Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 5, Number 5, October 2005
Contents
Erythropoietin in Heart Failure and Other CardiovascularDiseases:
Hematopoietic and Pleiotropic Effects Pp. 355-375
Antonis S. Manolis, Stylianos Tzeis, Kostas Triantafyllou,
John Michaelidis, Ioannis Pyrros, Nikolaos Sakellaris, Athanasios
Kranidis and Helen Melita
[Abstract]
Role of PPAR-γ
Agonist Thiazolidinediones in Treatment of Pre-iabetic and
Diabetic Individuals: A Cardiovascular Perspective Pp.
377-386
Rupal Dumasia, Kim A. Eagle, Eva Kline-Rogers, Niquole
May,Leslie Cho and Debabrata Mukherjee
[Abstract]
The Role of Renin Angiotensin System Blockade in theTreatment
of Atrial Fibrillation Pp. 387-402
Polychronis Dilaveris, Georgios Giannopoulos, Andreas
Synetos and Christodoulos Stefanadis
[Abstract]
Will this be the End of the Anticoagulation Clinic
for Patientswith Atrial Fibrillation? Pp. 405-408
Andrew R.J. Mitchell
[Abstract]
Drug Therapy in Brugada Syndrome Pp. 409-417
Manlio F. Márquez, Gabriel Salica, Antonio G. Hermosillo,Gustavo
Pastelín and Manuel Cárdenas
[Abstract]
An Old Drug with a New Purpose: Cardiovascular
Actions of Acetaminophen (Paracetamol) Pp. 419-429
Norell M. Spiler, Tyler H. Rork and Gary F. Merrill
[Abstract]
Abstracts
[Back to top]
Erythropoietin in Heart Failure and Other Cardiovascular
Diseases: Hematopoietic and Pleiotropic Effects
Antonis S. Manolis, Stylianos Tzeis, Kostas Triantafyllou,
John Michaelidis, Ioannis Pyrros, Nikolaos Sakellaris, Athanasios
Kranidis, Helen Melita
Erythropoietin is a hypoxia-induced hormone that is a major
regulator of normal erythropoiesis. Over the last decade,
the production of recombinant human erythropoietin has revolutionized
the treatment of anemia associated with chronic renal failure,
and has led to a greater understanding of anemia pathophysiology
and to the elucidation of the interactions of erythropoietin,
iron, and erythropoiesis. Anemia has been shown to be independently
associated with increased mortality and disease progression.
Potential survival benefits associated with correction of
anemia have expanded considerably the indications of erythropoietin
use in various patient populations and are leading to consideration
of earlier, more aggressive treatment of mild to moderate
anemia. The results of such treatment are promising in a variety
of new clinical settings, including anemia associated with
congestive heart failure. Furthermore, the erythropoietin
receptor is widely distributed in the cardiovascular system,
including endothelial cells, smooth muscle cells and cardiomyocytes
and preclinical studies have established erythropoietin to
be a pleiotropic cytokine with anti-apoptotic activity and
tissue-protective actions in the cardiovascular system, beyond
correction of hemoglobin levels. Despite some potential adverse
effects, such as hypertension, and the occurrence of erythropoietin
resistance, early studies in heart failure patients with anemia
suggest that erythropoietin therapy is safe and effective
in reducing left ventricular hypertrophy, enhancing exercise
performance and increasing ejection fraction.
Anemia is found in about one-third of all cases of congestive
heart failure (CHF). The most likely common cause is chronic
renal insufficiency, which is present in about half of all
CHF cases. However, anemia can occur in CHF without renal
insufficiency and is likely to be due to excessive cytokine
production. The anemia itself can worsen cardiac function,
both because it causes cardiac stress through tachycardia
and increased stroke volume, and because it can cause a reduced
renal blood flow and fluid retention, adding further stress
to the heart. Long-standing anemia of any cause can cause
left ventricular hypertrophy, which can lead to cardiac cell
death through apoptosis and worsen CHF. Therefore, a vicious
circle, cardio-renal anemia syndrome, is set up wherein CHF
causes anemia, and the anemia causes more CHF and both damage
the kidneys worsening the anemia and the CHF further and increasing
mortality. There is now evidence that early correction of
the CHF anemia with subcutaneous erythropoietin and intravenous
iron improves shortness of breath and fatigue, cardiac function,
renal function and exercise capacity, reducing the need for
hospitalization and improving quality of life.
