bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative Chronotropic Effect of β-Blockade Therapy Reduces Myocardial Oxygen Expenditure for Nonmechanical Work
Authors: Yamakawa Hideyuki , Takeuchi Motoshi , Takaoka Hideyuki , Hata Katsuya , Mori Masuki , Yokoyama Mitsuhiro
Published: June 2012

Background
The negative chronotropic effect of β-blocking agents is likely to provide hemodynamic and energetic advantages. However, the negative chronotropic effect on cardiac energetics observed on the initiation of β-blockade therapy has not been fully elucidated.

Methods and Results
In 18 patients with heart failure, left ventricular pressure and volume, external work (EW), myocardial oxygen consumption per beat (total V̇
o
2
), mechanical efficiency (EW/total V̇
o
2
), and V̇
o
2
for nonmechanical work (total V̇
o
2
−2·EW) were measured with the use of conductance catheter and Webster catheter at the following three states: under control conditions and after β-blockade (0.15±0.07 mg/kg propranolol IV) with and without atrial pacing to keep the heart rate at control levels. Heart rate decreased after atrial pacing was stopped. EW decreased during β-blockade with pacing and returned to the control level after pacing was stopped. Total V̇
o
2
did not change during β-blockade with or without pacing, whereas V̇
o
2
for nonmechanical work increased with pacing and returned to the control level after pacing was stopped. As a result, mechanical efficiency decreased during β-blockade with pacing and returned to the control level after pacing was stopped.

Conclusions
The negative chronotropic effect of a β-blocking agent may offset the mechanoenergetical deterioration resulting from its negative inotropic effect through a reduction in oxygen expenditure for nonmechanical work. These findings suggest that the negative chronotropic effect is an important aspect of β-blockade therapy.
Insights From Three-dimensional Echocardiographic Laser Stereolithography
Authors: Gilon Dan , Cape Edward G. , Handschumacher Mark D. , Jiang Leng , Sears Charles , Solheim Joan , Morris Eleanor , Strobel John T. , Miller-Jones Stockton M. , Weyman Arthur E. , Levine Robert A.
Published: June 2012

Background
Three-dimensional echocardiography can allow us to address uniquely three-dimensional scientific questions, for example, the hypothesis that the impact of a stenotic valve depends not only on its limiting orifice area but also on its three-dimensional geometry proximal to the orifice. This can affect the coefficient of orifice contraction (Cc=effective/anatomic area), which is important because for a given flow rate and anatomic area, a lower Cc gives a higher velocity and pressure gradient, and Cc, routinely assumed constant in the Gorlin equation, may vary with valve shape (60% for a flat plate, 100% for a tube). To date, it has not been possible to study this with actual valve shapes in patients.

Methods and Results
Three-dimensional echocardiography reconstructed valve geometries typical of the spectrum in patients with mitral stenosis: mobile doming, intermediate conical, and relatively flat immobile valves. Each geometry was constructed with orifice areas of 0.5, 1.0, and 1.5 cm
2
by stereolithography (computerized laser polymerization) (total, nine valves) and studied at physiological flow rates. Cc varied prominently with shape and was larger for the longer, tapered dome (more gradual flow convergence proximal and distal to the limiting orifice): for an anatomic orifice of 1.5 cm
2
, Cc increased from 0.73 (flat) to 0.87 (dome), and for an area of 0.5 cm
2
, from 0.62 to 0.75. For each shape, Cc increased with increasing orifice size relative to the proximal funnel (more tubelike). These variations translated into important differences of up to 40% in pressure gradient for the same anatomic area and flow rate (greatest for the flattest valves), with a corresponding variation in calculated Gorlin area (an effective area) relative to anatomic values.

Conclusions
The coefficient of contraction and the related net pressure loss are importantly affected by the variations in leaflet geometry seen in patients with mitral stenosis. Three-dimensional echocardiography and stereolithography, with the use of actual information from patients, can address such uniquely three-dimensional questions to provide insight into the relations between cardiac structure, pressure, and flows.
Bradykinin and Its Metabolite, Arg-Pro-Pro-Gly-Phe, Are Selective Inhibitors of α-Thrombin–Induced Platelet Activation
Authors: Hasan Ahmed A.K. , Amenta Styliani , Schmaier Alvin H.
Published: June 2012

Background
Plasma kininogens are selective inhibitors of α-thrombin activation of platelets and endothelial cells. In the present study, we localized the α-thrombin inhibitory sequence of kininogens and describe its mechanism of action.

Methods and Results
Bradykinin and an analogue, MKRPPGFSPFRSSRIG, inhibited α-thrombin–induced platelet aggregation and secretion with an IC
50
of 0.25 and 1 mmol/L and of 0.23 and 0.5 mmol/L, respectively. The minimal inhibitory peptide was RPPGF. Bradykinin and its analogues did not inhibit ADP-, collagen-, U46619-, or SFLLRN-induced platelet activation or the ability of α-thrombin to cleave chromogenic substrates, clot fibrinogen, or block α-thrombin binding to platelets. Bradykinin, MKRPPGFSPFRSSRIG, and RPPGF abolished α-thrombin–induced (1 nmol/L) calcium mobilization. On flow cytometry, bradykinin and MKRPPGFSPFRSSRIG blocked α-thrombin from removing the epitope of its cleavage site on the cloned thrombin receptor. Furthermore, peptide RPPGF or high-molecular-weight kininogen prevented α-thrombin from cleaving the thrombin receptor peptide, NATLDPRSFLLR, between arginine and serine.

