Circulation. 2008;117:2841-2843
doi: 10.1161/CIRCULATIONAHA.108.189729
(Circulation. 2008;117:2841-2843.)
© 2008 American Heart Association, Inc.
Clinical Summaries
 |
Accessory Atrioventricular Myocardial Connections in the Developing Human Heart: Relevance for Perinatal Supraventricular Tachycardias
|
|---|
Atrioventricular reentrant tachycardias presenting in fetal
or neonatal life can be life-threatening but also tend to resolve
in the majority of patients in the first year of life. The origin
of accessory pathway–mediated tachycardias in the perinatal
period has not been elucidated. In early embryonic development,
the atrial and ventricular myocardia are continuous in the primitive
atrioventricular canal. The atrioventricular conduction axis
will then develop, which coincides with separation of the atrial
and ventricular myocardium by formation of the annulus fibrosus.
Annulus fibrosus development involves several processes in which
the endocardial atrioventricular cushions that line the luminal
side of the primitive atrioventricular canal, together with
the inward migration of the epicardially located atrioventricular
sulcus tissue, have an important role. In postseptated human
hearts, we demonstrated the presence of numerous accessory atrioventricular
myocardial connections around both the mitral and tricuspid
annulus during normal cardiac development. At the end of the
second trimester, the connections gradually decreased in number
and size and were located primarily around the tricuspid annulus.
The persistence of fetal atrioventricular connections may serve
as substrate for atrioventricular reentrant tachycardia in the
fetus and newborn. The self-limiting character of most of these
tachycardias could be explained by loss of the substrate due
to the ongoing development of the annulus fibrosus, a process
not completely finished by the time of birth. See p
2850.
|
Radial Artery Versus Saphenous Vein Patency Randomized Trial: Five-Year Angiographic Follow-Up
|
|---|
Recent publications highlight the ongoing role for and importance
of coronary artery bypass surgery in the interventional management
of ischemic heart disease. There is still debate as to the role
of radial artery grafts in this procedure. As Gardner stated
last year in an editorial in
Circulation, "Additional clarity
about the usefulness and reliability of the radial artery ...
will ... come from late studies of radial artery graft function
especially angiographic studies
5 years after CABG" (Gardner
TJ. Searching for the second-best coronary artery bypass graft:
is it the radial artery?
Circulation. 2007:115:676–680).
This small randomized trial is the first to report such data.
It is important to note the good 5-year patency (86%) that can
be achieved in the modern era with saphenous vein grafts. The
radial artery patency rate at 5 years was excellent (98%), significantly
superior to that of saphenous vein grafts and comparable to
internal mammary artery patency. Another important finding was
the complete absence of occlusive graft disease in the radial
grafts. In addition to previous 1-year data from this and other
radial artery trials, we believe that these 5-year patency rates
and the absence of graft disease should substantially change
clinical practice, with much more widespread and acceptable
use of the radial artery as an aortocoronary bypass graft. See
p
2859.
|
Phase 1b Randomized Study of Antidote-Controlled Modulation of Factor IXa Activity in Patients With Stable Coronary Artery Disease
|
|---|
Animal models of thrombosis have demonstrated favorable ratios
of antithrombotic activity to bleeding risk with factor IXa
inhibition. However, it is unknown whether factor IXa inhibition
produces an appropriate anticoagulant effect when combined with
platelet-directed therapy in patients with stable coronary artery
disease. REG1 consists of RB006 (drug), an injectable RNA aptamer
that specifically binds and inhibits factor IXa, and RB007 (antidote),
the complementary oligonucleotide that neutralizes its anti-IXa
activity. We evaluated the safety, tolerability, and pharmacodynamic
profiles of REG1 in a randomized, double-blind, placebo-controlled
study, assigning 50 subjects with coronary artery disease taking
aspirin and/or clopidogrel to 4 dose levels of RB006 and RB007.
RB006 achieved rapid dose-dependent anticoagulation, whereas
RB007 restored normal coagulation promptly and durably, without
any major bleeding or other serious adverse events. The pharmacodynamic
profile of REG1 mirrored previous observations in both preclinical
models and healthy volunteers, laying the foundation for ongoing
studies in patients undergoing revascularization procedures.