In the present review we discuss the data on current clinical
use of erythropoietin in cardiovascular disease, with the
main focus on the treatment of congestive heart failure, and
summarize the advances and progress made in the understanding
of the hematopoietic and pleiotropic effects of erythropoietin
in the cardiovascular system.
[Back to top]
Role of PPAR- γ
Agonist Thiazolidinediones in Treatment of Pre-Diabetic and
Diabetic Individuals: A Cardiovascular Perspective
Rupal Dumasia, Kim A. Eagle, Eva Kline-Rogers, Niquole
May, Leslie Cho and Debabrata Mukherjee
The peroxisome proliferator-activated receptors (PPARs)
are nuclear fatty acid receptors, which contain a type II
zinc finger DNA binding motif and a hydrophobic ligand binding
pocket. These receptors are thought to play an important role
in metabolic diseases such as obesity, insulin resistance,
and coronary artery disease. Three subtypes of PPAR receptors
have been described: PPARα,
PPARδ/β,
and PPARγ.
PPARα
is found in the liver, muscle, kidney, and heart. In the liver,
its role is to up-regulate genes involved in fatty acid uptake
(β-oxidation
and ω-oxidation).
PPARδ/β
is involved in fatty acid oxidation in muscle. PPARγ
has high expression in fat, low expression in the liver, and
very low expression in the muscle. The thiazolidinediones
(TZD) are synthetic ligands of PPARγ.
By activating a number of genes in tissues, PPARγ
increases glucose and lipid uptake, increases glucose oxidation,
decreases free fatty acid concentration, and decreases insulin
resistance.
There is a sound rationale for the use of TZDs in patients
with type 2 diabetes mellitus and promising preliminary data
in patients with patients with pre-diabetes. In patients with
type 2 diabetes, thiazolidinediones had been shown to decrease
mean HbA1c by 1.5% and lower HbA1c to less than 7% in 30%
of patients. Decreased muscle insulin resistance primarily
mediates the glucose lowering effect. In addition, there are
several nonhypoglycemic effects of TZDs which may be beneficial
to both diabetics and patients with pre-diabetes. These include
effects on lipid metabolism, blood pressure, endothelial function,
atherosclerotic plaque, coagulation, and albuminuria.
In a pilot study, we recently demonstrated that insulin sensitizers
such as thiazolidinediones appear to be associated with better
clinical outcomes compared to insulin providers in diabetic
patients presenting with acute coronary syndromes. In another
study, we showed that the prediabetic state is a marker for
worse prognosis in patients with acute coronary syndromes.
In this article, we review the existing literature on the
effectiveness of PPAR-γ
agonists in patients with either overt diabetes or a prediabetic
state.
[Back to top]
The Role of Renin Angiotensin System Blockade in the
Treatment of Atrial Fibrillation
Polychronis Dilaveris, Georgios Giannopoulos, Andreas
Synetos and Christodoulos Stefanadis
Atrial fibrillation (AF) is the most common cardiac arrhythmia
seen in clinical practice. The understanding of the pathophysiology
of AF has changed drastically during the last several decades.
Recent observations have challenged the concept of the multiple
circuit reentry model in favor of single focus or single circuit
reentry models. Atrial electrical dysfunction provides a favorable
substrate and transmembrane ionic currents are key determinants.
Recent research is focusing increasingly on the atrial structural
remodeling, which underlies the development of AF in different
pathological conditions. This has led to concepts about how
interfering with the substrate might prevent AF development
and recurrence. Particular interest has been generated in
the role of renin angiotensin system (RAS) blockade in reversing
the electrical and structural remodeling of diseased atria.
The mechanisms for the preventive effect of angiotensin converting
enzyme inhibitors (ACEi) or angiotensin-II (AT-II) type 1
receptor blockers (ARB) in AF are probably complex. They may
comprise general haemodynamic changes leading to lower intra-atrial
pressure and wall-stress, or reduce in atrial fibrosis, connexin43
over-expression and conduction delay. The promising results
of several clinical trials concerning RAS blockade may herald
a whole new era of AF treatment, where AF is prevented and
treated by modifying its substrate rather than fighting it
electrically. This review centers on the pathophysiology of
the structural and electrical remodeling in AF, the possible
mechanisms by which RAS blockade may reverse electrical and
structural remodeling of diseased atria and on the role of
ACEi or ARB blockers in AF prevention and treatment that has
already been postulated both experimentally and clinically.