Conclusions
These results indicate that bradykinin and its metabolites are selective antithrombins by preventing α-thrombin cleavage of the cloned thrombin receptor between arginine-41 and serine-42. These newly recognized antithrombin peptides, which are termed thrombostatins, contribute to the cardioprotective nature of kinins.
Factors Influencing Regional Myocardial Contractile Response to Inotropic Stimulation
Authors: Skopicki Hal A. , Abraham Stephen A. , Weissman Neil J. , Mukerjee Anil K. , Alpert Nathaniel M. , Fischman Alan J. , Picard Michael H. , Gewirtz Henry
Published: June 2012

Background
We hypothesized that the response of a myocardial segment to maximal dobutamine reflects not only maximal blood flow but also tethering, metabolic, and β-blocker status.

Methods and Results
Patients with stable ischemic heart disease (n=27) had positron emission tomographic measurement of blood flow at rest and with adenosine, and echocardiography at rest and with dobutamine. Positron emission tomographic measurement of [
18
F]fluorodeoxyglucose myocardial distribution also was made. Adenosine blood flow in segments that contracted normally at peak dobutamine was similar to that of segments that became hypokinetic (1.06±0.72 versus 1.02±0.77 mL·g
−1
·min
−1
). Segments that became akinetic failed to augment blood flow (0.68±0.30 mL·g
−
1
·min
−
1
). Fluorodeoxyglucose–blood flow mismatch was more common in segments with abnormal wall motion at peak dobutamine (24 of 59, 41%) versus those that contracted normally (63 of 269, 23%; χ
2
, 7.40;
P
<.01). In patients off β-blockers, segments that contracted normally at peak dobutamine increased blood flow with adenosine (0.70±0.31 to 0.86±0.46 mL·g
−
1
·min
−
1
;
P
<.05), whereas those that became abnormal did not (0.63±0.24 to 0.65±0.19 mL·g
−
1
·min
−
1
;
P
=NS). Segments of patients on β-blockers that contracted normally at peak dobutamine increased blood flow with adenosine (0.78±0.31 to 1.10±0.70 mL·g
−
1
·min
−
1
;
P
<.05), as did segments that became abnormal (0.74±0.34 to 1.06±0.82 mL·g
−
1
·min
−
1
;
P
=NS). However, segments adjacent to ones with abnormal wall motion at rest had higher frequency of abnormal response at peak dobutamine in groups on (48% versus 16%; χ
2
, 14.1;
P
<.001) and off (51% versus 21%; χ
2
, 10.9;
P
<.01) β-blockers.

Conclusions
Augmented contraction at maximal dobutamine depends not only on increased myocardial blood flow but also on tethering, metabolic, and β-blocker status. Furthermore, impaired flow reserve does not preclude a normal response to maximal dobutamine, since blood flow need not increase greatly to meet demand.
HERG, a Primary Human Ventricular Target of the Nonsedating Antihistamine Terfenadine
Authors: Roy Mary-Louise , Dumaine Robert , Brown Arthur M.
Published: June 2012

Background
Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K
+
current (I
Kur
) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go–related gene that expresses a delayed rectifier current (I
Kr
) in human ventricle and produces hereditary long QT syndrome when defective.

Methods and Results
We therefore heterologously expressed Kv1.5 and HERG in
Xenopus
oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent
K
d
values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 μmol/L, respectively. These
K
d
values compare well with values reported for terfenadine block of I
Kr
and I
Kur
currents in human atrial myocytes. The
K
d
value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range.

Conclusions
Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.
Quantitative Echocardiographic Analysis of the Aortic Arch Predicts Outcome of Balloon Angioplasty of Native Coarctation of the Aorta
Authors: Kaine Stephen F. , O'Brian Smith E. , Mott Antonio R. , Mullins Charles E. , Geva Tal
Published: June 2012

Background
The use of balloon angioplasty for treatment of native aortic coarctation is controversial. Cineangiographic data suggest that aortic arch hypoplasia and isthmic narrowing are associated with angioplasty failure. This study of echocardiographic measurements of preangioplasty aortic arch morphology was performed to identify potential anatomic predictors of outcome noninvasively.

Methods and Results
The preangioplasty echocardiograms of 105 patients 3 days to 17 years old with native coarctation of the aorta were analyzed off-line. Angioplasty was considered successful if the residual coarctation gradient was <20 mm Hg and no intervention for recoarctation occurred. Univariate analysis identified young age at angioplasty, presence of a patent ductus arteriosus, and the diameters of the aortic isthmus, distal transverse arch, and aortic valve as predictors of early and late outcomes. Multivariate analysis showed that the preangioplasty aortic isthmus
z
value was the best independent predictor of outcome, eliminating the effect on outcome of age and associated cardiac defects. An isthmus
z
value ≤−2.16 predicted early failure with 91% sensitivity and 85% specificity. Kaplan-Meier analysis demonstrated that 90% of patients with an isthmus
z
value >−1.0 remained free of recoarctation at late follow-up, whereas 89% of patients with a preangioplasty isthmus
z
value ≤−2.0 developed recoarctation within 36 months.