This RNA aptamer drug-antidote construct specific for factor
IXa may have a future role in minimizing the bleeding risk associated
with revascularization procedures. See p
2865.
|
Cost-Effectiveness of Aspirin Treatment in the Primary Prevention of Cardiovascular Disease Events in Subgroups Based on Age, Gender, and Varying Cardiovascular Risk
|
|---|
Aspirin is effective for the primary prevention of cardiovascular
events, but it remains unclear for which subgroups of individuals
aspirin is beneficial. We assessed the cost-effectiveness of
aspirin separately for men and women of different ages with
various levels of cardiovascular disease risk. Our analyses
demonstrated that aspirin treatment for the primary prevention
of cardiovascular disease was cost-effective for men with a
10-year cardiovascular disease risk >10% and for women when
the risk was >15%. In general, this occurs much later in
life for women than men. Treatment with aspirin was cost-effective
for men 75 years of age regardless of the number of risk factors
present and for 55- and 65-year-old men with
2 cardiovascular
risk factors (such as diabetes mellitus, hypertension, hyperlipidemia,
or cigarette smoking). For most women, aspirin treatment resulted
in increased costs and worse health outcomes. However, aspirin
was cost-effective for women 65 years of age with high cardiovascular
risk and women 75 years of age with moderate cardiovascular
risk. Therefore, opportunities for primary prevention of aspirin
seem limited in women, and a gender-differentiated preventive
strategy seems warranted. See p
2875.
|
When More Is Not Better: Treatment Intensification Among Hypertensive Patients With Poor Medication Adherence
|
|---|
It is important for clinicians to determine whether patients
are taking already prescribed medications before increasing
doses or numbers of medications ("intensifying" medications).
Intensifying medications before addressing adherence difficulties
is ineffective, costly, and could even be dangerous if patients
suddenly start taking all their prescribed medications. In a
large cohort of patients with hypertension, we investigated
the extent to which providers increased medications in the face
of poor patient blood pressure control when there was evidence
of poor patient medication adherence. We conclude with recommendations
for effective approaches to assess and address medication adherence
problems. See p
2884.
|
Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction
|
|---|
Left ventricular noncompaction has recently been classified
as a primary cardiomyopathy. The echocardiographic characteristics
in affected individuals include a severely thickened, 2-layered
myocardium, numerous prominent trabeculations, and deep intertrabecular
recesses. The clinical features consist of both asymptomatic
and symptomatic patients with progressive deterioration of cardiac
function. Major complications are congestive heart failure,
arrhythmias, thromboembolic events, and sudden cardiac death.
The genetic basis of the disease is still unresolved in a large
proportion of patients. Both familial and sporadic cases have
been described. For familial cases, the predominant mode of
transmission is autosomal dominant. Detailed pedigree analysis
and cardiac evaluation of first-degree family members of affected
individuals is recommended. In this study, we describe that
left ventricular noncompaction is within the diverse spectrum
of cardiac morphologies triggered by sarcomere protein gene
defects. Heterozygous mutations in left ventricular noncompaction
were found in 3 genes: β-myosin heavy chain (
MYH7),
-cardiac
actin (
ACTC), and cardiac troponin T (
TNNT2). Mutations in several
sarcomeric protein genes have previously been implicated in
familial hypertrophic cardiomyopathy and in dilated cardiomyopathy.
Our findings support the hypothesis that there is a shared molecular
origin of different cardiomyopathic phenotypes. It is increasingly
realized that the current nomenclature fails to adequately describe
the substantial overlap between the classic cardiomyopathy syndromes.
Indeed, this discordance between the origin and the "clinical
syndrome" is one of the main messages of our study. See p
2893.
|
Molecular Imaging of Endothelial Vascular Cell Adhesion Molecule-1 Expression and Inflammatory Cell Recruitment During Vasculogenesis and Ischemia-Mediated Arteriogenesis
|
|---|
Multiple protective mechanisms guard against severe ischemic
injury caused by coronary and peripheral arterial disease. Structural
remodeling of the microcirculation occurs when disease becomes
so severe that autoregulation is exhausted and ischemia is produced
by minimal exertion or at rest. Proliferation and enlargement
of vessels at the arteriolar level lower total vascular resistance
and promote flow distribution through microvascular collateral
circuits. However, the ability to mount an arteriogenic response
varies considerably between tissues, species, and even individual
patients with similar degrees of ischemic burden. Understanding
the key regulatory processes is critical for developing methods
to modulate vascular remodeling as palliative therapy in patients
with no other treatment options. Ischemia-mediated inflammation
is thought to be an important contributor to arteriogenesis
and angiogenesis. The aim of this study was to determine whether
it is possible to use noninvasive ultrasound to evaluate key
aspects of the inflammatory response involved in vascular remodeling.
