|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 25, 2008
Contents
Metabolic Therapy: An Important
Therapeutic Option for the Treatment of Cardiovascular Diseases
Executive Editors: G.M.C. Rosano and G. Barbaro
Editorial: Pp. 2519-2520
Cardiac Metabolism in Diabetes Mellitus Pp.
2521-2526
M. Yoshimura, R. Anzawa and S.
Mochizuki
[Abstract] [Purchase
Article]
Medical Management of the Diabetic Patient with
Coronary Artery Disease Pp. 2527-2536
K. Karastergiou and J.C. Kaski
[Abstract] [Purchase
Article]
Optimization of Cardiac Metabolism in Diabetes
Mellitus Pp. 2537-2550
C. Vitale and P. Collins
[Abstract] [Purchase
Article]
Cardiac Metabolism in Myocardial Ischemia
Pp. 2551-2562
G.M.C. Rosano, M. Fini, G. Caminiti and
G. Barbaro
[Abstract] [Purchase
Article]
Modulation of Cardiac Metabolism During Myocardial
Ischemia Pp. 2563-2571
A.C.P. Chagas, P.M.M. Dourado and T.
de Fátima Gonçalves Galvão
[Abstract] [Purchase
Article]
Physiological Basis for Contractile
Dysfunction in Heart Failure Pp. 2572-2581
L. Dalla Libera, G. Vescovo and M.
Volterrani
[Abstract] [Purchase
Article]
Metabolic Therapy of Heart Failure
Pp. 2582-2591
G. Fragasso, A. Salerno, R. Spoladore, G.
Bassanelli, F. Arioli and A. Margonato
[Abstract] [Purchase
Article]
The Role of Amino Acids in the Modulation of Cardiac
Metabolism During Ischemia and Heart Failure
Pp. 2592-2604
G. Marazzi, S. Rosanio, G. Caminiti, F.S.
Dioguardi and G. Mercuro
[Abstract] [Purchase
Article]
The Role of Statins in Preventing the
Progression of Congestive Heart Failure in Patients with Metabolic
Syndrome Pp. 2605-2612
G. Fazio, G.R. Amoroso, G. Barbaro, G. Novo
and S. Novo
[Abstract] [Purchase
Article]
General Articles
Role of Asymmetric Dimethylarginine (ADMA) in Diabetic Vascular
Complications Pp. 2613-2618
S-i. Yamagishi, S. Ueda, K. Nakamura, T.
Matsui and S. Okuda
[Abstract] [Purchase
Article]
Inhibition of RNA Virus Infections with Peptide-Conjugated
Morpholino Oligomers Pp. 2619-2634
D.A. Stein
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
Editorial:Metabolic Therapy: An Important
Therapeutic Option for the Treatment of Cardiovascular Diseases
The concept of metabolic modulation has an important
part in the treatment of cardiovascular disease. It is now
clear that ischemic heart disease, heart failure and diabetic
cardiomyopathy have in common a derangement of cardiac metabolism
shifted towards a greater utilization of free fatty acids
and a reduced efficiency of the Krebs cycle. Over the past
decades, several dugs that have been shown to improve cardiac
metabolism in patients with ischemic heart disease and more
recently in those with heart failure. These drugs include
carnitine palmitoyl transferase (CPT)- I and/or -II inhibitors,
such as etomoxir and perhexiline, essential amino acids, and
long-chain 3-ketoacyl coenzyme A thiolase (LC3-KAT) inhibitors,
such as trimetazidine and ranolazine. Some of these drugs
are believed to work by partially inhibiting the oxidation
of fatty acids in ischemic myocytes, others by improving the
efficiency of the Krebs cycle. Since the oxidation of glucose
is more energy efficient than fatty acid oxidation it becomes
clear that enhancement of glucose metabolism should be pursued
when oxygen availability is limited in underperfused cardiac
tissue and in failing cardiomyocytes. Most of the drugs modulating
cardiac metabolism are approved for the treatment of angina
pectoris in most of Europe, Asia and Australia but not in
the United States. On the contrary, ranolazine that was thought
to be a metabolic agent but that now is supposed to have a
different, yet not clear, mechanism of action, is approved
for use in the United States but not in Europe.