Conclusions

Echocardiographic measurements of the aortic arch predict both early and late outcomes of balloon angioplasty for native aortic coarctation, and the preangioplasty aortic isthmus
z
value was the best independent predictor. Quantitative aortic arch analysis may improve selection of angioplasty candidates who are likely to benefit from the procedure.
Nonmuscle and Smooth Muscle Myosin Heavy Chain Expression in Rejected Cardiac Allografts
Authors: Suzuki Jun-ichi , Isobe Mitsuaki , Aikawa Masanori , Kawauchi Motohiro , Shiojima Ichiro , Kobayashi Naoto , Tojo Akihiro , Suzuki Toru , Kimura Kenjiro , Nishikawa Toshio , Sakai Tatsuo , Sekiguchi Morie , Yazaki Yoshio , Nagai Ryozo
Published: June 2012

Background
Diagnosis of acute rejection and graft arteriosclerosis (chronic rejection) is critical to the success of cardiac transplantation, but accurate diagnosis is often difficult. We have reported that there are three types of vascular myosin heavy chain (MHC) isoforms: SM1, SM2, and SMemb. SM2 is specifically expressed in differentiated smooth muscle cells (SMCs). SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of fetal aorta.

Methods and Results
To evaluate the usefulness of MHC expression for diagnosis and analysis of acute and chronic rejection, heterotopic cardiac transplantation was performed in rats and monkeys. Immunohistochemistry, electron microscopy, and Northern blot assay were performed to evaluate MHC expression. SMemb was expressed in spindle-shaped cells located in acutely rejected myocardium in the rats and monkeys. These cells were also observed in areas lacking cellular infiltration. These SMemb-positive cells were activated fibroblasts or myofibroblasts. SMemb mRNA was enhanced parallel to the progression of acute rejection. In the coronary arteries of chronically rejected allografts, enhanced SMemb and reduced SM2 expression was observed in both thickened intima and media. The reduced medial SM2 expression was observed before the intimal thickening occurred. These cells were phenotypically modulated SMCs.

Conclusions
Altered expression of MHC isoforms is a sensitive indicator in the diagnosis of acute and chronic cardiac rejection. The pathophysiology of this alteration in MHC isoform expression should be studied further to elucidate the pathogenesis of cardiac rejection.
Fish Intake May Limit the Increase in Risk of Coronary Heart Disease Morbidity and Mortality Among Heavy Smokers
Authors: Rodriguez Beatriz L. , Sharp Dan S. , Abbott Robert D. , Burchfiel Cecil M. , Masaki Kamal , Chyou Po-Huang , Huang Boji , Yano Katsuhiko , Curb Jess David
Published: June 2012

Background
Research has shown that fish consumption limits damage to the lungs caused by cigarette smoking, possibly by the effects of fish on arachidonic acid metabolism. We explored this fish-smoking interaction using coronary heart disease (CHD) incidence and mortality as the outcome.

Methods and Results
The Honolulu Heart Program began in 1965 to follow a cohort of 8006 Japanese-American men aged 45 to 65 years who lived on Oahu, Hawaii, in 1965. Fish intake was measured at baseline by use of a questionnaire. For current smokers at baseline (n=3310) who reported low fish intake (<2 times/wk), age-adjusted 23-year CHD mortality rates increased with the number of cigarettes smoked per day (2.3, 3.1, and 6.9 per 1000 person-years for men who smoked <20, 20 to 30, and >30 cigarettes/d, respectively; trend test
P
<.0001). Among current smokers whose fish intake was high (≥2 times/wk), CHD mortality rates showed no relation with cigarettes/d (3.7, 3.2, and 3.7 per 1000 person-years for the corresponding levels of smoking). A Cox proportional hazards model based on current smokers, adjusted for age, years in Japan, calories/d, alcohol intake, physical activity index, years smoked, hypertension, and serum cholesterol, blood glucose, and uric acid levels, was examined. In the high-smoking group, the risk factor–adjusted relative risk (RR) for CHD mortality among those with high fish intake was half that of those with low fish consumption (RR=0.5, 95% confidence interval=0.28 to 0.91). A Cox model that adjusted for similar risk factors confirmed a significant interaction of cigarettes/d and fish intake (
P
<.01) on CHD mortality. Analyses for CHD incidence showed similar results.

Conclusions
Despite the findings of this investigation, the public health message for smokers continues to be to stop smoking. However, an interaction between fish intake and cigarette smoking is biologically plausible and deserves further investigation. The study of this phenomenon may shed light on the biological mechanisms by which cigarette smoking leads to CHD.
Evidence for Functional Relevance of an Enhanced Expression of the Na
+
-Ca
2+
Exchanger in Failing Human Myocardium
Authors: Flesch Markus , Schwinger Robert H.G. , Schiffer Frank , Frank Konrad , Su¨dkamp Michael , Kuhn-Regnier Ferdinand , Arnold Georg , Bo¨hm Michael
Published: June 2012

Background
The present study aimed at investigating the expression of the Na
+
-Ca
2+
exchanger and its functional role in human failing myocardium.

