Lehr EJ, Ye C, Wang S. Left ventricular epicardial lead implantation via left minithoracotomy. Thorac cardiovasc Surg.
2009;57 (06):329–332.
16. Jais P, Douard H, Shah DC, Barold S, Barat JL, Clementy J.
Endocardial biventricular pacing. Pacing Clin Electrophysiol.
1998;21 (11 Pt 1):2128–2131.
17. Garrigue S, Jaı̈s P, Espil G, Labeque J-N, Hocini M, Shah DC,
Haı̈ssaguerre M, et al. Comparison of chronic biventricular
pacing between epicardial and endocardial left ventricular
stimulation using Doppler tissue imaging in patients with heart
failure. Am J Cardiol. 2001;88 (8):858–862.
18. Kassai I, Foldesi C, Szekely A, Szili-Torok T. New method for
cardiac resynchronization therapy: transapical endocardial
lead implantation for left ventricular free wall pacing. Europace. 2008;10 (7):882–883.
Heart Metab. 2011; 49:25–28
Refresher corner
Cardiac amyloidosis
Pascal Schmidheiny and Otto M. Hess
Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
Correspondence: Otto M. Hess, Professor of Cardiology, Swiss Cardiovascular Center, University Hospital,
CH-3010 Bern, Switzerland. Tel.: +41 31 632 9653;
fax: +41 31 632 4771
Abstract
Amyloidosis is a family of disorders of the immune system in which one or more organs in the body
accumulate amyloid. There are four different forms of amyloidosis: systemic amyloid light chain (AL)
amyloidosis, amyloid A (AA) amyloidosis, hereditary, and senile amyloidosis. The abnormal proteins
can be found as Bence-Jones proteins in urine mainly in patients with light chain (AL) amyloidosis.
Cardiac amyloidosis is a myocardial disease characterized by extracellular amyloid infiltration
throughout the heart and is an important cause of progressive heart failure (restrictive
cardiomyopathy) with a wide spectrum of clinical manifestations. Typically, cardiac arrhythmias
and diastolic heart failure occur, followed by sudden cardiac death in many cases. The diagnosis of
cardiac amyloidosis is a combination of clinical, electrocardiographic and imaging methods, but
definite diagnosis is based on endomyocardial biopsy. Prognosis of AL amyloidosis is poor and treatment
is often a challenge, although a combination of high-dose chemotherapy, autologous stem cell
transplantation and heart transplantation have shown survival benefits. Reactive AA amyloidosis
may respond to anti-inflammatory and immunosuppressive drugs.
Heart Metab. 2011;49:29–31.
Keywords: Autologous stem cell transplantation, cardiac amyloidosis, cardiac arrhythmias,
endomyocardial biopsy, restrictive cardiomyopathy
Background
Amyloidosis is a family of disorders of the immune
system in which one or more organ systems in the
body accumulate deposits of abnormal proteins [1].
The name ‘‘amyloidosis’’ was first used more than 100
years ago, yet only within the past 25 years have
physicians understood the specific make-up and
structure of amyloid protein. Amyloidosis represents
a diverse group of diseases characterized by the
common factor of deposition of twisted ß-pleated
sheet fibrils (amyloid) formed as a result of the misfolding of various proteins produced in several different pathological states [1].
The various forms of amyloidosis are classified by
the composition of the amyloid fibril. The three major
types of amyloidosis are different from each other.
Amyloid light chain (AL) amyloidosis (also known as
primary amyloidosis) is a plasma cell disorder that
originates in the bone marrow. It is the most common
Heart Metab. 2011; 49:29–31
type of amyloidosis and occasionally occurs with
multiple myeloma. The deposits in this type of the
disease are made up of immunoglobulin light chain
proteins, which may be deposited in any bodily
tissues or organs. The disease results when enough
amyloid protein builds up in one or more organs to
cause the organ(s) to malfunction. The heart, kidneys,
nervous system, and gastrointestinal tract are most
often affected. Secondary amyloidosis is caused by a
chronic infection or inflammatory disease such as
rheumatoid arthritis, familial Mediterranean fever,
osteomyelitis, or granulomatous ilei-tis. The deposits
in this type of the disease are made up of a protein
called the amyloid A (AA) protein. Familial amyloidosis is the only type of amyloidosis that is inherited.