In this issue of Current Pharmaceutical Design, the metabolic
basis of myocardial ischemia and dysfunction and the rationale
for metabolic therapy in ischemic heart disease and heart
failure are carefully reviewed by international experts who
have mostly contributed in this area of research and matured
a sound clinical experience.Yoshimura et al. [1]
discuss the metabolic changes that occur in patients with
diabetes mellitus and some of the metabolic therapeutic options
currently available. Karastergiou and Kaski [2] discuss in
depth the medical management of the diabetic patient with
ischemic heart disease and highlight the need of optimization
of cardiac metabolism. Vitale et al. [3] analyse
the effects of drugs (e.g., dichloroacetate, L-carnitine,
propionyl L-carnitine, CPT-I and LC3-KAT inhibitors) that
may optimize the cardiac metabolism in patients with diabetes
mellitus. Rosano et al. [4] review the metabolic
changes that occur during myocardial ischemia, with related
therapeutic implications, whereas Chagas et al. [5]
review the importance of modulation of cardiac metabolism
in patients with ischemic heart disease and the use of pharmacological
strategies to improve the cardiac metabolism by the activation
of pyruvate dehydrogenase (e.g., dichloroacetate), reduction
of cellular uptake of free fatty acids (e.g., glucose and
insulin), inhibition of mitochondrial transport of free fatty
acids by CPT-I inhibitors (e.g., perhexiline and etomoxir),
and inhibition of beta-oxidation of free fatty acids by LC3-KAT
inhibitors (e.g., trimetazidine and, possibly, ranolazine).
Heart failure is often the late stage of chronic ischemic
heart disease. Dalla Libera et al. [6] review the
patho-physiological and molecular (e.g., cardiomyocyte apoptosis)
phenomena responsible for contractile dysfunction in heart
failure, whereas Fragasso et al.[7] examine the possible
effect of modulation of cardiac metabolism in patients with
heart failure by acting on different metabolic pathways (e.g.,
inhibition of free fatty acids oxidation, xantine-oxidase
inhibition, mitochondrial metabolic oxidation). Marazzi et
al. [8] analyze the role of amino acids in the modulation
of cardiac metabolism during myocardial ischemia and heart
failure by multiple actions they can provide (e.g., improvement
of the oxidative stress by counteracting the action of radical
oxygen species; positive action on endothelial function; increase
of protein synthetic efficiency of myocardial cells by regulating
gene expression; modulation of hormonal activity). Finally,
Fazio et al. [9] critically revise the literature
data on the possible role of statins (mainly, their pleiotropic
effects) in preventing the progression of congestive heart
failure in patients with metabolic syndrome.
We wish to thank all the authors for their important contributions.
It is our hope that this issue may represent a useful guide
for a reasoned approach to metabolic therapy in patients with
ischemic heart disease and/or heart failure.
References
[1] Yoshimura M, Anzawa R, Mochizuki S. Cardiac Metabolism
in diabetes mellitus. Curr Pharm Des 2008; 14(25): 2521-2526.
[2] Karastergiou K, Kaski JC. Medical Management of the Diabetic
Patient with Coronary Artery disease. Curr Pharm Des 2008;
14(25): 2527-2536.
[3] Vitale C, Collins P. Optimization of cardiac metabolism
in Diabetes Mellitus. Curr Pharm Des 2008; 14(25): 2537-2550.
[4] Rosano GMC, Fini M, Caminiti G, Barbaro G. Cardiac metabolism
in myocardial ischemia. Curr Pharm Des 2008; 14(25): 2551-2562.
[5] Chagas ACP, Dourado PMM, Goncalves Galvao T. Modulation
of Cardiac Metabolism during myocardial ischemia. Curr Pharm
Des 2008; 14(25): 2563-2571.
[6] Dalla Libera L, Vescovo G, Volterrani M. The Physiological
Basis for Contractile Dysfunction in Heart Failure. Curr Pharm
Des 2008; 14(25): 2572-2581.
[7] Fragasso G, Salerno A, Spoladore R, Bassanelli G, Arioli
F, Margonato A. Metabolic therapy of heart failure. Curr Pharm
Des 2008; 14(25): 2582-2591.