Methods and Results
Na
+
-Ca
2+
exchanger mRNA and protein levels were examined in nonfailing (NF, n=8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n=8) or ischemic heart disease (ICM, n=6). The inotropic effect of the Na
+
channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37°C) from nonfailing (n=8) and failing (n=8) human hearts. Na
+
-Ca
2+
exchanger mRNA levels were significantly increased, by 79% (
P
<.001) in DCM and by 58% (
P
<.01) in ICM compared with NF; protein levels increased by 36% (
P
<.001) and by 20% (
P
<.05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (
P
<.01) EC
50
value (NYHA class IV, 0.18 [0.16 to 0.22] μmol/L; NF, 1.65 [1.3 to 3.0] μmol/L). In NYHA class IV, BDF 9148 (0.1 μmol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction.

Conclusions
The increased expression of the Na
+
-Ca
2+
exchanger is a possible explanation for the increased inotropic potency of the Na
+
channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na
+
concentration. Enhancement of Na
+
-Ca
2+
exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.
Lack of Increased Coronary Atherosclerotic Risk Due to Elevated Lipoprotein(a) in Women ≥55 Years of Age
Authors: Sunayama Satoshi , Daida Hiroyuki , Mokuno Hiroshi , Miyano Hiroshi , Yokoi Hisashi , Lee Young Joon , Sakurai Hidehiko , Yamaguchi Hiroshi
Published: June 2012

Background
Numerous studies have indicated that there is an association between lipoprotein(a) [Lp(a)] and coronary artery disease (CAD) in middle-aged men; however, few studies have addressed this issue in women or the elderly.

Methods and Results
Serum Lp(a) concentrations were determined in 354 women and 706 men with or without angiographically defined CAD (one or more coronary arteries with narrowing of ≥75%). The age-specific impact of elevated Lp(a) (≥30 mg/dL) on CAD was examined in each sex. In the younger age group (<55 years old), elevated Lp(a) was independently associated with CAD in both sexes (adjusted odds ratio [OR]: women, 6.90,
P
<.01; men, 2.63,
P
<.05). The age-specific ORs declined with age, and elevated Lp(a) no longer conferred an increased CAD risk in either elderly men or women ≥65 years old. In the age group of 55 to 64 years, elevated Lp(a) was positively associated with CAD for men (adjusted OR: 2.45,
P
<.05) but not for women (adjusted OR: 0.56,
P
=NS).

Conclusions
For both sexes, elevated Lp(a) appears to be an independent risk factor for premature CAD and the importance of Lp(a) appears to decrease with age. However, for women, the risk estimate of Lp(a) began to decline at an age ≈10 years younger than for men. These data suggest that not only age- but also sex-specific factors such as menstrual status may interact with the association between Lp(a) and CAD.
Prognostic Significance of Admission Troponin T Concentrations in Patients With Myocardial Infarction
Authors: Stubbs Peter , Collinson Paul , Moseley David , Greenwood Trevor , Noble Mark
Published: June 2012

Background
New, highly specific cardiac structural proteins can now be measured. The early presence of one of these proteins, troponin T, has been found to have important prognostic significance in patients with unstable angina pectoris. The prognostic significance of its presence on admission was assessed in patients with myocardial infarction.

Methods and Results
Two hundred forty patients admitted with myocardial infarction were studied and followed prospectively for a median of 3 years. The prognostic significance of an admission troponin T concentration ≥0.2 ng/mL for subsequent cardiac death and/or reinfarction was assessed and compared with other variables in a regression model. Any detectable troponin T on admission was associated with a worse prognosis on follow-up. An admission concentration of ≥0.2 ng/mL was associated with a higher risk of subsequent cardiac death (χ
2
, 13.3;
P
=.0002) and death or nonfatal reinfarction (χ
2
, 16;
P
=.00006). The excess risk was seen primarily in patients with admission ECG ST-segment elevation (cardiac death χ
2
, 9.7;
P
=.001; death or nonfatal reinfarction χ
2
, 10.3;
P
=.001). In a stepwise regression model for cardiac death or nonfatal reinfarction, troponin T was superior to most of the other variables entered in both myocardial infarction subgroups.

Conclusions
The presence of admission troponin T in patients with myocardial infarction defines a subgroup, particularly those with ST-segment elevation, at increased risk of subsequent cardiac events and identifies a group that may benefit from alternative early management strategies.
Local Intraluminal Infusion of Biodegradable Polymeric Nanoparticles
Authors: Guzman Luis A. , Labhasetwar Vinod , Song Cunxian , Jang Yangsoo , Lincoff A. Michael , Levy Robert , Topol Eric J.
Published: June 2012

Background
Several perfusion balloon catheters are under investigation for local drug delivery; however, sustained tissue drug levels are difficult to achieve with these techniques. To overcome this problem, sustained-release, biodegradable nanoparticles represent a potential alternative for prolonged local delivery.