The deposits in this type are most commonly made up
of the transthyretin protein, which is manufactured in
the liver [1].
In elderly persons, cardiac amyloidosis is an important cause of progressive heart failure and refractory
29
Refresher corner
Pascal Schmidheiny &Otto M. Hess
arrhythmia of obscure origin [2]. The average survival
time of amyloid heart disease after the onset of symptoms is less than three years. Clinically, amyloid heart
disease may mimic constrictive pericarditis, coronary
artery disease, valvular heart disease, and hypertrophic or congestive cardiomyopathy.
Cardiac amyloidosis belongs to the family of restrictive cardiomyopathies. Restrictive cardiomyopathy is
characterized by abnormal diastolic function with
either thickened or rigid ventricular walls leading to
elevated filling pressures of the left- or right-sided
cardiac chambers. The classification of restrictive
cardiomyopathy is based on etiological and clinical
findings. Primary forms are Löffler’s endocarditis and
endomyocardial fibrosis. To the secondary forms
belong infiltrative diseases, storage diseases, and
post-radiation disease. Secondary forms are classified
by the specific type of material deposition (infiltration), storage, or replacement.
conduction system, and/or vessels, with consequent
clinical manifestations.
Clinical presentation of cardiac amyloidosis
Clinical suspicion of cardiac amyloidosis arises in the
following circumstances: cardiac disease in the setting of established AL amyloidosis and/or plasma cell
dyscrasia; ventricular dysfunction or arrhythmia and
longstanding connective tissue disease or other
chronic inflammatory disorder; any patient with
restrictive cardiomyopathy of unknown etiology; left
ventricular (LV) hypertrophy on echocardiography but
a low-voltage electrocardiogram (ECG); and congestive heart failure of unknown origin refractory to
standard medical therapy.
Diagnosis of cardiac amyloidosis
Acquired amyloidosis
In primary (or AL) amyloidosis, the fibrillar protein is
composed of K and l immunoglobulin light chains,
produced by a proliferating clone of plasma cells [3].
These immunoglobulins can be found in urine as
Bence-Jones proteins. A systemic disease that tends
to follow a rapidly progressive course, primary amyloidosis is often seen in conjunction with plasma cell
dyscrasia such as multiple myeloma or monoclonal
gammopathies. Secondary (or AA) amyloidosis occurs
in association with chronic inflammatory disorders
such as rheumatoid arthritis, ankylosing spondylitis,
and familial Mediterranean fever. Nephrotic syndrome and renal failure are common at presentation.
The preliminary work-up for a patient with suspected
cardiac amyloidosis includes a 12-lead ECG and twodimensional echocardiography, with or without
Holter monitoring [5]. A low-voltage ECG with
increased sep-tal and posterior LV wall thickness on
echocardiography is specific for cardiac amyloidosis
on non-invasive testing [5]. Other investigations that
are of value include protein electrophoresis and
genetic testing. A confirmatory biopsy (multiple specimens) is needed for diagnosis (Figure 1), since cardiac
amyloidosis has no pathognomonic symptoms
and signs, nor diagnostic findings. However, with
advances in imaging, cardiovascular magnetic resonance (Figure 2) may prove to have value in diagnosis,
treatment, and follow-up in cardiac amyloidosis [6].
Hereditary amyloidosis
Management and outcome
Hereditary amyloidosis is the result of a mutation in
one of a number of fibril precursor proteins, including
transthyretin, apolipoproteinA-I or A-II, lysozyme,fibrinogen Aa chain, gelsolin, and cystatin C. The
phenotype varies according to the protein affected.
Autosomal-dominant inheritance is typical.
Treatment is directed at both the underlying disease
process and the cardiac complications. Systemic
therapy is type-specific (i.e., chemotherapy), underscoring the importance of determining the precise
etiology of amyloidosis [7]. Prognosis of AL amyloidosis is poor; however, in subgroups of patients,
combined treatment with high-dose melphalan and
autologous stem cell transplantation has resulted in
hematological remission, improved five-year survival,
and reversal of amyloid-related disease [5]. In contrast, senile systemic amyloidosis is characterized by
slow progression not requiring alkylating agents [8].
