Circulation. 2008;117:1353
doi: 10.1161/CIRCULATIONAHA.107.189182
(Circulation. 2008;117:1353.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Improving Hypertension Control in Diabetes Mellitus: The Effects of Collaborative and Proactive Health Communication
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Uncontrolled hypertension is the primary risk factor for the
macrovascular complications of diabetes mellitus. Clinical trials
have demonstrated reductions in cardiovascular morbidity when
high blood pressure is controlled. Despite the availability
of numerous treatments, hypertension remains uncontrolled in
more than half of all diabetic individuals receiving treatment.
Communication that facilitates patient–clinician collaboration
when setting goals and treatment plans may overcome barriers
to hypertension control in routine diabetes care. We assessed
particular characteristics of patient–clinician communication
to determine their associations with hypertension control in
diabetes care independent of patient characteristics, medication
adherence, and self-management behaviors. Three communication
factors had significant associations with hypertension control.
Two factors, patients’ preference for shared decision
making with their clinician and proactive communication with
their clinician about abnormal results after blood pressure
self-monitoring, had direct independent associations with hypertension
control. A third factor, collaborative communication by clinicians
when setting treatment goals, had an indirect effect on hypertension
control. The impact of this factor was most apparent when a
patient did not endorse a shared decision-making style. This
study provides preliminary evidence that patient–clinician
communication can facilitate collaborative blood pressure goals
and proactive recognition by patients of inadequate treatment.
Collaborative communication during clinical encounters initiated
by patients or clinicians may improve rates of hypertension
control in diabetes care independent of medication adherence.
See p
1361.
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Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization
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Cardiac resynchronization therapy (CRT) is arguably the most
important therapeutic advance in heart failure treatment since
the turn of the 21st century. It is used in patients with discoordinate
contraction from conduction delays that in turn depresses global
function and efficiency and induces regional loading disparities.
This can exacerbate molecular stress signaling and stimulate
cell death. CRT improves chamber mechanoenergetics, but whether
or how it affects molecular stress/survival signaling is unknown.
Because this is nearly impossible to study in humans, we developed
a canine model using left bundle-branch radiofrequency ablation
and rapid atrial pacing (3 weeks) to generate dyssynchronous
heart failure, followed by rapid biventricular pacing (3 weeks)
to offset dyssynchrony (CRT). Controls were atrially tachypaced
for 6 weeks. CRT slightly improved function, but both groups
had persistent substantial heart failure. Yet, although dyssynchrony
amplified lateral wall activation of p38 mitogen-activated protein
kinase, calcium-calmodulin–dependent kinase II, and tumor
necrosis factor-
, these disparities were absent with CRT. Cell
death globally rose in dyssynchronous hearts but was diminished
by CRT. This was linked to the activation of the serine-threonine
kinase Akt and distal phosphorylation of apoptosis-regulating
protein BAD, enhanced BAD–14-3-3 interaction, and reduced
phosphatase PP1
. Other Akt-coupled modulators of apoptosis (forkhead—FOXO-3
and glycogen synthase kinase 3β) were less involved. These
findings represent the first detailed analysis of stress and
cell-survival signaling in failing dyssynchronous hearts and
highlight the importance of synchronous contraction and the
novel benefits of CRT. These mechanisms likely contribute to
enhanced cardiac performance and outcome from this therapy.
See p
1369.
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Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress
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A variety of cardioprotective agents used in clinical practice
for the management of patients with acute myocardial infarction
such as β-adrenergic receptor blockers, adenosine, and
morphine are thought to be cardioprotective because of altered
signaling through their cognate G protein–coupled receptor
(GPCR). Of note, the GPCRs acted on by these drugs can couple
to the adenylyl cyclase inhibitory G protein
subunit (Gi).