The results indicate that endothelial cell activation and monocyte
recruitment, which herald vasculogenesis and arteriogenesis,
can be quantified by molecular imaging. This approach shows
great promise for studying the contributing role of different
inflammatory cells in vascular remodeling and how manipulation
of the proinflammatory cytokines can be best used as a therapeutic
approach. See p
2902.
|
Multidrug Resistance Protein-1 Affects Oxidative Stress, Endothelial Dysfunction, and Atherogenesis via Leukotriene C4 Export
|
|---|
Multidrug resistance proteins (MRPs) are active transporters
for a variety of endogenously produced and exogenously administered
molecules, including glutathione, oxidized glutathione, estrogen,
and leukotriene C
4 (LTC
4), all of which are of potential importance
for the regulation of reactive oxygen species production in
vascular cells. In endothelial cells, MRP1 blockade or depletion
stabilized the intracellular redox potential and decreased reactive
oxygen species–induced endothelial cell apoptosis. LTC
4 is a mediator of inflammation, increases postcapillary permeability,
causes vasoconstriction, and induces oxidative stress. LTC
4 is metabolized in VSMCs, macrophages, and leukocytes. The release
of LTC
4 can be triggered by angiotensin II. The biological effects
of LTC
4 are mediated via the Cys-LT1 receptor. In this study,
we show that release of LTC
4 via MRP1 is important for atherogenesis
and endothelial function in apolipoprotein E–deficient
mice and that inside-outside transport of LTC
4 resembles a relevant
pro-oxidant mechanism. There are 2 potential ways to interfere
with this mechanism. The first way is to block MRP1 and therefore
interrupt the release of LTC
4. The second way to interrupt LTC
4-mediated
effects is the blockade of the Cys-LT1 receptor. Montelukast
is a Cys-LT1 receptor antagonist used for asthma treatment.
So far, the effect of montelukast on vascular functions has
remained undetermined. We now demonstrate that pharmacological
inhibition of MRP1, as well as Cys-LT1 receptors, prevents angiotensin
II–induced reactive oxygen species production, improves
endothelial function, and reduces atherosclerotic plaque formation
in apolipoprotein E–deficient knockout mice. This mechanism
might also be of importance in humans. See p
2912.
|
Contribution of Macromolecular Structure to the Retention of Low-Density Lipoprotein at Arterial Branch Points
|
|---|
We characterized the microstructure of the major macromolecules,
elastin and collagen, in the arterial wall using state-of-the-art
optical microscopy techniques. This structural examination of
macromolecular structures revealed a surprising result, namely
the near absence of the internal elastin layer at vascular branch
points, which are among the sites most prone to atherosclerosis.
The reason for the lack of a surface elastin layer at the branch
points is unknown but could be due to the unique flow or mechanical
characteristics at the branch. We hypothesized that the lack
of an elastin layer may contribute to the initial infiltration
and/or retention of low-density lipoprotein (LDL) at these sites
and the subsequent development of atherosclerosis. Consistent
with this hypothesis, we found that LDL binding was most extensive
in the arterial branch points where the elastin layer was absent.
Steady-state LDL binding studies in branch points revealed a
highly nonlinear cooperative binding characteristic that resulted
in a disproportionate increase in LDL retention with only relatively
small increases in LDL beyond a certain LDL threshold. This
highly nonlinear dependence of LDL retention in the arterial
branch is similar to the clinical observation of a certain threshold
of LDL needed to initially develop atherosclerosis and the further
marked increased risk for coronary artery disease with increasing
levels of LDL. See p
2919.
|
Converging Evidence in Support of the Serotonin Hypothesis of Dexfenfluramine-Induced Pulmonary Hypertension With Novel Transgenic Mice
|
|---|
The serotonin hypothesis of pulmonary arterial hypertension
(PAH) arose in the 1960s because of the incidence of PAH associated
with the intake of the anorexigenic drug aminorex, which was
withdrawn from the market. Dexfenfluramine was used as an anorexigen
in the 1980s. Like aminorex, it is a serotonin transporter substrate
and indirect serotinergic agonist. It also was subsequently
associated with an increased risk of developing PAH. An understanding
of the pharmacology of dexfenfluramine is essential and important
to identify other drugs that may also be risk factors for PAH.
There has been much controversy, however, about the mechanism
by which dexfenfluramine mediated PAH. It has both serotinergic
and nonserotinergic effects and has been reported to both exacerbate
and protect against PAH in hypoxic animal models of the disease.
Here, we show for the first time that dexfenfluramine-induced
PAH is dependent on peripheral serotonin synthesis rather than
its nonserotinergic effects. We also report that overexpression
of the serotonin transporter may be a risk factor for dexfenfluramine-induced
PAH. Intriguingly, we report that dexfenfluramine can also inhibit
hypoxia-induced phosphorylation of p38 mitogen-activated protein
kinase, thus providing a mechanism by which dexfenfluramine
can protect against hypoxia-induced PAH in animal models. These
results have wider implications in light of recent reports on
the increased abuse of other serotonin transporter substrates
and indirect serotinergic agonists such as methamphetamine and
amphetamine, which may also be risk factors for the development
of PAH. See p
2928.