Reactive AA amyloidosis may respond to anti-inflammatory and immunosuppressive drugs that reduce
production of acute-phase reactant serum amyloid
A protein. Ventricular dysfunction secondary to
amyloidosis may be difficult to treat. Diuretics and
Cardiovascular involvement
Amyloidosis frequently affects the heart. The propensity for cardiovascular involvement is greatest in
primary, senile, and certain hereditary forms of the
disease. Cardiac disease is relatively less common in
AA amyloidosis, but is a marker of unfavorable prognosis when present [4]. Amyloid fibrils may be deposited in the myocardium, papillary muscles, valves,
30
Heart Metab. 2011; 49:29–31
Refresher corner
Cardiac amyloidosis
Figure 1. Subendocardial biopsy with Kongo red-positive extracellular amorphous deposits (arrow, panel a), disrupting the
organisation of the heart muscle. On the right (panel b) with optical double refraction, amyloid deposits partly with a
characteristic blue color (arrowhead). Photograph provided by Waschkowski G, MD, Institute of Pathology, University of
Bern.
vasodilators are used judiciously owing to the risk of
hypotension with excessive falls in preload. Digoxin is
contraindicated because it binds to amyloid fibrils and
toxicity may develop at ordinary therapeutic doses.
Complex ventricular arrhythmia has been documented in patients with cardiac amyloidosis and may be a
predictor of sudden cardiac death. Beta blockers are
administered with caution as they may promote atrio-
Figure 2. Short-axis view: diffuse, circumferential enhancement of the myocardium (asterisks) in late gadolinium CMR
picture. Photograph provided by Wahl A, MD, Department
of Cardiology, University of Bern.
Heart Metab. 2011; 49:29–31
ventricular (AV) block and their negative inotropism is
often poorly tolerated. Implantation of a permanent
pacemaker is indicated in patients with symptomatic
bradyarrhyth-mias or complete AV block.
REFERENCES
1. Hess OM, McKenna W, Schultheiss HP. (2009). Myocardial
Disease (Chapter 18). In: Camm AJ, Lüscher TF, Serruys PW
(eds), ESC Textbook of Cardiovascular Medicine, 2nd edn.
Oxford University Press, Oxford, 665–716
2. Gertz MA, Rajkumar SV. Primary systemic amyloidosis. Curr
Treat Options Oncol. 2002;3:261–271.
3. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA,
Gillmore JD, Pepys MB, Hawkins PN. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med.
2002;346:1786–1791.
4. Tanaka F, Migita K, Honda S, Fukuda T, Mine M, Nakamura T,
Yamasaki S, Ida H, Kawakami A, Origuchi T, Eguchi K. Clinical
outcome and survival of secondary (AA) amyloidosis. Clin Exp
Rheumatol. 2003;21:343–346.
5. Rahman JE, Helou EF, Gelzer-Bell R, Thompson RE, Kuo C,
Rodriguez R, Hare JM, Baughmann KL, Kasper EK. Noninvasive
diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll
Cardiol. 2004;43:410–415.
6. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I,
Sheppard MN, Poole-Wilson PA, Hawkins PN, Pennell DJ.
Cardiovascular magnetic resonance in cardiac amyloidosis.
Circulation. 2005;111:186–193.
7. Guidelines Working Group of UK Myeloma Forum; British
Committee for Standards in Haematology, British Society
for Haematology (2004) Guidelines on the diagnosis and
management of AL amyloidosis. Br J Haematol 125:681–
700
8. Kyle RA, Spittell PC, Gertz MA, Li CY, Edwards WD, Olson LJ,
Thibodeau SN. The premortem recognition of systemic senile
amyloidosis with cardiac involvement. Am J Med. 1996;101:
395–400.
31
Hot topics
Low diagnostic yield of coronary
angiography or not catching up with
heart disease pathophysiology?
