Circulation. 2009;120:1-2
doi: 10.1161/CIRCULATIONAHA.109.192562
(Circulation. 2009;120:1-2.)
© 2009 American Heart Association, Inc.
Circulation: Clinical Summaries
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Visually-Guided Balloon Catheter Ablation of Atrial Fibrillation: Experimental Feasibility and First-in-Human Multicenter Clinical Outcome
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Catheter-based electric isolation of the pulmonary veins can
successfully treat patients with paroxysmal atrial fibrillation.
Although conceptually straightforward, its clinical application
has been hindered by important technical hurdles related to
the complexity and patient-to-patient variability of pulmonary
venous anatomy, as well as the difficulty in sequentially positioning
the ablation catheter in a point-by-point contiguous fashion
to isolate the veins. These considerations have led to the development
of a balloon ablation catheter equipped with an endoscope that
allows direct visualization of the atrial-venous junction and
an easily maneuverable optical fiber that projects an arc of
ablative laser energy (980 nm) onto the tissue in contact with
the balloon face. This novel endoscopic ablation system was
used in a series of preclinical porcine experiments and a first-in-human
multicenter clinical study. The former demonstrated the feasibility
to electrically isolate the pulmonary veins both immediately
and persistently. In the clinical phase, a total of 30 patients
with paroxysmal atrial fibrillation were treated. In the short
term, >90% of the veins were successfully isolated with the
balloon system. Long term, the 12-month drug-free freedom from
atrial fibrillation after a single procedure was 60%. This study
establishes the feasibility for this novel paradigm of catheter
ablation of atrial fibrillation. Instead of relying on indirect
cues to the location of the ablation catheter in relation to
the pulmonary venous anatomy, endoscopic visualization permits
the operator to directly visualize the tissue being targeted
for ablation, an approach moving ever so closer to approximating
the surgical experience. See p
12.
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Safety and Efficacy of Recombinant Activated Factor VII: A Randomized Placebo-Controlled Trial in the Setting of Bleeding After Cardiac Surgery
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Activated recombinant factor VII (rFVIIa) has been widely reported
in the management of patients bleeding after cardiac surgery.
Given its widespread off-label use, physicians must be comfortable
with its efficacy in stopping bleeding and reducing transfusion.
However, no prospective information has been collected on the
safety profile of this agent in patients undergoing cardiac
surgical operations. We have looked at the potential risks and
possible benefits of rFVIIa in patients who bleed after cardiac
surgery. We randomized patients actively bleeding after cardiac
surgery in an intensive care unit to either placebo or rFVIIa.
Our results show a small numerical non-dose-dependent increase
in the number of critical serious adverse events suffered by
patients receiving rFVIIa. In an underpowered study, this was
not statistically significant. Fifty percent fewer patients
underwent reoperation for bleeding when treated with rFVIIa.
Those patients who received 80 µg/kg received considerably
fewer transfusions of allogeneic blood or blood products. Our
results imply that caution must be used if rFVIIa is given to
patients without congenital coagulopathic disorders in whom
its use is licensed. See p
21.
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Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals
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Many clinical trials have demonstrated that lowering low-density
lipoprotein cholesterol (LDL-C), predominantly with statins,
reduces the incidence of cardiovascular events across a broad
spectrum of patients at risk. Guidelines for the management
of patients at risk have been established in Europe and North
America, and older studies have indicated that most patients
did not reach the LDL-C targets specified by the guidelines.
In the Lipid Treatment Assessment Project (L-TAP) 2, we measured
lipid levels in >10000 dyslipidemic adults on stable therapy
in 9 countries (United States, Canada, Mexico, Brazil, Spain,
the Netherlands, France, Taiwan, and Korea) between September
2006 and April 2007. The primary end point was defined as the
success rate in achieving appropriate LDL-C goals for the patient’s
level of risk. Among 9955 evaluable patients, the proportion
achieving LDL-C goals according to relevant national guidelines
ranged from 47% to 84% across countries. The success rate for
LDL-C goal achievement was 86% in low-, 74% in moderate-, and
67% in high-risk patients (73% overall). However, among coronary
heart disease patients with
2 risk factors, only 30% attained
the optional LDL-C goal of <70 mg/dL. In the entire cohort,
high-density lipoprotein cholesterol was <40 mg/dL in 19%,
40 to 60 mg/dL in 55%, and >60 mg/dL in 26% of patients.
