Featured IAS Commentaries
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AUGUST
COMMENTARIES | SEPTEMBER COMMENTARIES
SEPTEMBER
2008
Teasing Out and Rebuilding
the Metabolic Syndrome: Hypertension and
Dyslipidemia in Obesity and Insulin Resistance, Atherosclerotic
Disease, and Pharmacotherapy
Authors: Keith Suckling
The detailed investigations which most of us
plan and carry out require an overall framework (or paradigm
or narrative) for their construction, understanding, and communication.
For atherosclerotic disease over the past several decades these
have been based on concepts focused on cholesterol, then in
more detail on LDL cholesterol and oxidized LDL, to which was
added inflammatory mechanisms and the pathology of the vulnerable
plaque. Clearly these offer many areas of detailed biology
to investigate in themselves, but in the past decade or so
the concept of the metabolic syndrome has provided a linking
of even more metabolic and physiological processes so offering
an even richer and more complex landscape to explore.
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Cardiometabolic Risk in Women with Polycystic Ovary Syndrome
Authors: Ronald Ching Wan Ma and Lai Ping Cheung
Polycystic ovary syndrome (PCOS) is a condition
that was first described by Drs. Stein and
Leventhal in 1935, when they described a group of women with
amenorrhea, hirsuitism, obesity,
and enlarged ovaries [1]. Over subsequent years, PCOS has become
recognized as a common
endocrine disorder which affects 6-12% of reproductive-aged
women in most populations,
making it the one of the most common endocrine disorders. The
exact prevalence varies in
different populations and according to the definitions used,
but has been reported to be as high as
28.3% among overweight and obese women from Spain [2]. In Asian
populations such as
Chinese, hirsuitism may not be a prominent feature [3], though
a recent study in southern
Chinese reported a prevalence of 2.2% among women of reproductive
age [4].
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Visfatin - Another Target to Reduce Cardiovascular
Risk?
Authors: Michael S. Kostapanos, M.D. and Haralampos J. Milionis,
M.D.
Visfatin is a novel adipokine secreted mostly
by adipose tissue, while ubiquitously present in many other
tissues such as the liver, muscles, and human bone marrow [1].
Increased visfatin expression or levels have been identified
in a variety of inflammatory diseases, including rheumatoid
arthritis, inflammatory bowel disease, and psoriasis, as well
as in acute processes such as acute lung injury, sepsis, and
amnionitis [2]. Recent evidence suggests that visfatin is associated
with several cardiovascular risk factors and may have a role
in the pathogenesis of atherosclerosis.
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Chlamydia Pneumoniae and Associated Risk Factors in Coronary Artery Disease
Patients in India
Authors: Aruna Mittal, Hem C Jha, and Jagdish Prasad
Coronary artery disease (CAD) is a major cause of morbidity
and mortality in humans and is predicted to be the leading
cause of death in the world particularly in developing countries
such as India [1,2]. It is reported that Asian Indians have
the highest risk of CAD and the prevalence rate of CAD in India
has been estimated to be 11% [3,4]. Chronic infection has been
proposed as a possible causative agent in the development of
acute coronary artery syndrome [5]. Infectious agents in particular
Chlamydia pneumoniae (Cp) has been postulated to be the trigger
for each of the major phases of atherosclerosis as it causes
a chronic infectious state and upregulation of cytokines and
adhesion molecules [6-8]. In addition, conventional risk factors
among CAD patients such as sex, smoking, alcohol intake, genetic
predisposition, hypertension, and diabetes mellitus impose
additional risks for the severity of CAD. We reported high
prevalence of Cp (29.6%) in CAD patients in India as revealed
by nested PCR which is a matter of concern. Positive nested
PCR findings in conjunction with Cp specific antibody prevalence
may suggest an ongoing infection [9].
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Cholesterol Synthesis Inhibition Elicits an Integrated Molecular
Response in Human Livers Including Decreased ACAT2
Authors:
Mats Eriksson, M.D., Ph.D. and Paolo Parini, M.D.
Inhibition of the enzyme hydroxyl-methyl-glutaryl coenzyme
A (HMG-CoA) reductase, which leads to a reduced cholesterol
synthesis, represents a major breakthrough in modern medicine.
By cholesterol synthesis inhibition (ChSI), plasma levels of
atherogenic LDL particles can be substantially reduced resulting
in lower cardiovascular morbidity and mortality, in patients
with and without manifest disease [1]. The lipid lowering effects
of this class of drugs (statins) are generally ascribed to
the compensatory increase in hepatic LDL receptor expression,
which results from the activation of the transcription factor
sterol regulatory element binding protein 2 (SREBP-2) that
follows the reduced intracellular cholesterol [2]. At higher
degrees of HMG-CoA reductase inhibition, the secretion VLDL
cholesterol and triglycerides are also reduced, whereas HDL
cholesterol levels may tend to be higher, unchanged, or somewhat
lowered depending on the administered statin [3,4]. The mechanism(s)
behind the latter changes are less well characterized, and
their relationship to the more positive clinical effects of
high-dose ChSI on cardiovascular disease has been debated.