Alda Huqi
Cardiovascular Medicine Division, Cardio Thoracic Department, University of Pisa, Pisa, Italy
Correspondence: Dr Alda Huqi, Cardiovascular Medicine Division, Cardio Thoracic Department, University of
Pisa, Via Paradisa, 2 56100 Pisa, Italy.
Tel: +39 32972 56426; e-mail: [email protected]
Fifty years after its introduction, coronary angiography
remains the reference technique to assess coronary
anatomy. Its impact on the diagnosis and management of ischemic heart disease (IHD) is corroborated
by the fact that coronary angiography is still essential
for aortocoronary bypass grafting and for percutaneous coronary interventions.
Given the invasiveness and the measurable risk
associated with coronary angiography, noninvasive
tests are widely used to select candidates for angiography and for therapy planning. The large majority of
the noninvasive tests are focused on ischemia detection and left ventricular (LV) function assessment.
Latest additions are more focused on coronary
anatomy. In the early phase of application, all tests
were extensively compared with coronary angiography as the gold standard and achieved reasonable
sensitivity, specificity, and overall diagnostic
accuracy. Heated debates and large trials have
addressed the question of which test is the best, but
final conclusions have not yet been reached and
probably will never be. The main reasons for this
are inconsistencies in the results of different tests in
the same patient and the common assumption that
coronary stenosis always implies myocardial ischemia. The frequent mismatch between noninvasive
tests and coronary anatomy are justified by generic
inaccuracies of the noninvasive tools or inaccurate
measurement of stenosis severity.
Recently, a study with a catchy title— ‘‘Low diagnostic yield of coronary angiography’’ [1]— was
published in the New England Journal of Medicine.
Data were obtained from a large cardiac-catheterization registry to assess the effectiveness of current
practices in enhancing the yield of diagnostic
cardiac catheterization as measured by the prevalence of obstructive coronary artery disease (CAD).
The study enrolled 397,954 patients without known
CAD undergoing cardiac catheterization and noninvasive testing was performed in 83.9% of them. A
Heart Metab. 2011; 49:33–35
positive test result was recorded in 68.6% of all the
patients in the cohort. Surprisingly enough, only a
minority of patients (37.6%) had obstructive CAD.
Patients with higher Framingham Risk Score (FRS)
were more likely to have obstructive CAD, but the
results of the noninvasive testing had a limited additive value for presence of obstructive CAD. In light of
such results, the authors concluded that ‘‘better strategies for risk stratification, in order to increase
the diagnostic yield of cardiac catheterization are
needed.’’
The claim that there is ‘‘a need for better strategies
to risk stratify patients’’ represents just another coupler in the scaffold around the rising use of cardiac
imaging modalities. Between 1993 and 2001, stress
imaging (particularly stress gated single photon
emission computed tomography [SPECT] imaging
and stress echocardiography) presented an annual
increase rate of 6%, which is far in excess with
respect to the increase in cardiac catheterization,
revascularization, or acute myocardial infarction
[2]. More recently, morphologic imaging techniques
such as magnetic resonance imaging (MRI) and computed tomography coronary angiography (CTCA)
have become a more prominent component of the
increase. However, this increasing use has also
generated continuous disputation, mainly related to
two worrisome issues.
Inconsistencies among different techniques
and rate of ‘‘false positive’’ and ‘‘false
negative’’ results with respect to the ‘‘gold
standard’’ for coronary atherosclerosis:
invasive coronary angiography (ICA)
A patient with angina and documented ischemia is
classified as a patient with IHD only when coronary
stenosis can be documented. A test result is rated as
‘‘false positive’’ even in the presence of symptoms and
33
Hot topics
signs of myocardial ischemia if no obstructive CAD
can be detected at the control ICA. Conversely, a test
result is rated as ‘‘false negative’’ if, in the absence of
symptoms and signs of myocardial ischemia, obstructive CAD is detected at the control ICA. Despite
continuous technical progress, differences in CAD
detection continue to exist among the various techniques. The major gap is generally found between
functional and morphological tests, often without any
geographical association between the distribution of
coronary plaque and perfusion defects [3]. Unfortunately, this issue does not seem to bother physicians,
who are rather concentrated on improving their own
technique, in order to ‘‘unmask’’ as much CAD as
they can.
