Circulation. 2009;120:1743-1744
doi: 10.1161/CIRCULATIONAHA.109.192658
(Circulation. 2009;120:1743-1744.)
© 2009 American Heart Association, Inc.
Clinical Summaries
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Genetic Testing for Long-QT Syndrome: Distinguishing Pathogenic Mutations From Benign Variants
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Genetic testing for congenital long-QT syndrome has become an
established part of the clinical armamentarium for physicians
encountering patients with a personal or family history of ventricular
tachyarrhythmias and sudden cardiac death. However, the presence
of a positive genetic test result must be reviewed carefully.
Most mutations identified in cases of long-QT syndrome are novel
missense mutations and thus must be distinguished as either
background noise or function-altering/disease-causing mutations.
Specifically, even in the general healthy population, genetic
variation, including known polymorphisms and novel, rare variants,
may be demonstrated. Thus, the presence of a genetic mutation
should be interpreted as a probabilistic measure of likelihood
of disease rather than as a binary indicator of its presence
or absence. This work indicates that mutation type, mutation
location, and ethnic-specific background rates are critical
factors in predicting the pathogenicity of novel mutations.
However, in certain cases, distinguishing pathogenic mutations
from rare variants may not be possible without additional functional
characterization or linkage analyses. Although mutations localizing
to certain specialized regions may be expected with high probability
to be disease causing, mutations in other regions should be
seen as variants of uncertain significance and should be interpreted
in the clinical context and lead to further investigation rather
than prompting assumption of disease presence and resulting
therapeutic interventions. This classification of genetic test
results as a probabilistic rather than absolute measure of disease
causation has potential implications when counseling patients,
especially as genetic testing becomes less expensive, more easily
available, and more commonly used. These findings may also have
implications for other genetic disorders involving mutational
analysis where benign genetic variation is sure to exist and
must be distinguished from disease-causing mutations. See p
1752.
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Prevalence of the Congenital Long-QT Syndrome
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This prospective ECG study, performed in 44 596 infants 15 to
25 days old and complemented by molecular screening in those
with a markedly prolonged QT interval, indicates that the prevalence
of the long-QT syndrome (LQTS) among whites is 1:2534 live births
(95% confidence interval, 1:1583 to 1:4350), which is much higher
than suspected previously. Furthermore, reasonable inferences
on the infants with a prolonged QT interval who were not genotyped
suggest that this prevalence may be close to 1:2000 live births.
This is the first data-based estimate of the prevalence of an
arrhythmogenic disease of genetic origin. As such, it will allow
health authorities in countries with a prevalent white population
to estimate the number of new LQTS patients they may expect
every year and to assess approximately the number of LQTS patients
who may be living in their countries. Of note, 51% of the family
members of the affected infants were also mutation carriers.
The study carries practical implications. Infants with a corrected
QT interval >460 ms in the first month of life and whose
corrected QT interval remains prolonged at 1 year have >90%
probability of carrying a LQTS-causing mutation. Whereas genetic
screening should be performed immediately in infants with a
corrected QT interval >485 ms, the normalization within 1
year for 75% of the infants with a corrected QT interval between
460 and 485 ms may suggest postponement of their genetic screening
until the end of their first year of life. ECG-guided molecular
screening can identify most infants affected by LQTS and unmask
affected relatives, thus allowing the early institution of effective
preventive measures. See p
1761.
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N-Terminal Pro-B-Type Natriuretic Peptide Is a Major Predictor of the Development of Atrial Fibrillation: The Cardiovascular Health Study
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Atrial fibrillation (AF) is a ubiquitous cardiac arrhythmia
and is associated with significant morbidity, mortality, and
economic burden. In the United States,
5% of the population
is affected by age 65 years; therefore, efforts to prevent AF
are vital. N-terminal pro-B-type natriuretic peptide (NT-proBNP)
is associated with many of these conditions, as well as with
AF. In this analysis of 5445 participants in the Cardiovascular
Health Study, elevated NT-proBNP levels were found to be highly
associated with prevalent AF (hazard ratio of 147 for the highest
quintile compared with the lowest after adjustment for associated
risk factors). Over the median follow-up period of 10 years,
there were 1126 incident cases of AF. Elevated levels of NT-proBNP
were robustly predictive of the development of AF; the hazard
ratio for the highest quintile was 4 compared with the lowest,
after adjustment for a comprehensive number of clinical and
echocardiographic covariates. Elevated levels of NT-proBNP were
by far the most powerful predictor of incident AF. These findings
suggest that NT-proBNP might be useful in identifying patients
at risk for AF many years before its occurrence. This provides
a way to target future therapeutic research aimed at preventing
AF to a group at particularly high risk. In the future, this
simple test might allow an early initiation of therapies designed
to prevent the development of AF. In addition, these findings
offer insight into the pathophysiology underlying AF. See p
1768.