[8] Marazzi G, Rosanio S, Caminiti G, Dioguardi FS, Mercuro
G. The role of Amino Acids in the modulation of cardiac metabolism
during ischemia and heart failure. Curr Pharm Des 2008; 14(25):
2592-2604.
[9] Fazio G, Amoroso GR, Barbaro G, Novo G, Novo S. The role
of statins in preventing the progression of congestive heart
failure in patients with metabolic syndrome. Curr Pharm Des
2008; 14(25): 2605-2612.
Giuseppe M.C. Rosano
Department of Medical Sciences
Centre for Clinical and Basic Research
IRCCS San Raffaele, Rome
Italy
E-mail: giuseppe.rosano@sanraffaele.it
Giuseppe Barbaro
Department of Medical Pathophysiology
University La Sapienza, Rome
Italy
E-mail: g.barbaro@tin.it
[Back to top]
[Purchase
Article]
Cardiac Metabolism in Diabetes Mellitus
M. Yoshimura, R. Anzawa and S.
Mochizuki
Diabetes mellitus is one of the most common chronic illnesses
throughout the world. Diabetic cardiomyopathy is a specific
syndrome, consisting of cardiomegaly, left ventricular dysfunction,
electrical remodeling of the ventricle, and symptoms of congestive
heart failure, that is seen in diabetic patients in the absence
of other predisposing factors. Many researchers have suggested
that inhibition of the renin-angiotensin-aldosterone system
and the sympathetic nervous system may exert a therapeutic
effect in individuals with diabetic cardiomyopathy. Indeed,
angiotensin II and aldosterone blockade may be effective,
partly because aldosterone blockade down-regulates Na+/H+
exchanger 1 activity. Further study of the alterations in
ion channel physiology in the context of diabetic cardiomyocytes
may be of benefit.
[Back to top]
[Purchase
Article]
Medical Management of the Diabetic Patient with Coronary
Artery Disease
K. Karastergiou and J.C. Kaski
The prevalence of type 2 diabetes is rising at an alarming
rate worldwide. Coronary artery disease (CAD) is the leading
cause of morbidity and mortality in the diabetic population.
Future CAD risk should be routinely assessed in patients with
diabetes as specific subgroups might benefit from information
derived from cardiac stress testing and other diagnostic procedures.
Risk factor control is of paramount importance in all cases
and it usually requires sustained lifestyle modifications,
coupled with pharmacological interventions. Statins and angiotensin-converting
enzyme (ACE) inhibitors are the first-line agents for the
treatment of dyslipidaemia and hypertension, respectively.
Microvascular, but not macrovascular, complications of diabetes
are effectively prevented by good glycaemic control. Metformin
is considered the first-choice agent in overweight diabetic
subjects, while the role of thiazolidinediones is currently
the focus of medical research. The diagnosis of acute coronary
events in patients with diabetes is often challenging because
of the high prevalence of silent ischaemia in these subjects.
All acute cardiac events need to be promptly treated and myocardial
reperfusion attempted without delay. Maintaining glucose levels
as close to normal as possible, during and shortly after an
acute event, improves prognosis in patients with diabetes.
Risk factor control remains the cornerstone of secondary prevention;
beta-blockers, ACE-inhibitors and antiplatelet agents confer
additional symptomatic and survival benefit. Similar therapeutic
principles also apply to patients with type 1 diabetes. This
article addresses the complex problem of managing patients
with diabetes and coronary artery disease.
[Back to top]
[Purchase
Article]
Optimization of Cardiac Metabolism in Diabetes Mellitus
C. Vitale and P. Collins
Cardiovascular disease is a major health problem in all
over the world. The prevalence of type 2 diabetes mellitus
has been rapidly increasing, together with the risk for cardiovascular
events. Patients with diabetes, and/or with insulin resistance
as well, have an impaired myocardial metabolism of glucose
and free fatty acids (FFA) and accelerated and diffuse atherogenesis,
with involvement of peripheral coronary segments. Significant
metabolic alterations in diabetic patients are the decreased
utilization of glucose and the increase in muscular and myocardial
FFA uptake and oxidation, occurring as a consequence of the
mismatch between blood supply and cardiac metabolic requirements.
These metabolic changes are responsible both for the increased
susceptibility of the diabetic heart to myocardial ischemia
and for a greater decrease of myocardial performance for a
given amount of ischemia, compared to non diabetic hearts.