This behavior is unfortunately driving us into a blind
alley. Although there are several technical challenges
related to individual testing, these cannot explain the
overall rate of ‘‘false positive’’ and ‘‘false negative’’
results. In the so-called ‘‘real world’’, CAD automatically implies ischemic heart disease. However, the
presence of true stress-induced ischemia in the
absence of obstructive CAD is a well-established
phenomenon [4,5]. Conversely, 25% of patients with
normal stress SPECT images have been reported to
have obstructive CAD on CTCA [6]. In line with these
findings, autopsy studies of young adults dying from
traffic accidents, homicides, and suicides have found
that 60% between the ages of 30 and 39 years of age
have left anterior descending (LAD) plaques of American Heart Association (AHA) grade 2 or higher [7],
nonetheless, none of them suffered ischemic heart
disease.
The rate of ‘‘false positives’’ and ‘‘false negatives’’
should therefore not always be regarded as a technical
challenge, but rather as a laid-back attitude to something we just do not get.
Economic issues together with the ability of a
diagnostic test to predict future clinical
outcomes and to affect prognosis
It should be admitted that, by its inherent properties as
a diagnostic rather than therapeutic intervention, an
imaging test merely supports clinical decision-making
and does not by itself have an impact on outcomes.
Moreover, additional concerns challenge the overall
value of cardiologic diagnostic tests: a) dozens of
studies in tens of thousands of patients have consistently shown that patients with known or suspected
CAD who do not have demonstrable stress-induced
ischemia have a good prognosis with very low event
rates over the subsequent 3 to 7 years [8]; b) although
abnormalities in perfusion imaging tests are associated with higher risk of death and myocardial infarction, this does not necessarily imply that treatment of
34
patients with abnormal tests results in reduction of
events [9,10]; and c) the preponderance of CAD
responsible for myocardial infarction or sudden cardiac death is due to non-obstructive coronary artery
plaques [11].
Given this intricate relationship between CAD and
myocardial ischemia, the limited prognostic impact
of noninvasive testing should no longer come as
a surprise. Nevertheless, as mentioned previously,
noninvasive testing currently constitutes one of
the most blooming areas of cardiology. A carefully
conducted study from Canada with contemporary
controls [12] demonstrated that the rate of normal
invasive coronary angiograms decreased after introduction of CTCA, but the overall rate of ICA
increased.
Turning back to our study, is this the way authors
hope to achieve a ‘‘higher’’ diagnostic yield of coronary angiography? For what purpose?
Ischemic heart disease, which includes acute coronary syndromes and chronic angina, is a leading
cause of death all over the world. Because disease
presentation is often fatal and a number of those who
die suddenly have no previously recognized symptoms, the development of imaging strategies capable
of predicting and thereafter preventing such a risk has
been regarded as a remedy.
The first step in the evaluation of patients is a
careful history and physical examination to provide
an estimate of the likelihood of increased risk for
coronary events. This is generally followed by a
noninvasive assessment, which then determines
the need for ICA. All these efforts point towards the
same target: identification and local treatment of
obstructive CAD.
Cardiologists have known for many years that coronary angiography yields similar results in patients
with both stable and acute coronary syndromes.
Now we have learned that coronary angiography
yields similar results in patients with myocardial
ischemia and in patients without. How can we still
assume that coronary anatomy dictates clinical conditions?
In fact, studies aimed at determining the impact of
removal of coronary stenosis have yielded disappointing results, both in terms of prognosis and symptom
relief [9,13]. In line with these findings, there are no
data to show that information from imaging techniques benefits patients. Morphologic imaging techniques consume large amounts of resources, yet their
role, if any, appears to be in reclassifying patients at
intermediate risk with traditional risk-factor models.