Methods and Results
A biodegradable polylactic-polyglycolic acid (PLGA) copolymer was used to formulate nanoparticles. Fluorescent-labeled nanoparticles were intraluminally administered in a single, 180-second infusion after balloon injury in the rat carotid model. Localization and retention at different time points and biocompatibility of nanoparticles were evaluated. To evaluate the potential of the system in the prevention of neointimal formation, dexamethasone was incorporated into the particles and delivered locally as above. Nanoparticles were seen in the three layers of the artery at 3 hours and 24 hours. At 3 days, they were mainly present in the adventitial layer, decreasing at 7 days, with no fluorescent activity at 14 days. The PLGA nanoparticles appeared to be fully biocompatible. In the dexamethasone nanoparticle study, a significant amount of dexamethasone was present in the treated segment for up to 14 days after a single infusion, with no plasma levels detected after the first 3 hours. There was a 31% reduction in intima-media ratio in animals treated with local dexamethasone nanoparticles compared with control.

Conclusions
Nanoparticles successfully penetrated into the vessel wall and persisted for up to 14 days after a short, single intraluminal infusion. Local administration of nanoparticles with incorporated dexamethasone significantly decreased neointimal formation. This methodology appears to have important potential for clinical applications in local drug delivery.
Intracoronary Stent Implantation Without Ultrasound Guidance and With Replacement of Conventional Anticoagulation by Antiplatelet Therapy
Authors: Karrillon Gae¨tan J. , Morice Marie Claude , Benveniste Edgar , Bunouf Pierre , Aubry Pierre , Cattan Simon , Chevalier Bernard , Commeau Philippe , Cribier Alain , Eiferman Charles , Grollier Gilles , Guerin Yves , Henry Michel , Lefevre Thierry , Livarek Bernard , Louvard Yves , Marco Jean , Makowski Serge , Monassier Jean Pierre , Pernes Jean Marc , Rioux Philippe , Spaulding Christian , Zemour Gilles
Published: June 2012

Background
Stenting reduces both acute complications of coronary angioplasty and restenosis rates but increases subacute thrombosis rates and hemorrhagic complications when used with coumadin anticoagulation.

Methods and Results
To simplify postcoronary stenting treatment and to reduce these drawbacks, we evaluated the 1-month outcome of a prospective registry of 2900 patients in whom successful coronary artery stenting was performed without coumadin anticoagulation. Patients received 100 mg/d aspirin and 250 mg/d ticlopidine for 1 month. Low-molecular-weight heparin (LMWH) treatment was progressively reduced in four consecutive stages, from 1-month treatment to none. Event-free outcome at 1 month was achieved in 2816 patients (97.1%). Major stent-related cardiac events were subacute closure in 51 patients (1.8%), including death in 12 (0.5%), acute myocardial infarction in 17 (0.6%), and coronary artery bypass graft surgery in 9 (0.3%). Stent thrombosis was more frequent with balloon size of <3.0 mm (≤2.5 mm, 10%; 3.0 mm, 2.3%; ≥3.5 mm, 1.0%;
P
<.001), bail-out situations (6.67% versus 1.38%,
P
<.001), and patients with unstable angina or acute myocardial infarction (2.2% versus 1.12%,
P
=.02). Bleeding complications that required transfusion, surgical repair, or both occurred in 55 patients (1.9%). Bleeding complications were related to female gender (4.0% versus 1.51%,
P
<.001), duration of LMWH treatment (3.83% in phase II/III versus 0.69% in phase IV/V,
P
<.001), sheath size (6F, 0.52%; 7F, 1.04%; ≥8F, 4.23%;
P
<.001), bail-out situations (4.76% versus 1.67%,
P
<.01), and saphenous graft stenting (4.38% versus 1.75%,
P
=.04).

Conclusions
These results suggest that poststenting treatment by ticlopidine/aspirin is an effective alternative to coumadin anticoagulation, achieving low rates of subacute closure and bleeding complications. LMWH treatment does not improve subacute reocclusion rates but increases bleeding complications. Furthermore, as bleeding complications were independently related to sheath size, we suggest that stenting with 6F guiding catheters may prevent local complications. Furthermore, the ticlopidine/aspirin combination allows a low-cost stenting strategy without ultrasound assessment of stent deployment and permits short in-hospital stay.
Circulatory Status and Response to Cardiac Rehabilitation in Patients With Heart Failure
Authors: Wilson John R. , Groves Jay , Rayos Glenn
Published: June 2012

Background
We recently reported that some patients with heart failure and exercise intolerance exhibit severe hemodynamic dysfunction during exercise, whereas others have normal cardiac output responses to exercise. We postulated that patients with preserved cardiac output responses to exercise are limited by deconditioning and would respond to exercise training, whereas patients with reduced cardiac output responses are limited by skeletal muscle underperfusion and would not improve with exercise training. The present study was undertaken to test this hypothesis.

Methods and Results
Thirty-two patients with heart failure were studied. Hemodynamic response to maximal treadmill exercise was measured; then patients were enrolled in a standard 3-month cardiac rehabilitation program. Peak exercise V
o
2
, lactate threshold, and quality-of-life questionnaires were assessed at 1, 2, and 3 months. Twenty-one patients had normal cardiac output responses to exercise. All 21 patients participated in the rehabilitation program without difficulty, and 9 (43%) responded to rehabilitation, defined as a >10% increase in both peak exercise V
o
2
and the anaerobic threshold. Of the 11 patients with reduced cardiac output responses to exercise, 3 discontinued rehabilitation because of severe exhaustion, and only 1 qualified as a responder (9%;
P
<.04 versus preserved cardiac output).