We conclude that, although there is room for improvement, particularly
in very-high-risk patients, lipid-lowering therapy is being
applied much more successfully than it was a decade ago. See
p
28.
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Urinary N-Terminal Prohormone Brain Natriuretic Peptide Excretion in Patients With Chronic Heart Failure
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In patients with chronic heart failure, plasma N-terminal prohormone
brain natriuretic peptide (NT-proBNP) levels are elevated, usually
attributed to increased production by the ventricles. NT-proBNP
is completely excreted by the kidneys, but the renal handling
of increased levels of NT-proBNP in patients with heart failure
and left ventricular dysfunction is not well understood. We
studied renal handling of NT-proBNP in 94 patients with chronic
heart failure. Renal function was assessed by clearance of
125I-iothalamate
and
131I-hippuran. NT-proBNP levels were determined in both
plasma and 24-hour urine collections. As expected, plasma NT-proBNP
levels were >10 times higher in patients compared with 20
age- and sex-matched control subjects. However, urinary NT-proBNP
excretion was >10 times lower in patients compared with control
subjects. In both heart failure patients and control subjects,
we found a strong and inverse relationship between plasma NT-proBNP
and urinary NT-proBNP excretion. Interestingly, urinary NT-proBNP
excretion was independent of glomerular filtration rate but
was related to effective renal plasma flow. These findings suggest
an active process of tubular NT-proBNP reabsorption, although
this remains speculative. If true, elevated levels of NT-proBNP
in chronic heart failure are related not only to increased production
but also to decreased renal excretion. See p
35.
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Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension
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The role of exercise training in current clinical management
of patients with pulmonary arterial hypertension (PH) remains
controversial. Traditionally, these patients were advised to
limit their physical activity because exercise was presumed
to superimpose an additional right ventricular load on an already
compromised heart. Recently, exercise training was found to
greatly improve exercise capacity and quality of life in clinically
stable PH patients. It remains uncertain, however, if exercise
training is beneficial for all PH patients, including the effects
on the right ventricle. Therefore, in the present study, we
studied the effects of exercise training in a rodent model,
inducing 2 distinct clinical phenotypes of PH. Training was
found to be beneficial in stable PH with preservation of cardiac
function. However, training was detrimental in progressive PH
because it accelerated the progression toward right heart failure
and induced widespread right ventricular inflammation. These
findings imply that disease progression and right ventricular
adaptation might be important clinical determinants for favorable
response to exercise training in PH. Because clinical PH tends
to be a progressive disease, defining "stable" PH might be challenging.
In the absence of prospectively validated criteria, PH patients
could be classified as stable when there is constancy of clinical
findings in repeated evaluations over a 3-month period. These
findings should include New York Heart Association classification,
6-minute walk distance, N-terminal prohormone brain natriuretic
peptide levels, and right ventricular function/dimensions. Prospective
clinical studies should evaluate these criteria for stable PH
to translate the findings of the present study and to detect
PH patients who will benefit from an exercise training program.
See p
42.
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Inhibition of Prolyl Hydroxylase Domain Proteins Promotes Therapeutic Revascularization
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Therapeutic neovascularization represents an alternative treatment
modality for patients with advanced ischemic coronary or peripheral
artery occlusive disease. Numerous animal studies have established
that angiogenesis of ischemic tissue can be enhanced with exogenous
growth factors or vascular progenitor cells, and clinical studies
have been initiated. However, clinical trials to date are negative
or give conflicting results. The hypoxia-inducible transcription
factor (HIF) is a master regulator controlling genes involved
in several processes that promote neovascularization, making
modulation of HIF activity an attractive approach for the treatment
of ischemic disease. In normoxia, HIF-
is hydroxylated by the
prolyl hydroxylases domain proteins (PHDs), leading to ubiquitylation
of HIF-1
and subsequently degradation by the proteasome. In
contrast, under acute hypoxia, the PHD activity is compromised,
allowing the stabilization and translocation of HIF-
in the
nucleus and upregulation of wide repertoire of genes involved
in vessel growth. In the present study, we used short hairpin
RNAs to downregulate murine PHD1, PHD2, or PHD3 levels and analyzed
their efficiency as a therapeutic strategy in a model of mice
hindlimb ischemia. We demonstrated that a direct inhibition
of PHDs, and more particularly PHD3, promoted therapeutic revascularization
via specific activation of proangiogenic molecules, including
vascular endothelial growth factor-A and endothelial nitric
oxide synthase, and proarteriogenic proinflammatory pathways.