On the other hand, it has been widely demonstrated
that prevention is probably the most important part of
managing heart disease [14]. It is also a definitively
more economic strategy and can be based on simpler
risk factor-models such as FRS, which seem to be good
Heart Metab. 2011; 49:33–35
Hot topics
Low (< 10%)
Intermediate
High (> 20%)
100
physiological link between CAD and ischemic heart
disease.
90
Obstructive CAD (%)
80
REFERENCES
70
60
50
40
30
20
10
0
Positive
Negative
Equivocal
No test
Results of noninvasive tests
Figure 1. Patients with obstructive coronary artery disease
(CAD), according to noninvasive test results. Results are
presented according to the Framingham Risk Score (low,
intermediate, or high). Reprinted with permission from
[1]. ß2010 Massachusetts Medical Society. All rights
reserved.
CAD predictors. Contrary to the authors’ intentions,
Patel et al.’s paper [1] provides strong evidence that
coronary risk factors, as assessed by FRS, have a clear
relation with coronary atherosclerosis but are not
predictive of IHD (see Fig. 1).
In conclusion, CAD is a widely accepted predictor
of adverse clinical outcomes and its extent and
severity are considered important prognostic factors.
However, its use as a surrogate marker does not
always coincide with the presence of established
IHD. In this regard, the ‘‘low diagnostic yield’’ of
coronary angiography points to the flawed patho-
Heart Metab. 2011; 49:33–35
1. Patel MR, et al. Low diagnostic yield of elective coronary
angiography. N Engl J Med. 2010;362:886–895.
2. Lucas FL, et al. Temporal trends in the utilization of diagnostic
testing and treatments for cardiovascular disease in the United
States, 1993–2001. Circulation. 2006;113:374–379.
3. Lin F, et al. Multidetector computed tomography coronary
artery plaque predictors of stress-induced myocardial ischemia by SPECT. Atherosclerosis. 2008;197:700–709.
4. Wieneke H, et al. Non-invasive characterization of cardiac
microvascular disease by nuclear medicine using singlephoton emission tomography. Herz. 1999;24:515–521.
5. Soman P, et al. Vascular endothelial dysfunction is associated
with reversible myocardial perfusion defects in the absence of
obstructive coronary artery disease. J Nucl Cardiol. 2006;13:
756–760.
6. van Werkhoven JM, et al. Anatomic correlates of a normal
perfusion scan using 64-slice computed tomographic coronary angiography. Am J Cardiol. 2008;101:40–45.
7. McGill HC Jr et al. Association of coronary heart disease risk
factors with microscopic qualities of coronary atherosclerosis
in youth. Circulation. 2000;102:374–379.
8. Gibbons RJ. Noninvasive diagnosis and prognosis assessment
in chronic coronary artery disease: stress testing with and
without imaging perspective. Circ Cardiovasc Imaging.
2008;1:257–269; discussion 269.
9. Boden WE, et al. Optimal medical therapy with or without PCI
for stable coronary disease. N Engl J Med. 2007;356:1503–1516.
10. Henderson RA, et al. Seven-year outcome in the RITA-2 trial:
coronary angioplasty versus medical therapy. J Am Coll Cardiol. 2003;42:1161–1170.
11. Narula J, Strauss HW. The popcorn plaques. Nat Med.
2007;13:532–534.
12. Chow BJ, et al. Diagnostic accuracy and impact of computed
tomographic coronary angiography on utilization of invasive
coronary angiography. Circ Cardiovasc Imaging. 2009;2:16–23.
13. Adamu U, et al. Results of interventional treatment of stress
positive coronary artery disease. Am J Cardiol. 2010;105: 1535–
1539.
14. Mosca L, et al. Waist circumference predicts cardiometabolic
and global Framingham risk among women screened during
National Woman’s Heart Day. J Womens Health (Larchmt).
2006;15:24–34.
35
Glossary
Glossary
Gary D. Lopaschuk
Amyloidosis
A large, heterogeneous group of diseases characterized by themisfolding of extracellular protein. Misfolding occurs in parallel or as an alternative to
physiological folding and generates insoluble protein
aggregates (bundles of b-sheet fibrillar protein).
Despite possessing heterogeneous structures and
functions, fibrillar proteins are morphologically
similar. Organ dysfunction results from the deposition
and cytotoxic effects of insoluble amyloid proteins.
