bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobilization of Endothelial Progenitor Cells in Patients With Acute Myocardial Infarction
Authors: Shintani Satoshi , Murohara Toyoaki , Ikeda Hisao , Ueno Takafumi , Honma Tomoki , Katoh Atsushi , Sasaki Ken-ichiro , Shimada Toshifumi , Oike Yuichi , Imaizumi Tsutomu
Published: September 2007

Background
—Endothelial progenitor cells (EPCs) circulate in adult peripheral blood (PB) and contribute to neovascularization. However, little is known regarding whether EPCs and their putative precursor, CD34-positive mononuclear cells (MNC
CD34+
), are mobilized into PB in acute ischemic events in humans.

Methods and Results
—Flow cytometry revealed that circulating MNC
CD34+
counts significantly increased in patients with acute myocardial infarction (n=16), peaking on day 7 after onset, whereas they were unchanged in control subjects (n=8) who had no evidence of cardiac ischemia. During culture, PB-MNCs formed multiple cell clusters, and EPC-like attaching cells with endothelial cell lineage markers (CD31, vascular endothelial cadherin, and kinase insert domain receptor) sprouted from clusters. In patients with acute myocardial infarction, more cell clusters and EPCs developed from cultured PB-MNCs obtained on day 7 than those on day 1. Plasma levels of vascular endothelial growth factor significantly increased, peaking on day 7, and they positively correlated with circulating MNC
CD34+
counts (
r
=0.35,
P
=0.01).

Conclusions
—This is the first clinical demonstration showing that lineage-committed EPCs and MNC
CD34+
, their putative precursors, are mobilized during an acute ischemic event in humans.
Rapid Three-Dimensional Echocardiography
Authors: Belohlavek Marek , Tanabe Kazuaki , Jakrapanichakul Decho , Breen Jerome F. , Seward James B.
Published: September 2007

Background
—Clinical applicability of conventional ultrasonographic systems using mechanical adapters for 3D echocardiographic imaging has been limited by long acquisition and processing times. We developed a rapid (6-s) acquisition technique that collects apical tomograms using a continuously internally rotating transthoracic transducer. This study was performed to examine the clinical feasibility of rapid-acquisition 3D echocardiography to estimate left ventricular end-diastolic and end-systolic volumes using electron-beam computed tomography as the reference standard.

Methods and Results
—We collected a series of 6 to 11 apical echocardiographic tomograms, depending on heart rate, in 11 patients. There was good correlation, low variability, and low bias between rapid 3D echocardiography and electron-beam computed tomography for measuring left ventricular end-diastolic volume (
r
=0.96; standard error of the estimate, 21.34 mL; bias, −4.93 mL) and left ventricular end-systolic volume (
r
=0.96; standard error of the estimate, 14.78 mL; bias, −6.97 mL).

Conclusions
—The rapid-acquisition 3D echocardiography extends the use of a multiplane, internally rotating handheld transducer so that it becomes a precise and clinically feasible tool for assessing left ventricular volumes and function. A rapid-image acquisition time of 6 s would allow repeated image collection during the course of a clinical echocardiographic examination. Additional work must address rapid and automated data processing.
High-Dose Recombinant Apolipoprotein A-I
Milano
Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E–Deficient Mice
Authors: Shah Prediman K. , Yano Juliana , Reyes Odette , Chyu Kuang-Yuh , Kaul Sanjay , Bisgaier Charles L. , Drake Sandra , Cercek Bojan
Published: September 2007

Background
—Repeated doses of recombinant apolipoprotein A-I
Milano
phospholipid complex (apoA-I
m
) reduce atherosclerosis and favorably change plaque composition in rabbits and mice. In this study, we tested whether a single high dose of recombinant apoA-I
m
could rapidly mobilize tissue cholesterol and reduce plaque lipid and macrophage content in apoE-deficient mice.