A therapeutic approach aimed at an improvement of cardiac
metabolism, through manipulations of the utilization of metabolic
substrates, may improve myocardial ischemia and left ventricular
function. Modulation of myocardial FFA metabolism, in addition
to optimal medical therapy, should be the key target for metabolic
interventions in patients with coronary artery disease and
diabetes. In diabetic patients the effects of modulation of
FFA metabolism should be even greater than those observed
in patients without diabetes.
[Back to top]
[Purchase
Article]
Cardiac Metabolism in Myocardial Ischemia
G.M.C. Rosano, M. Fini, G. Caminiti and
G. Barbaro
Myocardial ischemia occurs for a mismatch between blood
flow and metabolic requirements, when the rate of oxygen and
metabolic substrates delivery to the myocardium is insufficient
to meet the myocardial energy requirements for a given myocardial
workload. During ischemia, substantial changes occur in cardiac
energy metabolism, as a consequence of the reduced oxygen
availability. Some of these metabolic changes are beneficial
and may help the heart adapt to the ischemic condition. However,
most of the changes are maladaptive and contribute to the
severity of the ischemic injury leading stunned or hibernating
myocardium, cell death and ultimately to contractile disfuction.
Dramatic changes in cardiac metabolism and contractile function,
also occur during myocardial reperfusion as a consequence
of the generation of oxygen free radicals, loss of cation
homeostasis, depletion of energy stores, and changes in subcellular
activities. The reperfusion injury may cause in the death
of cardiac myocytes that were still viable immediately before
myocardial reperfusion. This form of myocardial injury, by
itself can induce cardiomyocyte death and increase infarct
size.
During acute ischemia the relative substrate concentration
is the prime factor defining preference and utilization rate.
Allosteric enzyme regulation and protein phosphorylation cascades,
partially controlled by hormones such as insulin, modulate
the concentration effect; together they provide short-term
adjustments of cardiac energy metabolism. The expression of
metabolic genes is also dynamically regulated in response
to developmental and (patho)physiological conditions, leading
to long-term adjustments. Specific nuclear receptor transcription
factors and co-activators regulate the expression of these
genes. Understanding the functional role of these changes
is critical for developing the concept of metabolic intervention
for heart disease. The paper will review the alterations in
energy metabolism that occur during acute and chronic ischemia.
[Back to top]
[Purchase
Article]
Modulation of Cardiac Metabolism During Myocardial
Ischemia
A.C.P. Chagas, P.M.M. Dourado and
T. de Fátima Gonçalves Galvão
Metabolic modulation during myocardial ischemia is possible
by the use of specific drugs, which may induce a shift from
free fatty acid towards predominantly glucose utilization
by the myocardium to increase ATP generation per unit oxygen
consumption. Three agents (trimetazidine, ranolazine, and
perhexiline) have well-documented anti-ischaemic effects.
However, perhexiline, the most potent agent currently available,
requires plasma-level monitoring to avoid hepatoneuro-toxicity.
Besides, the long-term safety of trimetazidine and ranolazine
has yet to be established. In addition to their effect in
ischemia, the potential use of these drugs in chronic heart
failure is gaining recognition as clinical and experimental
data are showing the improvement of myocardial function following
treatment with several of them, even in the absence of ischemia.
Future applications for this line of treatment is promising
and deserves additional research. In particular, large, randomised,
controlled trials investigating the effects of these agents
on mortality and hospitalization rates due to coronary artery
disease are needed.
[Back to top]
[Purchase Article]
Physiological Basis for Contractile Dysfunction in Heart Failure
L. Dalla Libera, G. Vescovo and M.
Volterrani
The purpose of this review is to enlighten the mechanisms
of skeletal muscle dysfunction in heart failure. The muscle
hypothesis suggests that chronic heart failure (CHF) symptoms,
dyspnoea and fatigue are due to skeletal muscle alterations.