Beta-oxidation inhibitors
Compounds or drugs that inhibit mitochondrial fatty
acid beta-oxidation. They do so primarily by either
directly inhibiting mitochondrial fatty acid betaoxidation enzymes (i.e., trimetazidine, an inhibitor of 3ketoacyl CoA thiolase), or preventing the uptake of
fatty acids into the mitochondria (i.e., perhexiline, an
inhibitor of carnitine palmitoyl transferase).
Cardiomyopathy
Cardiomyopathy simply means ‘‘heart muscle disease’’, and refers to any type of deterioration of heart
muscle function. If this dysfunction is due to ischemia,
it is referred to as ischemic cardiomyopathy, or if it is
due to underlying diabetes, it is referred to as
diabetic cardiomyopathy.
Carnitine palmitoyl transferase 1 (CPT-1)
inhibitors
Compounds or drugs that inhibit the mitochondrial
outer membrane enzyme CPT-1, which is the ratelimiting enzyme for mitochondrial fatty acid uptake
and subsequent beta-oxidation. Therefore, CPT-1
inhibitors inhibit mitochondrial fatty acid beta-oxidation secondary to an inhibition of its uptake into
the mitochondria.
Dichloroacetate (DCA)
Dichloroacetate (DCA) is an inhibitor of pyruvate
dehydrogenase kinase, which is the enzyme responHeart Metab. 2011; 49:37–38
sible for phosphorylating and inactivating pyruvate
dehydrogenase, the rate-limiting enzyme of glucose
oxidation. DCA therefore activates pyruvate dehydrogenase and increases subsequent glucose oxidation
rates.
Free fatty acids (FFAs)
Acid moieties found in the circulation bound to albumin, or derived from triacylglycerol contained in
chylomicrons or very-low density lipoprotein. Following cellular uptake, free fatty acids are activated via
esterification to coenzyme A, and can be metabolized
via mitochondrial fatty acid b-oxidation to generate
reducing equivalents (e.g., nicotinamide adenine
dinucleotide [NADH]) for the electron transport chain
and oxidative phosphorylation.
Immunoabsorption (affinity chromatography)
A chromatographic method for the purification of a
specific molecule(s) from a complex mixture(s) based
on the highly specific biological interaction between
twomolecules (i.e., antibody and antigen). The interaction is usually reversible, and purification is
achieved by immobilizing one of the molecules (affinity ligand) onto a solid matrix, thereby creating a
stationary phase, while the target ligand is in a mobile
phase as part of a complex mixture. Capture of the
target molecule is typically followed by washing and
elution, which results in the recovery of a purified
molecular species.
Nicotinamide adenine dinucleotide
(NADþ/NADH)
A coenzyme critical to life in all living cells that
consists of two nucleotides joined through a phosphate group. One of the nucleotides possesses an
adenine base, whereas the other possesses nicotinamide. As a coenzyme, it is involved in numerous
redox reactions that occur in metabolism. One of
its major roles is to act as a reducing agent and
electron donor during the electron transport chain,
which is critical to adenosine-5’-triphosphate (ATP)
37
Glossary
Gary D. Lopaschuk
production during the process of oxidative phosphorylation.
Pyruvate dehydrogenase (PDH)
Pyruvate dehydrogenase (PDH) is a mitochondrial
enzyme that catalyzes the committed step of pyruvate
oxidation (i.e., oxidative decarboxylation), thereby
generating acetyl coenzyme A (CoA) for the tricar-
38
boxylic acid cycle and nicotinamide adenine dinucleotide (NADH) for the electron transport chain.
PDH is part of a multienzyme complex, consisting
of PDH kinase and PDH phosphatase. Phosphorylation of PDH by PDH kinase inhibits its activity, while
dephosphorylation by PDH phosphates increases its
activity. PDH activity is also sensitive to inhibition by
substrate/product ratios as decreased ratios of NADþ/
NADH and CoA/ acetyl-CoA decrease the rate of
pyruvate oxidation.
Heart Metab. 2011; 49:37–38