Related Articles:
-
When More Is Not Better: Treatment Intensification Among Hypertensive Patients With Poor Medication Adherence
- Michele Heisler, Mary M. Hogan, Timothy P. Hofer, Julie A. Schmittdiel, Manel Pladevall, and Eve A. Kerr
Circulation 2008 117: 2884-2892.
[Abstract]
[Full Text]
-
Cost-Effectiveness of Aspirin Treatment in the Primary Prevention of Cardiovascular Disease Events in Subgroups Based on Age, Gender, and Varying Cardiovascular Risk
- Jacoba P. Greving, Erik Buskens, Hendrik Koffijberg, and Ale Algra
Circulation 2008 117: 2875-2883.
[Abstract]
[Full Text]
-
Radial Artery Versus Saphenous Vein Patency Randomized Trial: Five-Year Angiographic Follow-Up
- Peter Collins, Carolyn M. Webb, Chee F. Chong, Neil E. Moat for the Radial Artery Versus Saphenous Vein Patency (RSVP) Trial Investigators
Circulation 2008 117: 2859-2864.
[Abstract]
[Full Text]
-
Molecular Imaging of Endothelial Vascular Cell Adhesion Molecule-1 Expression and Inflammatory Cell Recruitment During Vasculogenesis and Ischemia-Mediated Arteriogenesis
- Carolyn Z. Behm, Beat A. Kaufmann, Chad Carr, Miles Lankford, John M. Sanders, C. Edward Rose, Sanjiv Kaul, and Jonathan R. Lindner
Circulation 2008 117: 2902-2911.
[Abstract]
[Full Text]
-
Phase 1b Randomized Study of Antidote-Controlled Modulation of Factor IXa Activity in Patients With Stable Coronary Artery Disease
- Mark Y. Chan, Mauricio G. Cohen, Christopher K. Dyke, Shelley K. Myles, Laura G. Aberle, Min Lin, James Walder, Steven R. Steinhubl, Ian C. Gilchrist, Neal S. Kleiman, David A. Vorchheimer, Nicholas Chronos, Chiara Melloni, John H. Alexander, Robert A. Harrington, Ross M. Tonkens, Richard C. Becker, and Christopher P. Rusconi
Circulation 2008 117: 2865-2874.
[Abstract]
[Full Text]
-
Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction
- Sabine Klaassen, Susanne Probst, Erwin Oechslin, Brenda Gerull, Gregor Krings, Pia Schuler, Matthias Greutmann, David Hürlimann, Mustafa Yegitbasi, Lucia Pons, Michael Gramlich, Jörg-Detlef Drenckhahn, Arnd Heuser, Felix Berger, Rolf Jenni, and Ludwig Thierfelder
Circulation 2008 117: 2893-2901.
[Abstract]
[Full Text]
-
Multidrug Resistance Protein-1 Affects Oxidative Stress, Endothelial Dysfunction, and Atherogenesis via Leukotriene C4 Export
- Cornelius F.H. Mueller, Kerstin Wassmann, Julian D. Widder, Sven Wassmann, Chia Hui Chen, Barbara Keuler, Alexey Kudin, Wolfram S. Kunz, and Georg Nickenig
Circulation 2008 117: 2912-2918.
[Abstract]
[Full Text]
-
Contribution of Macromolecular Structure to the Retention of Low-Density Lipoprotein at Arterial Branch Points
- Gina P. Kwon, Jamie L. Schroeder, Marcelo J. Amar, Alan T. Remaley, and Robert S. Balaban
Circulation 2008 117: 2919-2927.
[Abstract]
[Full Text]
-
Accessory Atrioventricular Myocardial Connections in the Developing Human Heart: Relevance for Perinatal Supraventricular Tachycardias
- Nathan D. Hahurij, Adriana C. Gittenberger-De Groot, Denise P. Kolditz, Regina Bökenkamp, Martin J. Schalij, Robert E. Poelmann, and Nico A. Blom
Circulation 2008 117: 2850-2858.
[Abstract]
[Full Text]
-
Converging Evidence in Support of the Serotonin Hypothesis of Dexfenfluramine-Induced Pulmonary Hypertension With Novel Transgenic Mice
- Yvonne Dempsie, Ian Morecroft, David J. Welsh, Neil A. MacRitchie, Nigel Herold, Lynn Loughlin, Margaret Nilsen, Andrew J. Peacock, Anthony Harmar, Michael Bader, and Margaret R. MacLean
Circulation 2008 117: 2928-2937.
[Abstract]
[Full Text]
Top
Accessory Atrioventricular...
Radial Artery Versus Saphenous...