Hyperventilation due to altered ergoreflex seems to be the
cause of shortness of breath. Qualitative and quantitative
changes occurring in the skeletal muscle, such as muscle wastage
and shift from slow to fast fibers type, are likely to be
responsible for fatigue. Mechanisms leading to muscle wastage
in chronic heart failure, include cytokine-triggered skeletal
muscle apoptosis, but also ubiquitin/proteasome and non-ubiquitin-dependent
pathways. The regulation of fibre type involves the growth
hormone/insulin-like growth factor 1/calcineurin/ transcriptional
coactivator PGC1 cascade. The imbalance between protein synthesis
and degradation plays an important role. Protein degradation
can occur through ubiquitin-dependent and non-ubiquit-independent
pathways. Systems controlling ubiquitin/ proteasome activation
have been described. These are triggered by tumour necrosis
factor and growth hormone/ insulin-like growth factor 1. However,
an important role is played by apoptosis. In humans, and experimental
models of heart failure, programmed cell death has been found
in skeletal muscle and interstitial cells. Apoptosis is triggered
by tumour necrosis factor and in vitro experiments
have shown that it can be induced by its second messenger
sphingosine. Apoptosis correlates with the severity of the
heart failure syndrome. It involves activation of caspases
3 and 9 and mitochondrial cytochrome c release. Sarcomeric
protein oxidation and its consequent contractile impairment
can form another cause of skeletal muscle dysfunction in CHF.
[Back to top]
[Purchase
Article]
Metabolic Therapy of Heart Failure
G. Fragasso, A. Salerno, R. Spoladore, G.
Bassanelli, F. Arioli and A. Margonato
Alterations of cardiac metabolism can be present in several
cardiac syndromes. Heart failure may itself promote metabolic
changes such as insulin resistance, in part through neurohumoral
activation, and determining an increased utilization of non-carbohydrate
substrates for energy production. In fact, fasting blood ketone
bodies as well as fat oxidation have been shown to be increased
in patients with heart failure. The result is depletion of
myocardial ATP, phosphocreatine and creatine kinase with decreased
efficiency of mechanical work. A direct approach to manipulate
cardiac energy metabolism consists in modifying substrate
utilization by the failing heart. To date, the most effective
metabolic treatments include several pharmacological agents,
such as trimetazidine and perhexiline, that directly inhibit
fatty acid oxidation. These agents have been originally adopted
to increase the ischemic threshold in patients with effort
angina. However, the results of current research is supporting
the concept that shifting the energy substrate preference
away from fatty acid metabolism and toward glucose metabolism
could be an effective adjunctive treatment in patients with
heart failure, in terms of left ventricular function and glucose
metabolism improvement. In fact, these agents have also been
shown to improve overall glucose metabolism in diabetic patients
with left ventricular dysfunction. In this paper, the recent
literature on the beneficial therapeutic effects of modulation
of cardiac metabolic substrates utilization in patients with
heart failure is reviewed and discussed.
[Back to top]
[Purchase
Article]
The Role of Amino Acids in the Modulation of Cardiac
Metabolism During Ischemia and Heart Failure
G. Marazzi, S. Rosanio, G. Caminiti, F.S.
Dioguardi and G. Mercuro
During ischemia and heart failure, myocardial cells suffer
for chronic energy starvation resulting in metabolic and contractile
dysfunction. In normal conditions fatty acids, glucose, and
lactate are the principal oxidative fuels in myocardium, while
amino acids serve a minor role as an oxidative fuel. However,
in pathological conditions, myocardial uptake of several amino
acids increases significantly as a consequence of a metabolic
remodelling. Amino acids are involved in a variety of key
biochemical and physiological activities, that counteract
the deleterious cellular effects of reduced oxygen availability.
Several amino acids are a direct source of substrate for energy
production, and they modulate the activity of some enzymes
involved in the glucose metabolism. They increase contractile
performance both in isolated animal and human myocardium.
Furthermore, amino acids improve the oxidative stress counteracting
the action of radical oxygen species, being either precursors
of glutathione synthesis, or of substrate of nitric oxide
biosynthesis; they act on endothelial function and increase
protein synthetic efficiency of myocardial cells by regulating
gene expression and modulating hormonal activity. An amount
of studies have demonstrated that amino acids administration,
on patients with ischemic heart disease and heart failure,
can improve several clinical endpoints. Here, we present an
overview of the principal effects of the most experienced
amino acids and of amino acid derivatives on ischemia and
heart failure.