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Peripheral Vascular Adaptation and Orthostatic Tolerance in Fontan Physiology
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This study involves 9 well-compensated patients several years
after the Fontan repair who were compared with 6 age-matched
controls. Important differences between the Fontan and control
subjects were seen in several vascular compartments. Calf capacitance
was lower and resting venous pressure was higher in the Fontan
group, suggesting a stiffer peripheral venous compartment, especially
in the lower extremities. The reduced venous compliance and
increased filtration thresholds possibly act as adaptive mechanisms
in maintaining venous return in Fontan circulation. These well-compensated
Fontan subjects also demonstrated superior orthostatic tolerance
resulting from decreased compartmental fluid shifts in response
to head-up tilt and higher vascular resistance. This results
from increased venous stiffness and decreased splanchnic capacitance
and may also be an adaptive mechanism to maintain venous return
in these patients while standing. One may infer a contracted
blood volume with poor tolerance to blood loss (or sudden vasodilatory
stress as in sepsis), leading to sudden and severe hemodynamic
deterioration, even in relatively asymptomatic Fontan subjects.
We believe that this study contributes to an understanding of
postoperative single-ventricle physiology, especially in regard
to compartmental fluid shifts as well as changes in peripheral
vascular properties in well-compensated patients exposed to
the Fontan circulation over a long period of time. This study
may form the baseline for further studies both in the immediate
postoperative period and in decompensated patients to examine
whether these protective mechanisms were somehow deranged, causing
circulatory decompensation in failing Fontan patients. See p
1775.
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Relation Between Alkaline Phosphatase, Serum Phosphate, and All-Cause or Cardiovascular Mortality
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Recent reports have shown that vascular calcification and markers
of mineral metabolism such as higher levels of serum phosphate
are associated with adverse outcomes among people with normal
kidney function. These findings have prompted examination of
the link between vascular calcification, mineral metabolism,
and symptomatic vascular disease in the general population.
Alkaline phosphatase (AlkP) catalyzes the hydrolysis of organic
pyrophosphate, an inhibitor of vascular calcification. Two recent
articles reported a strong independent association between AlkP
and the risk of adverse outcomes in patients with kidney failure.
The authors speculated that this association was due to abnormal
bone metabolism, perhaps mediated by vascular calcification,
which is common among dialysis patients. We first studied people
with a prior history of myocardial infarction who were free
of kidney failure at baseline. We then validated findings from
this first data set in an independent, nationally representative
sample of the general US population. We found a graded, independent
relation between higher levels of AlkP and all-cause mortality
that was consistent in both the derivation and validation samples.
The excess risk of death was present in people without evidence
of kidney disease and was particularly high among people with
higher levels of both AlkP and serum phosphate. Future studies
should identify factors that are associated with higher levels
of AlkP and evaluate the possibility of a causal link to vascular
calcification. See p
1784.
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Iloprost Prevents Contrast-Induced Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention
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Contrast-induced renal vasoconstriction is believed to play
a pivotal role in the pathogenesis of contrast-induced nephropathy
(CIN). The present study found that prophylactic periprocedural
intravenous administration of the prostacyclin analog iloprost
at a dose of 1 ng · kg
–1 · min
–1 in
patients with renal dysfunction undergoing a coronary procedure
reduced the incidence of CIN by
70% (odds ratio, 0.29; 95% confidence
interval, 0.12 to 0.69;
P=0.005). Importantly, the rate of side
effects leading to iloprost discontinuation or dose reduction
was very low and comparable to that observed in the control
group. The important new information provided by this study
is the proof of principle that CIN can be prevented by a mechanism
distinct from volume expansion or direct antioxidant effects,
namely prostacyclin replenishment. Furthermore, the efficacy
of iloprost to prevent CIN at the dose studied is noteworthy.
The prevention of CIN, which accounts for considerable morbidity
and mortality, remains a vexing problem. Although preliminary
data, mostly from single studies, have previously suggested
that numerous specific pharmaceuticals had a preventive effect,
more recent research has failed to confirm their efficacy. With
questions lingering, volume expansion remains the only indisputable
CIN preventive strategy. In this respect, although the results
of this trial appear convincing and support the use of iloprost
for efficient prevention of CIN in high-risk patients undergoing
a coronary procedure, recommendation for widespread use should
await further trial confirmation. See p
1793.