Conclusions
Patients with heart failure and normal cardiac output responses to exercise frequently improve with exercise training. Patients with severe hemodynamic dysfunction during exercise usually do not improve with training, which suggests that they are limited primarily by circulatory factors.
Influence of Dofetilide on QT-Interval Duration and Dispersion at Various Heart Rates During Exercise in Humans
Authors: De´molis Jean-Louis , Funck-Brentano Christian , Ropers Jacques , Ghadanfar Mathieu , Nichols Donald J. , Jaillon Patrice
Published: June 2012

Background
The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects.

Methods and Results
Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QT
max
and QT
min
were calculated similarly, and QT-interval dispersion was measured as QT
max
−QT
min
at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7±8.7% at a heart rate of 60 bpm (
P
<.01) and by 7.4±8.2% at a heart rate of 150 bpm (
P
<.05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate.

Conclusions
Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.
Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo
Authors: Juul Klaus , Nielsen Lars B. , Munkholm Klaus , Stender Steen , Nordestgaard Børge G.
Published: June 2012

Background
The aim of the present study was to investigate whether oxidized LDL (ox-LDL) in the arterial intima could be derived from LDL already oxidized in plasma.

Methods and Results
Rabbits received an intravenous injection of
125
I-labeled normal LDL (N-LDL) mixed with
131
I-labeled LDL that had been mildly oxidized through exposure to Cu
2+
. The aortic accumulation of undegraded labeled LDL was expressed as plasma equivalents and calculated as radioactivity in the intima/inner media (cpm/cm
2
) divided by the time-averaged concentration of radioactivity in plasma (cpm/nL): for the thoracic aorta, the accumulation of undegraded ox-LDL in the intima/inner media exceeded that of undegraded N-LDL by 286% (n=6,
P
<.04), 863% (n=7,
P
<.02), and 364% (n=8,
P
<.01) after 1, 3, and 24 hours of exposure, respectively. There was a strong positive association between the extent of oxidation and the excess accumulation of undegraded ox-LDL compared with N-LDL (thoracic aorta; 3 hours of exposure:
r
=.97, n=14,
P
<.00001). To measure degradation of N-LDL and ox-LDL,
125
I-LDL labeled with
131
I-tyramine cellobiose was injected intravenously 24 hours before the aortic intima/inner media was removed: for the thoracic aorta, the accumulation of degradation products from ox-LDL (n=6) exceeded that from N-LDL (n=6) by 301% (
P
<.04).

Conclusions
The present data suggest a novel mechanism: mildly oxidized LDL may circulate in plasma for a period sufficiently long to enter, accumulate, and be degraded in the arterial intima in preference to N-LDL.
Precapillary Servo Control of Blood Pressure and Postcapillary Adjustment of Flow to Tissue Metabolic Status
Authors: Groebe Karlfried
Published: June 2012

Background
There are several shortcomings in current understanding of how the microvasculature maintains tissue homeostasis. Presently unresolved issues include (1) integration of the potentially conflicting needs for capillary perfusion and hydrostatic pressure regulation, (2) an understanding of signal transmission pathways for conveying information about tissue energetic status from undersupplied tissue sites to the arterioles, (3) accounting for the experimentally observed interrelations between precapillary and postcapillary resistances, and (4) an explanation of how precise local adjustment of perfusion to metabolic demands is achieved.

Methods and Results
A novel conceptualization of how local microvascular control mechanisms are coordinated is proposed, according to which blood flow is adjusted to the metabolic needs of the tissue by the venules. Arteriolar action is merely called on for controlling capillary pressure through myogenic response and shear stress–induced vasodilation. A mathematical model of this theory is introduced and evaluated using well-established experimental data from the literature on regulating mechanisms of microvessel diameters exclusively. The model results demonstrate the suggested mode of microvascular operation to be functional and efficient under conditions present in vivo. Moreover, the predicted vascular responses are large enough to cover the entire range observed in exercising skeletal muscle during adjustment of perfusion to higher performance levels.

Conclusions
Precapillary pressure regulation combined with postcapillary adjustment of perfusion to tissue metabolic status is suitable to resolve the above shortcomings in our current understanding of microvascular control. With mathematical modeling based on experimental data, this mode of microvascular operation is shown to be functional and effective in controlling muscle microcirculation.
Radiofrequency Catheter Ablation of Right Ventricular Tachycardia Late After Repair of Congenital Heart Defects
Authors: Gonska Bernd-Dieter , Cao Kejiang , Raab Johann , Eigster Georg , Kreuzer Heinrich
Published: June 2012

Background
Ventricular arrhythmias after repair of congenital heart defects are a common finding and possibly contribute to sudden death in these patients. Optimal antiarrhythmic management has not yet been defined.

Methods and Results
The study population consisted of 16 patients in whom ventricular arrhythmias occurred 11 to 42 years after complete surgical repair of congenital heart defects. Fifteen patients had a history of symptomatic sustained or nonsustained ventricular tachycardia, and 1 had frequent nonsustained ventricular tachycardia. The diagnostic mapping procedure to identify the origin of the arrhythmia included pace mapping during sinus rhythm, activation mapping, and pacing interventions during ventricular tachycardia. Catheter ablation was carried out by means of radiofrequency energy in the temperature-controlled mode. The follow-up period was 6 to 33 months (mean, 16 months). A right ventricular origin of the tachycardia in the surgically corrected area could be determined in all patients. Catheter ablation was carried out without complications. Immediate noninducibility was achieved in 15 of the 16 patients. One patient in whom the tachycardia was again inducible at repeat stimulation 1 week later was successfully treated with amiodarone. Eleven patients were taken off antiarrhythmic drugs. During follow-up, none of them had a recurrence of the tachycardia that had been ablated.