[Back to top]
[Purchase
Article]
The Role of Statins in Preventing the Progression of Congestive
Heart Failure in Patients with Metabolic Syndrome
G. Fazio, G.R. Amoroso, G. Barbaro, G. Novo
and S. Novo
Heart Failure (CHF) is a very important public health
problem in the world and certainly one of the most common
debilitating diseases and cause of mortality. Current knowledge
underlines that incidence rates are also influenced by the
coexisting pathologic conditions that accelerate the development
of disease or increase its severity. Important scientific
evidence is emerging to demonstrate a strong correlation between
HF and the metabolic syndrome (MetS). Hypolipemia-inducing
medication offers the opportunity to discuss the possible
existence of pharmacological substances that in addition to
their specific targets have several demonstrated pleiotropic
effects that could be beneficial in HF. Although several trials
investigated statins treatment effects on HF in general, some
evidence exists about the role that these drugs can have in
the progression of the disease in the specific category of
HF patients affected by MetS. In this review the possible
positive effects of the statins treatment in this specific
subset of patients are discussed.
[Back to top]
[Purchase
Article]
Role of Asymmetric Dimethylarginine (ADMA) in Diabetic Vascular
Complications
S-i. Yamagishi, S. Ueda, K. Nakamura, T.
Matsui and S. Okuda
Nitric oxide (NO) is a well-recognized anti-atherogenic
factor; it inhibits the inflammatory-proliferative processes
in atherosclerosis. Indeed, endothelial dysfunction due to
reduced synthesis and/or bioavailability of NO is thought
to be an early step in the course of atherosclerotic cardiovascular
disease (CVD). NO is synthesized from L-arginine via
the action of NO synthase (NOS), which is known to be blocked
by endogenous L-arginine analogues such as asymmetric dimethylarginine
(ADMA), a naturally occurring amino acid found in plasma and
various types of tissues. Recently, it has been demonstrated
that plasma levels of ADMA are elevated in patients with diabetes.
These findings suggest that the elevated ADMA in diabetes
could contribute to acceleration atherosclerosis in this population.
Further, since ADMA is mainly metabolized by dimethylarginine
dimethylaminohydrolase (DDAH), it is conceivable that the
inhibition of ADMA via up-regulation of DDAH may
be a novel therapeutic target for the prevention of CVD in
patients with diabetes. In this paper, we review the pathophysiological
role of ADMA and DDAH system for accelerated atherosclerosis
in diabetes and the therapeutic utility of ADMA suppression
in CVD in diabetes.
[Back to top]
[Purchase
Article]
Inhibition of RNA Virus Infections with Peptide-Conjugated
Morpholino Oligomers
D.A. Stein
RNA virus infections cause immense human disease burdens
globally, and few effective antiviral drugs are available
for their treatment. Peptide-conjugated phosphorodiamidate
morpholino oligomers (PPMO) are nuclease resistant and water-soluble
single-stranded-DNA-analogues that can enter cells readily
and act as steric-blocking antisense agents through stable
duplex formation with complementary RNA. Recently there have
been a number of publications documenting sequence-specific
and dose-dependent inhibition of non-retroviral RNA virus
infections by PPMO in both cell culture and murine experimental
systems. PPMO have suppressed viral titers by several orders
of magnitude in cell cultures, and have reduced viral replication
in and/or increased survivorship of mice experimentally infected
with poliovirus, coxsackievirus B3, dengue virus, West Nile
virus, Venezuelan Equine encephalitis virus, respiratory syncytial
virus, Ebola virus and influenza A virus. Along with evaluating
PPMO efficacy and toxicity, these studies also explored PPMO
mechanism of action, pharmacologic properties and the generation
and characterization of resistant virus. Effective PPMO target
sites in viral RNA have included regions of highly conserved
sequence thought to be important in the pre-initiation or
initiation of translation, or in long-range RNA-RNA interactions
involved in viral RNA synthesis. These studies provide guidance
for the design of steric-blocking antisense agents against
RNA viruses, insights into viral molecular biology and novel
strategies for the development of antiviral therapeutics.
The purpose of this review is to summarize notable findings
from the reports documenting antiviral activity by PPMO, with
a focus on the specific regions of viral RNA that provided
the most effective targets for PPMO-based inhibition of viral
replication.
|