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Potential Applications of Nanotechnology for Atherosclerosis
Imaging
Authors: Paul Schoenhagen, M.D.
Imaging of atherosclerotic plaque and in
particular features of plaque vulnerability is an area of
intense clinical research
[1]. Initial invasive imaging with grey-scale intravascular
ultrasound (IVUS), comparing lesion morphology in stable and
unstable patients found low-echodenity, small “spotty” calcium
deposits, and positive remodeling to be more prevalent in unstable
patients [2-4]. Advanced analysis of the IVUS backscatter information
(IVUS radiofrequency analysis, RFA) and optical coherence tomography
allows further plaque differentiation [5,6]. Non-invasive imaging
of atherosclerotic plaque has more recently become possible.
Similar to previous IVUS studies, initial results with computed
tomography (CT) suggest that mixed calcified lesions with spotty
calcification are related to plaque vulnerability [7-9].
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Cardiac CT in the Assessment of Non-Calcified Plaque: Progress in the Quest
for a Non-Invasive Definition of the Vulnerable Atheroma
Author: Harald Brodoefel
The majority of myocardial infarctions result
from rupture of vulnerable atheroma. The latter is characterized
by a distinct histology, notably a large lipid core covered
by a thin fibrous cap [1]. Due to the phenomenon of vascular
remodeling significant luminal stenosis may be absent in more
than half of these plaques which might thus be invisible to
two-dimensional invasive coronary angiography (ICA) [2]. Intravascular-ultrasound
(IVUS) is the current gold standard for the detection and quantification
of non-obstructive plaque. Only recently, a new technique has
been designed that relies on spectrum analysis of IVUS-derived
radiofrequency and, thereby, differentiates the major components
of coronary plaque [3,4]. This so-called IVUS virtual histology
(IVUS-VH) holds the promise of identifying non-obstructive
but vulnerable atheroma and may serve as a tool for risk stratification
or serial monitoring of therapy. However, the method is time-consuming,
costly, and ultimately restricted to a small number of highly
specialized centers. Also, IVUS is limited to proximal segments;
the plaque burden of the entire coronary tree cannot be assessed.
Together, these drawbacks have fuelled the quest for alternative
techniques to detect, quantify, and characterize the vulnerable
plaque.
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The Metabolic Syndrome and the Immediate Antihypertensive
Effects of Aerobic Exercise
Author: Linda S. Pescatello
The metabolic syndrome (Msyn) affects about 30%
of the general population [1] and 40% of those with hypertension
[2]. Middle-aged adults with high BP and the Msyn are at higher
cardiovascular disease risk (CVD) than those with high BP {systolic
BP (SBP) >115 mmHg} and without the Msyn [3,4]. Participation
in habitual physical activity and higher cardiovascular fitness
are inversely related to the prevalence of CVD, hypertension,
and the Msyn [5-7]. Lifestyle modifications are recommended
for the prevention, treatment, and control of hypertension
and the Msyn, with exercise being an essential component [5,7,8].
Some of the health benefits ascribed to aerobic exercise training
programs are due to the acute or immediate responses from a
single exercise session, effects that persist from one to three
days depending on the CVD risk factor targeted [5,9]. The immediate
antihypertensive effects of aerobic exercise, i.e. postexercise
hypotension (PEH), result in BP decreases of 5-7 mm Hg that
endure for up to 22 hours after the exercise session [5].
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Astaxanthin for the Metabolic Syndrome
Authors: Hidekatsu Yanai, M.D., Ph.D., F.A.C.P. and Norio Tada,
M.D., Ph.D., F.A.H.A.,
The National Cholesterol Education Program's
Adult Treatment Panel III report (ATP III) identified 6 components
of the metabolic syndrome that relate to cardiovascular disease:
1) abdominal obesity, 2) dyslipidemia, 3) raised blood pressure,
4) insulin resistance and/or glucose intolerance, 5) proinflammatory
state, and 6) prothrombotic state [1]. Astaxanthin (AX), a
red carotenoid pigment, is a biological antioxidant that occurs
naturally in a wide variety of living
organisms. AX has various potent pharmacological effects, including
anti-obesity, anti-inflammatory, anti-diabetic, anti-hypertensive
activities, and AX also improves lipid and adiponectin metabolisms.
These pharmacological effects of AX may be useful for the treatment
of metabolic syndrome. Here, the therapeutic application of
AX for the metabolic syndrome will be considered.
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The Metabolic Syndrome, Schizophrenia, and
Antipsychotics
Author: Jonathan M. Meyer, M.D.