Conclusions
In patients with symptomatic or frequent ventricular tachycardia late after complete surgical repair of congenital heart defects, catheter ablation by means of radiofrequency energy is feasible and safe and thus might be taken into consideration for these patients. Short-term follow-up results are promising.
Reduction in Myocardial Infarct Size by Basic Fibroblast Growth Factor After Temporary Coronary Occlusion in a Canine Model
Authors: Horrigan Mark C.G. , MacIsaac Andrew I. , Nicolini Francesca A. , Vince D. Geoffrey , Lee Philmo , Ellis Stephen G. , Topol Eric J.
Published: June 2012

Background
Basic fibroblast growth factor (bFGF) has been shown to reduce infarct size in canine acute myocardial infarction; however, the mechanism of tissue salvage remains uncertain. We evaluated the effect of bFGF on infarct size in a model of acute infarction in which coronary occlusion was followed by prolonged reperfusion and sought to determine whether reperfusion attenuates the stimulus for myocardial neovascularization.

Methods and Results
Anesthetized dogs undergoing 4-hour balloon occlusion of the left anterior descending coronary artery were treated with intracoronary bFGF (n=8) or vehicle (n=6). Ten-microgram doses of bFGF were administered 10 minutes after occlusion and again immediately before reperfusion. Left ventriculograms were obtained before occlusion, after reperfusion, and preceding euthanasia on day 7. Infarct size, expressed as a percentage of the area at risk, was reduced in bFGF-treated dogs (13.7±2.1% versus 28±3.4%;
P
=.002). Changes in left ventricular ejection fraction, capillary density, and cellular proliferation—assessed immunohistochemically with factor VIII and proliferating cell nuclear antigen antibodies—were similar in both groups. To assess coronary vasomotor responses to bFGF, a separate hemodynamic study was performed in five anesthetized nonischemic dogs in which incremental bFGF doses up to 100 μg induced no vasodilator response.

Conclusions
Treatment with bFGF was associated with a reduction in infarct size without hemodynamic effects or evidence of neovascularization. These data suggest that bFGF mediates myocardial salvage independently of angiogenesis and that reperfusion after infarction may attenuate the stimulus for neovascularization.
Relative Role of Alkalosis and Sodium Ions in Reversal of Class I Antiarrhythmic Drug–Induced Sodium Channel Blockade by Sodium Bicarbonate
Authors: Bou-Abboud Elias , Nattel Stanley
Published: June 2012

Background
Hypertonic sodium salts are used to treat sodium channel–blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na
+
]
o
) for various drugs are incompletely known.

Methods and Results
The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equi-effective concentrations (disopyramide 30 μmol/L, mexiletine 80 μmol/L, flecainide 7 μmol/L, imipramine 5 μmol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na
+
]
o
, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (V
max
) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na
+
]
o
contributed to the interaction with flecainide and mexiletine. The reversal of V
max
depression by increased [Na
+
]
o
and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in V
max
inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine.

Conclusions
Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel–blocking drugs.
Homocysteine and Risk of Premature Coronary Heart Disease
Authors: Gallagher Paula M. , Meleady Raymond , Shields Denis C. , Tan Kok Soon , McMaster Dorothy , Rozen Rima , Evans Alun , Graham Ian M. , Whitehead Alexander S.
Published: June 2012

Background
Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease.

Methods and Results
To examine the hypothesis that the allele (T) that codes for the thermolabile defect increases the risk of coronary heart disease, we studied 111 patients with clinical and objective investigational evidence of coronary heart disease and 105 control subjects. The frequencies of the thermolabile defect (T) in patients and control subjects were measured, and the prevalence of elevated plasma total homocysteine according to genotype was assessed. The frequency of the defective allele was higher in patients than in control subjects with an OR of 1.6 (95% CI, 1.1 to 2.4;
P
=.02). The OR in the coronary heart disease group for the homozygous TT genotype was 2.9 (95% CI, 1.2 to 7.2;
P
=.02); 17% of patients and 7% of control subjects had the TT genotype. Plasma total homocysteine levels were significantly associated with disease status, a relationship that matched the strength of the association between disease and homozygous inheritance of the defective enzyme.

Conclusions
Homozygotes for the defective allele (T) are at increased risk of premature coronary heart disease. MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population.
Reflex Coronary Vasoconstriction Caused by Gallbladder Distension in Anesthetized Pigs
Authors: Vacca Giovanni , Battaglia Antonio , Grossini Elena , Mary David A.S.G. , Molinari Claudio
Published: June 2012

Background
Gallbladder distension in anesthetized pigs reflexly increases heart rate and arterial pressure by means of afferent vagal pathways and efferent sympathetic mechanisms. The effect of such distension on the coronary circulation is unknown. The present study was undertaken to determine whether gallbladder distension primarily causes reflex changes in left circumflex blood flow.