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CC Chemokine Receptor-1 Activates Intimal Smooth Muscle–Like Cells in Graft Arterial Disease
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Graft arterial disease (GAD) remains a clinically important
limitation to human cardiac transplantation. Five-year and 10-year
patient survival rates after adult heart transplantation are
74% and 52%, respectively. Intravascular ultrasound demonstrates
GAD in 75% of patients at 3 years after transplantation. Intimal
smooth muscle–like cells (SMLCs) predominate in GAD lesions.
Ischemia-reperfusion, allospecific humoral and cellular effectors,
donor and host antigen-presenting cells, and atherogenic factors
contribute to the intimal lesion formation. Chemokines affect
GAD formation because they contribute to ischemia-reperfusion
injury and acute rejection; however, chemokines can also contribute
directly to vascular remodeling and angiogenesis beyond their
role in leukocyte chemotaxis. Intimal SMLCs likely have multiple
sources beyond simple recruitment from donor medial cells. Intimal
SMLCs are clonal and phenotypically distinct from medial smooth
muscle cells; SMLCs express hematopoietic markers such as CD14,
CD34, CD105, Thy-1, c-kit, flt1, and flt-3. Bone marrow–derived
or any other circulating precursor cell must access grafts from
the circulation; the presence of smooth muscle progenitor cells
in human peripheral blood corroborates this notion. We hypothesized
that SMLC receptors and their cognate ligands promote intimal
lesion formation. Such receptors must preferentially target
SMLCs compared with intrinsic arterial smooth muscle cells.
The present study demonstrates that RANTES can potentiate the
effects of proliferative signals and implies that chemokines
contribute to both the recruitment and expansion of intimal
cells in GAD lesions. Clinical application will require further
studies to evaluate the effect of CC chemokine receptor-1 depletion
and immunosuppressive therapy, alone or in combination, on allograft
rejection and GAD. See p
1800.
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Tobacco Smoke Exposure in Either the Donor or Recipient Before Transplantation Accelerates Cardiac Allograft Rejection, Vascular Inflammation, and Graft Loss
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Tobacco exposure in cardiac transplant recipients, before and
after transplantation, may increase the risk of cardiac allograft
vasculopathy and allograft loss. In this experimental study,
we provide the first direct evidence that pretransplantation
cigarette smoke exposure in the donor, recipient, or both accelerates
the demise of the cardiac allograft. Importantly, our series
of experiments reveal that the chain of deleterious events begins
with inflammation and oxidative stress in the pretransplantation
period of smoking exposure, which results in activation of molecular
alloimmune pathways after transplantation, subsequently leading
to accelerated cellular rejection, vascular inflammation, and
graft loss with shortened allograft survival. Thus, it is possible
to speculate that this cascade of events can be interrupted
at the time of transplantation with focused pharmacological
intervention in the antiinflammatory and antioxidant pathways.
Thus, in addition to cessation of tobacco exposure, use of pharmacological
agents such as n-acetyl cysteine (an antioxidant) or statin
drugs (antiinflammatory drugs) could prove useful in inhibiting
these adverse responses. These require independent study and
verification and should be considered only hypothesis generating.
Our studies also uniquely demonstrate that the adverse effects
of cigarette smoking stem not only from the smoke exposure to
the recipient smoker but also from donor smoke exposure to the
organ transplanted, which maybe equally harmful to eventual
allograft survival. See p
1814.
Related Articles:
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Tobacco Smoke Exposure in Either the Donor or Recipient Before Transplantation Accelerates Cardiac Allograft Rejection, Vascular Inflammation, and Graft Loss
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Relation Between Alkaline Phosphatase, Serum Phosphate, and All-Cause or Cardiovascular Mortality
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Peripheral Vascular Adaptation and Orthostatic Tolerance in Fontan Physiology
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[Abstract]
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CC Chemokine Receptor-1 Activates Intimal Smooth Muscle–Like Cells in Graft Arterial Disease
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Genetic Testing for Long-QT Syndrome: Distinguishing Pathogenic Mutations From Benign Variants
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[Abstract]
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Iloprost Prevents Contrast-Induced Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention
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Prevalence of the Congenital Long-QT Syndrome
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N-Terminal Pro-B-Type Natriuretic Peptide Is a Major Predictor of the Development of Atrial Fibrillation: The Cardiovascular Health Study
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