Methods and Results
—High cholesterol–fed, 26-week-old apoE-deficient mice received a single intravenous injection of saline (n=16), 1080 mg/kg dipalmitoylphosphatidylcholine (DPPC; n=14), or 400 mg/kg of recombinant apoA-I
m
complexed with DPPC (1:2.7 weight ratio; n=18). Blood was sampled before and 1 and 48 hours after injection, and aortic root plaques were evaluated for lipid content and macrophage content after oil-red O and immunostaining, respectively. One hour after injection, the plasma cholesterol efflux–promoting capacity was nearly 2-fold higher in recombinant apoA-I
m
–treated mice compared with saline and DPPC-treated mice (
P
<0.01). Compared with baseline values, serum free cholesterol, an index of tissue cholesterol mobilization, increased 1.6-fold by 1 hour after recombinant apoA-I
m
injection, and it remained significantly elevated at 48 hours (
P
<0.01). Mice receiving recombinant apoA-I
m
had 40% to 50% lower lipid content (
P
<0.01) and 29% to 36% lower macrophage content (
P
<0.05) in their plaques compared with the saline- and DPPC-treated mice, respectively.

Conclusions
—A single high dose of recombinant apoA-I
m
rapidly mobilizes tissue cholesterol and reduces plaque lipid and macrophage content in apoE-deficient mice. These findings suggest that this strategy could rapidly change plaque composition toward a more stable phenotype.
Impact of Viral and Bacterial Infectious Burden on Long-Term Prognosis in Patients With Coronary Artery Disease
Authors: Rupprecht Hans J. , Blankenberg Stefan , Bickel Christoph , Rippin Gerd , Hafner Gerd , Prellwitz Wilfried , Schlumberger Wolfgang , Meyer Jürgen
Published: September 2007

Background
—The number of infectious pathogens to which an individual has been exposed (infectious burden) may correlate with coronary artery disease (CAD). In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the risk for future fatal cardiac events among patients with angiographically documented CAD.

Methods and Results
—In 1018 patients, IgG or IgA antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus,
Haemophilus influenzae
,
Chlamydia pneumoniae
,
Mycoplasma pneumoniae
, and
Helicobacter pylori
were determined. Moreover, highly sensitive C-reactive protein was measured. Follow-up information on cardiovascular events was obtained (mean 3.1 years, maximum 4.3 years). Seropositivities to Epstein-Barr virus (
P
=0.001),
H pylori
(
P
=0.002), and herpes simplex virus type 2 (
P
=0.045) were independently associated with the future risk of cardiovascular death. An increasing number for pathogen burden was significantly predictive of the long-term prognosis (
P
<0.0001). Infectious burden divided into 0 to 3, 4 or 5, and 6 to 8 seropositivities was associated with an increasing mortality of 3.7%, 7.2%, and 12.6%, respectively. Patients seropositive to >5 pathogens compared with those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae (
P
<0.0001). The prognostic impact of total or viral pathogen burden was independent of the C-reactive protein level.

Conclusions
—These results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD.
Permanent Cardiac Pacing Versus Medical Treatment for the Prevention of Recurrent Vasovagal Syncope
Authors: Ammirati Fabrizio , Colivicchi Furio , Santini Massimo
Published: September 2007

Background
—This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope.

Methods and Results
—Patients from 14 centers were randomized to receive either a DDD pacemaker provided with rate-drop response function or the β-blocker atenolol at the dosage of 100 mg once a day. Inclusion criteria were age >35 years, ≥3 syncopal spells in the preceding 2 years, and positive response to tilt table testing with syncope occurring in association with relative bradycardia. The primary outcome was the first recurrence of syncope after randomization. Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1±14.3 years) had been enrolled and randomized, although follow-up data were available for all patients (46 patients in the pacemaker arm, 47 patients in the pharmacological arm). The interim analysis showed a significant effect in favor of permanent cardiac pacing (recurrence of syncope in 2 patients [4.3%] after a median of 390 days) compared with medical treatment (recurrence of syncope in 12 patients [25.5%] after a median of 135 days; OR, 0.133; 95% CI, 0.028 to 0.632;
P
=0.004). Consequently, enrollment and follow-up were terminated.