Methods and Results
In 21 pigs anesthetized with sodium pentobarbitone (16) or α-chloralose (5), left circumflex blood flow was measured with an electromagnetic flowmeter. A balloon positioned within the gallbladder was distended with volumes of Ringer's solution equal to the volumes of bile previously withdrawn (mean vol: 62 mL; mean gallbladder pressure: 12 mm Hg). Heart rate and arterial pressure were kept constant by atrial pacing and by a pressurized reservoir connected to the left femoral artery. Gallbladder distension always caused a decrease in circumflex blood flow. In 6 of the 16 sodium pentobarbitone–anesthetized pigs, this decrease was graded by step increments of distension. In 5 of these 16 pigs, the decrease in circumflex blood flow was not affected by atropine. In 10 of these 16 pigs, including those given atropine, the response was not affected by propranolol but was abolished by subsequently giving phentolamine. Cervical vagotomy abolished the coronary vasoconstriction in the remaining 6 pigs. In the 5 α-chloralose–anesthetized pigs, the response was not significantly affected by cutting the splanchnic nerves but was abolished by subsequent cervical vagotomy.

Conclusions
The present study showed that innocuous distension of the gallbladder in anesthetized pigs caused a reflex coronary vasoconstriction that involved efferent sympathetic mechanisms related to α-adrenoceptors and afferent vagal pathways.
Inhibition of Acute Stent Thrombosis Under High-Shear Flow Conditions by a Nitric Oxide Donor, DMHD/NO
Authors: Kaul Sanjay , Makkar Raj R. , Nakamura Masato , Litvack Frank I. , Shah Prediman K. , Forrester James S. , Hutsell Thomas C. , Eigler Neal L.
Published: June 2012

Background
Coronary stenting is limited by subacute thrombosis, especially in smaller-diameter vessels, in which shear rates are high. The objective of the present study was to determine whether local delivery of a new type of NO donor, the NO adduct of
N,N′
-dimethylhexanediamine (DMHD/NO), inhibits acute stent thrombosis (ST) at high-shear flow.

Methods and Results
Effects of local infusion of DMHD/NO, intravenous aspirin, and heparin on ST were evaluated in an ex vivo porcine AV shunt model. Nitinol stents (2 mm in diameter, n=120) were placed in a tubular chamber and perfused with blood from pigs (n=13) at a shear rate of 2100 s
−1
for 20 minutes. ST was quantified by measurement of dry thrombus weight (TW). Effects on platelet aggregation (PA), blood pressure, bleeding time, and activated clotting time (ACT) were also examined. There was a dose-dependent inhibition of ST and PA by DMHD/NO. TW was reduced by 95% (1±2 versus 16±4 mg control, mean±SD,
P
<.001), and PA was reduced by 75% (4±3 versus 14±9 Ω/min control,
P
<.05) at the highest dose of 10 μmol/L. DMHD/NO had no effects on bleeding time, ACT, or blood pressure. In contrast, aspirin (10 mg/kg), despite inhibiting PA, had no effects on TW (12±5 versus 16±8 mg control,
P
=.3). Heparin (200 U/kg) reduced TW by 33% (14±4 versus 21±3 mg control,
P
<.05) and prolonged ACT.

Conclusions
Local delivery of DMHD/NO produced a 15-fold inhibition of acute ST at high-shear flow without producing adverse systemic hemostatic or hemodynamic effects. Thus, treatment with DMHD/NO may be an effective strategy for prevention of stent thrombosis.
Comparison of Effective and Ineffective Target Sites That Demonstrate Concealed Entrainment in Patients With Coronary Artery Disease Undergoing Radiofrequency Ablation of Ventricular Tachycardia
Authors: Bogun Frank , Bahu Marwan , Knight Bradley P. , Weiss Raul , Paladino Walter , Harvey Mark , Goyal Rajiva , Daoud Emile , Man K. Ching , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
Concealed entrainment has been useful in guiding catheter ablation of monomorphic ventricular tachycardia in patients with coronary artery disease. However, not all sites with concealed entrainment result in successful ablation of the targeted ventricular tachycardia. The purpose of this prospective study was to identify factors at sites that demonstrate concealed entrainment that differentiate effective from ineffective target sites.

Methods and Results
In 14 consecutive patients with hemodynamically stable monomorphic ventricular tachycardia and coronary artery disease, radiofrequency ablation of 26 ventricular tachycardias was performed. Ablation was attempted at 46 sites that demonstrated concealed entrainment. Twenty-five of the targeted ventricular tachycardias (96%) were successfully ablated. The positive predictive value of concealed entrainment for successful ablation was 54%; it increased to 72% in the presence of a stimulus-QRS interval/ventricular tachycardia cycle length ratio of ≤70%, to 82% in the presence of a match of the stimulus-QRS and electrogram-QRS interval, and to 89% in the presence of isolated middiastolic potentials that could not be dissociated from ventricular tachycardia during entrainment.

Conclusions
The positive predictive value of concealed entrainment for identification of successful ablation sites in patients with sustained ventricular tachycardia and coronary artery disease can be significantly enhanced by the presence of associated mapping criteria, particularly an isolated mid diastolic potential that cannot be dissociated from the tachycardia.