In the past decade there has been increasing
recognition that schizophrenia patients represent a population
at high risk for cardiometabolic disorders. As the focus of
diabetes prevention has shifted to identification of prediabetic
conditions, data has emerged on metabolic syndrome (MS) prevalence
in patients with schizophrenia. The largest U.S. data set to
examine this issue derives from the Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) Schizophrenia
Trial, an NIH-funded study exploring outcomes in a broadly
representative group of chronic schizophrenia patients entering
the trial on a variety of medications (with 28% on no antipsychotic
medication), and randomized in a double-blind manner to one
of four newer, so-called second generation or atypical antipsychotics
(olanzapine [Zyprexaò], quetiapine [Seroquelò],
risperidone [Risperdalò], or ziprasidone [Geodonò])
or a typical antipsychotic (perphenazine).
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At the Crossroads of Hyperlipidemia and
Diabetes: Aldose Reductase and the Polyol Pathway in Atherosclerosis
Author:
Christian A. Gleissner, M.D.
Today, it is broadly accepted that atherosclerosis
is an inflammatory disease of the arterial wall [1]. Hyperlipidemia
and diabetes mellitus represent two of the most important yet
treatable risk factors for the development of atherosclerotic
disease. They enhance recruitment of monocytes into the endothelial
wall and promote formation of the atherosclerotic lesion by
various mechanisms [2,3].
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Clinical Value of Diagnosing Metabolic Syndrome in Type 2 Diabetes Mellitus
Authors: Soon H. Song, M.D., FRCP and Colin A. Hardisty, M.D.,
FRCP
The concept of metabolic syndrome (MetS) conferring
increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular
disease has been around for more than a couple of decades.
Recent publications of clinical definitions have transformed
MetS from a physiological curiosity to a major focus of research
and clinical and public health interest. The MetS refers to
the co-occurrence of obesity (in particular central obesity),
dysglycemia, dyslipidemia (raised triglyceride and low HDL
cholesterol), and hypertension and in many cases, this phenomenon
signifies underlying insulin resistance. As a clinical tool,
MetS has been promoted as a means to identify individuals at
increased risk for cardiovascular disease for lifestyle and
therapeutic interventions to intensively treat the atherogenic
risk factors and reduce incident cardiovascular complications.
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Relationships of Plasma Aldosterone with
Metabolic Syndrome and Left Ventricular Mass in Essential Hypertensive
Patients
Giuseppe Mulè, M.D., Emilio Nardi,
M.D., Paola Cusimano, M.D., Santina Cottone, M.D., Giovanna
Seddio,
M.D., Calogero Geraci, M.D., Alessandro Palermo, M.D., and
Giovanni Cerasola, M.D.
Although some controversies in the pathogenesis
and clinical importance of metabolic syndrome (MetS) still
remain [1], it is accepted that MetS carries an increased risk
of cardiovascular (CV) diseases, even in the absence of diabetes
[2-4]. It is conceivable that the increased cardiovascular
risk conferred by the MetS may in part be mediated through
preclinical cardiovascular and renal damage. Indeed, major
cardiovascular events in most subjects are preceded by the
development of asymptomatic cardiovascular and renal structural
and functional abnormalities. These abnormalities, such as
left ventricular (LV) hypertrophy, carotid atherosclerosis,
arterial stiffness, and microalbuminuria, are more often observed
in subjects with MetS than in those without it, and they are
recognized as significant independent predictors of adverse
cardiovascular outcomes [5-8].
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The Metabolic Syndrome as the Cause of Hypertension: An Opportunity for Prevention
Author: Bernard M.Y. Cheung, Ph.D., FRCP
The metabolic syndrome is characterized by several
features, including abdominal obesity, dyslipidemia (elevated
triglycerides and reduced HDL-cholesterol), elevated blood
glucose, and elevated blood pressure [1,2]. It is found in
34% of men and 35% of women in the United States [3,4]. Although
the metabolic syndrome is a new disease entity [5,6], recognition
of its importance is increasing because it is a predictor of
cardiovascular disease and the development of diabetes [7,8].
The syndrome is also associated with other markers of coronary
disease risk, such as increased serum levels of apolipoprotein
B, small dense low-density-lipoprotein (LDL) particles, C-reactive
protein, and plasminogen activator inhibitor 1 (PAI-1).
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The Significance of PKC to Atherosclerosis
and Diabetes Macrovascular Complications
Author: Francesco Beguinot
Protein kinases C (PKCs) are a family of kinase
phosphorylating protein substrates on serine or threonine residues.
At least ten PKC isoforms have been described and usually classified
according to whether they contain domains that bind Ca2+ and/or
diacylglycerol (DAG), both of which induce the kinase activity
[1]. Conventional PKCs, including the a, ß1, ß2
and ? isoforms, bind both activators; novel PKCs, including
the d, e, h, and q isoforms, bind DAG but not Ca2+, and atypical
PKCs (? and ? isoforms) bind neither (the mouse and rat homologue
of human PKC? is termed PKC?). PKC is ubiquitously expressed,
but different tissues feature specific isoform distribution,
due to tissue-specific transcriptional regulation of distinct
genes encoding each isoform. Homologies have been identified
between protein kinase A, protein kinase B (Akt), and PKC.
In addition, similarities exist in regulation of these enzyme
activities by phosphorylation [2].
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