Conclusions
—DDD pacing with rate-drop response function is more effective than β-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope.
Mechanoelectrical Feedback
Authors: Lerman Bruce B. , Engelstein Erica D. , Burkhoff Daniel
Published: September 2007

Background—

Augmented preload increases myocardial excitability by shortening action potential duration (APD). The mechanism governing this phenomenon is unknown. Because myocardial stretch increases intracellular cAMP, we hypothesized that load-dependent changes in myocardial excitability are mediated by β-adrenergic stimulation of a cAMP-sensitive K
+
current.

Methods and Results—

The effects of propranolol on load-induced changes in electrical excitability were studied in 7 isolated ejecting canine hearts. LV monophasic APD at 50% and 90% repolarization (MAPD
50
and MAPD
90
) and refractoriness were determined at low (9±3 mL) and high (39±4 mL) load before and after β-adrenergic blockade. During control, the MAPD
50
decreased from 193±26 to 184±26 ms with increased load, as did the MAPD
90
(238±28 to 233±28 ms),
P
≤0.04. Similar changes were observed in ventricular refractoriness. Treatment with propranolol completely abolished these load-induced effects. Myocardial catecholamine depletion with reserpine in 2 hearts also abolished changes in MAPD and excitability in response to increased preload.

Conclusions—

Increases in ventricular load mediate a decrease in ventricular APD and refractoriness through activation of the β-adrenergic receptor. An increase in a cAMP-mediated K
+
current, possibly the slowly activating delayed rectifier
I
Ks
, may account in part for this form of mechanoelectrical coupling.
Accelerated Atherosclerosis, Aortic Aneurysm Formation, and Ischemic Heart Disease in Apolipoprotein E/Endothelial Nitric Oxide Synthase Double-Knockout Mice
Authors: Kuhlencordt Peter J. , Gyurko Robert , Han Fred , Scherrer-Crosbie Marielle , Aretz Thomas H. , Hajjar Roger , Picard Michael H. , Huang Paul L.
Published: September 2007

Background

To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals.

Methods and Results

After 16 weeks of “Western-type” diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection.

Conclusions

eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.
Long-Term Prognostic Value of Coronary Calcification Detected by Electron-Beam Computed Tomography in Patients Undergoing Coronary Angiography
Authors: Keelan Paul C. , Bielak Lawrence F. , Ashai Khalid , Jamjoum Lama S. , Denktas Ali E. , Rumberger John A. , Sheedy, II Patrick F. , Peyser Patricia A. , Schwartz Robert S.
Published: September 2007

Background

Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events.

Methods and Results

Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease (
P
<0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores ≥100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively;
P
<0.05).

Conclusions

In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.
Prediction of Long-Term Outcomes by Signal-Averaged Electrocardiography in Patients With Unsustained Ventricular Tachycardia, Coronary Artery Disease, and Left Ventricular Dysfunction
Authors: Gomes J. Anthony , Cain Michael E. , Buxton Alfred E. , Josephson Mark E. , Lee Kerry L. , Hafley Gail E.
Published: September 2007

Background

An abnormal signal-averaged ECG (SAECG) is a noninvasive marker of the substrate of sustained ventricular tachycardia after myocardial infarction. We assessed its prognostic ability in patients with asymptomatic unsustained ventricular tachycardia, coronary artery disease, and left ventricular dysfunction.

Methods and Results

A blinded core laboratory analyzed SAECG tracings from 1925 patients in a multicenter trial. Cox proportional hazards modeling was used to examine individual and joint relations between SAECG variables and arrhythmic death or cardiac arrest (primary end point), cardiac death, and total mortality. We also assessed the prognostic utility of SAECG at different levels of ejection fraction (EF). A filtered QRS duration >114 ms (abnormal SAECG) independently predicted the primary end point and cardiac death, independent of clinical variables, cardioverter-defibrillator implantation, and antiarrhythmic drug therapy. With an abnormal SAECG, the 5-year rates of the primary end point (28% versus 17%,
P
=0.0001), cardiac death (37% versus 25%,
P
=0.0001), and total mortality (43% versus 35%,
P
=0.0001) were significantly higher. The combination of EF <30% and abnormal SAECG identified a particularly high-risk subset that constituted 21% of the total population. Thirty-six percent and 44% of patients with this combination succumbed to arrhythmic and cardiac death, respectively.