Furthermore, Gi is upregulated in failing myocardium at the
protein and transcript levels; however, the role of Gi signaling
in the context of myocardial ischemia and the progression toward
heart failure is controversial. To address Gi signaling in this
regard, we have developed a Gi-selective inhibitory peptide
to "functionally knock out" all GPCR-Gi–induced signals
in the heart. This peptide, called GiCT, can block the interaction
of the ligand-activated GPCR and G protein, thus selectively
inhibiting signals induced by Gi activation. Mice harboring
the GiCT transgene specifically in myocytes have allowed us
to directly address the role of Gi signaling in response to
stress in the form of myocardial ischemia, a causative agent
in the development of heart failure. This study demonstrates
a marked enhancement of myocardial infarct size and apoptotic
signaling after transient myocardial ischemia and reperfusion
when Gi signaling is blocked, thus indicating that signaling
via Gi activation appears to be prosurvival in the context of
myocardial ischemic injury. Our work suggests that the upregulation
of G
i2 in human heart failure may provide survival signals that
prevent apoptotic cell death induced by toxic levels of catecholamines
present in dysfunctional myocardium. See p
1378.
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Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat
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The present study describes a novel acellular approach consisting
of an injectable, bioresorbable, calcium-crosslinked alginate
that, when deployed into the infarcted region, undergoes phase
transition into a hydrogel implant that prevents infarct expansion.
Mechanistically, this hydrogel scaffold can stabilize degradation
of the extracellular matrix, increase scar thickness, and reduce
myocardial wall stress. These structural alterations act in
concert to mitigate ventricular dilation. From a therapeutic
perspective, preventing infarct expansion after acute myocardial
infarction and/or preventing the possible formation of a ventricular
aneurysm long term are beneficial in limiting progressive left
ventricular enlargement, chamber sphericity, and their adverse
sequelae. Controlling ventricular size and shape after MI is
likely to prevent or retard the development of congestive heart
failure and may possibly improve long-term outcome in this patient
population. This cell-free approach to ventricular reconstruction
after myocardial infarction may represent an alternative to
biological approaches such as stem cell–based therapy,
particularly in high-risk elderly patients and in patients with
significant comorbidities. See p
1388.
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Migraine Intervention With STARFlex Technology (MIST) Trial: A Prospective, Multicenter, Double-Blind, Sham-Controlled Trial to Evaluate the Effectiveness of Patent Foramen Ovale Closure With STARFlex Septal Repair Implant to Resolve Refractory Migraine Headache
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The Migraine Intervention With STARFlex Technology (MIST) trial
was the first randomized controlled clinical trial to evaluate
closure of a patent foramen ovale to treat refractory migraine
headaches. All other reports to date of migraine improvement
after patent foramen ovale closure were on patients with comorbid
conditions such as stroke, transient ischemic attack, or decompression
illness. The unique study design of the trial demonstrated that
a double-blind sham-controlled study was both feasible and ethically
justifiable in this condition. Although the study failed to
achieve its primary end point of complete cure of recurrent
migraine headaches, the modest treatment effect demonstrated
in this trial may have been mitigated by a number of confounding
factors. The length of follow-up, the assessment period, or
the impact of study medications in both arms may have affected
the results. Longer-term follow-up of the current study group
(including the crossover from the sham arm of the study) and
future trials should shed light on the efficacy and risk-to-benefit
ratio of patent foramen ovale closure for migraine. See p
1397.
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Role of Sulfonylurea Receptor Type 1 Subunits of ATP-Sensitive Potassium Channels in Myocardial Ischemia/Reperfusion Injury
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Early studies (eg, the University Group Diabetes Program) have
suggested an excess of cardiovascular mortality in tolbutamide-treated
subjects. Second-generation sulfonylureas are thought to pose
a lesser cardiovascular risk. The effects of sulfonylureas on
cardiovascular infarct size and ischemic arrhythmias remain
controversial. Molecular studies are needed to resolve this
complex question. In cardiac myocytes, the relevant K
ATP channel
subunits are generally thought to be Kir6.2 and SUR2A; however,
expression of other K
ATP channel subunit family members (Kir6.1
and SUR1) occurs in the heart, where their role remains undefined.