Therefore, silencing of PHDs by the transient and local upregulation
of endogenous HIF-1
improves vessel growth in ischemic tissue.
This study also paves the way for future strategy based on administration
of small interfering RNAs directed against PHD to promote therapeutic
revascularization in ischemic disease. See p
50.
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Twenty-Five-Year Outcome of Pediatric Coronary Artery Bypass Surgery for Kawasaki Disease
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Nearly 25 years have passed since the first operation for severe
inflammatory coronary artery pathology due to Kawasaki disease.
We present a comprehensive long-term follow-up study of 114
such patients. There were no operative or hospital deaths, but
5 late deaths, mostly sudden, occurred during the follow-up.
Nonsurvivors were characterized by previous myocardial infarction,
frequent ventricular arrhythmias, and a left ventricular ejection
fraction of
0.5. Survival after coronary bypass operation in
childhood and adolescence was excellent, with a 20- to 25-year
rate of 95% (95% confidence interval, 88 to 98). However, the
cardiac event-free rate declined to 67% at 20 years and 60%
(95% confidence interval, 46 to 72) at 25 years. Postoperative
interventions (percutaneous coronary intervention or reoperation)
were most common as a result of graft anastomotic stenosis (early
event), graft closure (midterm), new obstructive lesions, and
vein graft atherosclerosis (late events). The increase in cardiac
events with time can be successfully managed with reinterventions.
Internal thoracic artery grafts had significantly better 20-year
patency (87%; 95% confidence interval, 78 to 93) than vein grafts
(44%; 95% confidence interval, 26 to 61) (
P<0.001) regardless
of the patient’s age at operation or target coronary vessels.
All 109 survivors are symptom free, and 80% of them are performing
unlimited daily activities, although 77% are still receiving
1 to 6 medications, including aspirin in all and warfarin in
21 patients with a patent aneurysm not supported by distal grafts.
Pediatric coronary bypass surgery with the use of the internal
thoracic artery graft is an established effective treatment
for children and adolescents with complicated coronary lesions
due to Kawasaki disease. See p
60.
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Risk Score for Predicting Outcome in Patients With Asymptomatic Aortic Stenosis
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The decision to operate on asymptomatic patients with severe
aortic stenosis remains a source of debate. The risk of sudden
death without preceding symptoms remains a matter of concern
as well as the risk of irreversible myocardial damage due to
severe left ventricular hypertrophy. In the present study, we
developed a risk score based on the 3 independent predictors
of midterm outcome (ie, sex, peak aortic-jet velocity, and serum
B-type natriuretic peptide) in a population of 104 consecutive
patients with mostly severe aortic stenosis who were asymptomatic
at baseline and prospectively followed. This score was then
validated on an independent cohort of 107 consecutive patients.
According to this score, 80% of patients within the first quartile
remained free from events after 20 months of follow-up. In contrast,
only 7% of patients within the fourth score quartile remained
free of events after 20 months. The rationale for utilizing
this score rather than logistic models relies on its robustness
for predicting clinical outcome and its simplicity. Although
further validation is needed, this score may already be useful
in its present form to stratify risk in patient cohorts before
randomization in a prospective study. Finally, if further validation
is achieved, this score may be useful to predict outcome in
individual patients with asymptomatic aortic stenosis to select
those who might benefit from early surgery. See p
69.
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Risk Score for Predicting Outcome in Patients With Asymptomatic Aortic Stenosis
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Inhibition of Prolyl Hydroxylase Domain Proteins Promotes Therapeutic Revascularization
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Urinary N-Terminal Prohormone Brain Natriuretic Peptide Excretion in Patients With Chronic Heart Failure
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Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension
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Safety and Efficacy of Recombinant Activated Factor VII: A Randomized Placebo-Controlled Trial in the Setting of Bleeding After Cardiac Surgery
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Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals
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Visually-Guided Balloon Catheter Ablation of Atrial Fibrillation: Experimental Feasibility and First-in-Human Multicenter Clinical Outcome
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Twenty-Five-Year Outcome of Pediatric Coronary Artery Bypass Surgery for Kawasaki Disease
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