Conclusions

SAECG is a powerful predictor of poor outcomes in this population. The noninvasive combination of an abnormal SAECG and reduced EF may have utility in selecting high-risk patients for intervention.
Prophylaxis of Restenosis With
186
Re-Labeled Stents in a Rabbit Model
Authors: Tepe Gunnar , Dinkelborg Ludger M. , Brehme Ute , Muschick Peter , Noll Bernhard , Dietrich Tobias , Greschniok Annette , Baumbach Andreas , Claussen Claus D. , Duda Stephan H.
Published: September 2007

Background

Intraluminal β-irradiation has been shown to decrease neointimal proliferation after angioplasty in experimental models. The purpose of this study was to test the technical feasibility and biological effects of
186
Re-labeled stents.

Methods and Results

Thirty-four New Zealand White rabbits were fed a 0.5% cholesterol diet before balloon angioplasty and insertion of Palmaz stents in the infrarenal aorta. The animals were killed 7 weeks after stent implantation. Two of 34 animals died prematurely (aortic leak, pneumonia). Control stents (n=7) were compared with
186
Re stents (2.6 MBq [n=6], 8.1 MBq [n=5], 16.0 MBq [n=6], and 25.3 MBq [n=8]). Stent application was successful in all cases. No thrombus occlusion was observed. After 7 weeks, neointima formation was 2.2±0.2 mm
2
in the control group. In the treatment groups, a dose-dependent neointima reduction was detectable (0.5±0.5 mm
2
[2.6 MBq], 0.4±0.4 mm
2
[8.1 MBq], and 0 mm
2
[16.0 MBq, 25.3 MBq]). No induction of neointimal formation was observed at the edges of the stents. Radiation resulted in delayed reendothelialization.

Conclusions

186
Re stents were capable of reducing neointima formation in a dose-dependent fashion.
186
Re stents did not cause late thrombosis or neointimal induction at the stent margins in the observation period of 7 weeks.
Pioglitazone Enhances Cytokine-Induced Apoptosis in Vascular Smooth Muscle Cells and Reduces Intimal Hyperplasia
Authors: Aizawa Yoshiaki , Kawabe Jun-ichi , Hasebe Naoyuki , Takehara Naohumi , Kikuchi Kenjiro
Published: September 2007

Background

Cytokines induce apoptosis in vascular disease lesions through enhancement of inducible nitric oxide (NO) synthase (iNOS) activation. The thiazolidinediones, novel insulin-sensitizing agents, have been demonstrated to modulate cytokine-induced NO production. We have investigated the role of pioglitazone in the apoptosis of vascular smooth muscle cells (VSMCs) in vitro and developed intimal hyperplasia in vivo.

Methods and Results

Pioglitazone (0.1 to 10 μmol/L) significantly enhanced cytokine-induced expression of iNOS and NO production in a dose-dependent manner in rat VSMCs, but 15-deoxy-Δ
12,14
-prostaglandin J2 (up to 10 μmol/L), a native peroxisome proliferator-activated receptor-γ ligand, showed no effect. Pioglitazone also significantly enhanced reduction of cell viability, as evidenced by the increase in the number of TUNEL-positive cells. All of these effects of pioglitazone were blocked by treatment with
N
-monomethyl-
l
-arginine, an NO synthesis inhibitor. In an in vivo study with a balloon-injured rat carotid artery, neointimal thickness had reached maximum levels at 2 weeks after injury. Then, rats were fed with or without pioglitazone (3 mg · kg
−1
· d
−1
) for an additional week. The ratio of intima to media area of carotid artery was significantly decreased by 30%, and the ratio of apoptotic cells in neointima was significantly increased in pioglitazone-treated rats compared with vehicle-treated control rats.