The present study investigated the cardiovascular role of SUR1
subunits and found that mice lacking these subunits are markedly
protected from ischemia/reperfusion injury. Sulfonylureas bind
to SUR1 subunits of the K
ATP channel and inhibit K
+ efflux.
These data may have important ramifications for the cardiovascular
risk of diabetic patients treated with sulfonylureas. Specifically,
the prediction would be that blockade of SUR1-containing channels
with low sulfonylurea concentrations in the cardiovascular system
would be cardioprotective via a reduction in infarct size after
ischemia/reperfusion. A caveat is that blockade of a potassium
channel would also be proexcitatory and potentially proarrhythmic.
Effects on arrhythmias have not been investigated in the present
study, and further studies are needed to evaluate the cardiovascular
effects of SUR1-containing channels in the cardiovascular system.
Nevertheless, this study suggests a previously unrecognized
diversity of cardiovascular K
ATP channels that may affect cardiovascular
outcome with sulfonylurea treatment. See p
1405.
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Heart-Specific Ablation of Prkar1a Causes Failure of Heart Development and Myxomagenesis
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We describe here the heart-specific knockout of the cAMP-dependent
protein kinase (protein kinase A [PKA]) regulatory subunit type
1A (Prkar1a). Loss of this protein in the developing heart causes
enhanced activity of the enzyme, leading to reduced proliferation
of developing myocytes and embryonic death resulting from cardiac
failure. The connection between excess PKA activity and heart
failure is well known, and clinical research has consistently
demonstrated the substantial benefit of β-blockers in heart
failure patients. The β-adrenergic receptor (particularly
the β2 isoform) signals through PKA so that β-blockers
reduce PKA signaling, the converse of the effect observed in
mutant mouse embryos. Although hard evidence is lacking, the
data from this article suggest that this excess PKA activity
may interfere with the ability of endogenous cardiac stem cells
to proliferate and repair mild amounts of cardiac damage. The
use of β-blockers may restore this capability and thus
reduce cardiac mortality over the long term. In addition, the
hearts from the mutant animals exhibit myxomatous changes. One
interpretation of this data is that myxomas may arise as a result
of an aberrant proliferative response to heart damage/failure.
If this concept is correct, it might suggest more careful screening
of patients with heart failure, particularly when coupled with
anatomic defects in the interatrial septum, where most sporadic
myxomas arise. In any event, the present studies highlight the
importance of the PKA system in cardiac development and function
and may provide a new tool with which to better understand cardiac
development and physiology. See p
1414.
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Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal–Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways
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The role of protein tyrosine phosphatases in the heart is still
unknown. Our results are the first to reveal that the SH2 domain–containing
protein tyrosine phosphatase Shp2 is essential in the adult
heart and that postnatal deletion of Shp2 causes dilated cardiomyopathy
without an intervening hypertrophic phase. Our findings indicate
that Shp2 is required to mediate activation of Erk1/2 in response
to several agonist stimulations and is a required pathway for
regulation of normal cardiac function. In addition, our data
also reveal that wild-type cardiomyocytes treated with the Mek1/2
inhibitor UO126 cause the cells to appear longer and thinner,
resembling Shp2-deficient cardiomyocytes, albeit to a lesser
extent. In addition, Shp2 deficiency in cardiomyocytes causes
a significant upregulation in RhoA activation, and most strikingly,
inhibition of this pathway with the Y-27632 RhoA effector Rho
kinase inhibitor can reverse the dilated cardiomyocyte phenotype
in culture. Shp2-deleted hearts also cannot hypertrophy in response
to aortic banding, suggesting that Shp2 plays an integral role
in cardiac remodeling. These data are especially important because
Shp2 mutations have recently been implicated in human genetic
disorders affecting the heart. Together, our data suggest that
Shp2, by virtue of its actions on the extracellular signal–regulated
kinase/mitogen-activated protein kinase and RhoA signaling pathways,
serves a cardioprotective role and is essential for normal cardiac
function. See p
1423.
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