[Back to top]
Will this be the End of the Anticoagulation Clinic
for Patients with Atrial Fibrillation?
A.R.J. Mitchell
Atrial fibrillation is the most common clinical arrhythmia
and with an ageing population, it is an increasing cause of
hospital admissions, morbidity and mortality. The most feared
complication of atrial fibrillation is stroke. A number of
studies have demonstrated that warfarin is at least moderately
effective at reducing thromboembolic risk in stroke yet its
use in both the community and in secondary care is suboptimal.
Concerns about drug interactions, frequent blood monitoring
and the risks of over and under coagulation have led to under
prescription. Direct thrombin inhibitors are under investigation
as an alternative to warfarin for thromboembolic prophylaxis
in atrial fibrillation. Two large studies (SPORTIF III and
SPORTIF V) have recently been published examining the effectiveness
of the direct thrombin inhibitor ximelagatran at reducing
thromboembolic risk. Ximelagatran was shown to be non-inferior
to warfarin for the prevention of thromboembolic complications.
Concerns however have arisen about long-term safety, particularly
the possible effects on hepatic function. This review examines
the data and discusses whether the introduction of these drugs
could result in the end of the anticoagulation clinic for
patients with atrial fibrillation.
[Back to top]
Drug Therapy in Brugada Syndrome
Manlio F. Márquez, Gabriel Salica, Antonio G. Hermosillo,
Gustavo Pastelín and Manuel Cárdenas
Sudden cardiac death in healthy individuals with structurally
normal hearts and a characteristic morphology of the QRS complex
resembling a right bundle branch block with elevation of the
ST segment in V1 to V3 is known as Brugada syndrome (BrS).
Although placement of an implantable cardioverter-defibrillator
is considered the only effective therapy for symptomatic patients,
some authors have repeatedly reported a beneficial effect
of quinidine and isoproterenol in patients with BrS. Also,
isolated case reports on the usefulness of cilostazol, sotalol,
and mexiletine have been described. The present article reviews
the mechanisms by which these drugs may act and their role
in the pharmacotherapy of BrS. Other possible agents, mainly
Ito blockers, are also reviewed.
[Back to top]
An Old Drug with a New Purpose: Cardiovascular Actions
of Acetaminophen (Paracetamol)
Norell M. Spiler, Tyler H. Rork and Gary F. Merrill
For over 50 years, acetaminophen (paracetamol) has been
a staple in industrialized and non-industrialized countries
for the treatment of pain and fever. Although its precise
mechanisms of action are not known, the drug generates dose-dependent
reduction in circulating prostaglandins, inhibits myeloperoxidase
and the oxidation of lipoproteins, and appears to confer cardioprotection
by blocking the effects of hydroxyl radical, peroxynitrite,
and hydrogen peroxide. The drug might inhibit cyclooxygenase,
although its ultimate target(s) is (are) still unclear. Sadly,
since most investigations of acetaminophen have focused on
its analgesic/antipyretic properties and hepatotoxicity, the
effects of the drug on other mammalian organ systems, including
the heart and circulation, have been ignored. Recently, work
in our laboratory has shown acetaminophen to have a protective
role in the injured mammalian myocardium. The cardioprotection
was first observed in isolated, perfused guinea pig hearts
subjected to ischemia-reperfusion injury. Hearts pretreated
with acetaminophen recovered greater ventricular function
and exhibited improved myofibrillar ultrastructure when compared
to vehicle-treated hearts. More recent in vitro investigations
have suggested protective roles for acetaminophen in barbiturate-induced
arrhythmogenesis and myocardial hypoxia-reoxygenation injury.
We have also extended our work to the in vivo arena.
There, we found that acetaminophen reduced infarct size in
dogs exposed to 60 minutes regional myocardial ischemia and
180 minutes reperfusion. We invite and encourage readers of
this review to repeat/duplicate our experiments. Such work
is needed to either challenge or support our findings. Further,
more clinically-relevant work depends on these basic and related
translational experiments.
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