Conclusions

Pioglitazone enhanced apoptosis in an NO-dependent manner in cytokine-activated VSMCs and induced significant regression of intimal hyperplasia in balloon-injured rat carotid artery. It appears that pioglitazone is a potent apoptosis inducer in vascular lesions, providing a novel pharmacological strategy to prevent restenosis after vascular intervention.
Effects of Ramipril on Coronary Events in High-Risk Persons
Authors: Dagenais Gilles R. , Yusuf Salim , Bourassa Martial G. , Yi Qilong , Bosch Jackie , Lonn Eva M. , Kouz Simon , Grover John ,   on behalf of the HOPE Investigators
Published: September 2007

Background

In trials of patients with left ventricular dysfunction or heart failure, ACE inhibitor use was unexpectedly associated with reduced myocardial infarction (MI). Using the Heart Outcomes Prevention Evaluation (HOPE) trial data, we tested prospectively whether ramipril, an ACE inhibitor, could reduce coronary events and revascularization procedures among patients with normal left ventricular function.

Methods and Results

In the HOPE trial, 9297 high-risk men and women, ≥55 years of age with previous cardiovascular disease or diabetes plus 1 risk factor, were randomly assigned to ramipril (up to 10 mg/d), vitamin E (400 IU/d), their combination, or matching placebos. During the mean follow-up of 4.5 years, there were 482 (10.4%) patients with clinical MI and unexpected cardiovascular death in the ramipril group compared with 604 (12.9%) in the placebo group [relative risk reduction (RRR), 21% (95% CI) (11,30);
P
<0.0003]. Ramipril was associated with a trend toward less fatal MI and unexpected death [4.0% versus 4.7%; RRR, 16% (−3, 31)] and with a significant reduction in nonfatal MI [5.6% versus 7.2%; RRR, 23% (9,34)]. Risk reductions in MI were documented in participants taking or not taking β-blockers, lipid lowering, and/or antiplatelet agents. Although ramipril had no impact on hospitalizations for unstable angina [11.9% versus 12.2%; RRR, 3% (−9,14)], it reduced the risk of worsening and new angina [27.2% versus 30.0%; RRR, 12% (5,18);
P
<0.0014] and coronary revascularizations [12.5% versus 14.8%; RRR, 18%; (8,26)
P
<0.0005].

Conclusions

In this high-risk cohort, ramipril reduced the risk of MI, worsening and new angina, and the occurrence of coronary revascularizations.
Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery
Authors: Hwang Chao-Wei , Wu David , Edelman Elazer R.
Published: September 2007

Background

The first compounds considered for stent-based delivery, such as heparin, were chosen on the basis of promising tissue culture and animal experiments, and yet they have failed to stop restenosis clinically. More recent compounds, such as paclitaxel, are of a different sort, being hydrophobic in nature, and their effects after local release seem far more profound. This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of differences in biology or differences in physicochemical properties and targeting.

Methods and Results

We applied continuum pharmacokinetics to examine the effects of transport forces and device geometry on the distribution of stent-delivered hydrophilic and hydrophobic drugs. We found that stent-based delivery invariably leads to large concentration gradients, with drug concentrations ranging from nil to several times the mean tissue concentration over a few micrometers. Concentration variations were a function of the Peclet number (Pe), the ratio of convective to diffusive forces. Although hydrophobic drugs exhibited greater variability than hydrophilic drugs, they achieved higher mean concentrations and remained closer to the intima. Inhomogeneous strut placement influenced hydrophilic drugs more negatively than hydrophobic drugs, dramatically affecting local concentrations without changing mean concentrations.

Conclusions

Because local concentrations and gradients are inextricably linked to biological effect, our results provide a potential explanation for the variable success of stent-based delivery. We conclude that mere proximity of delivery devices to tissues does not ensure adequate targeting, because physiological transport forces cause local concentrations to deviate significantly from mean concentrations.
Comparison of Right and Left Ventricular Responses to Left Ventricular Assist Device Support in Patients With Severe Heart Failure
Authors: Barbone Alessandro , Holmes Jeff W. , Heerdt Paul M. , The’ Andrew H.S. , Naka Yoshifumni , Joshi Neel , Daines Michael , Marks Andrew R. , Oz Mehmet C. , Burkhoff Daniel
Published: September 2007

Background

—

Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown.

Methods and Results

—

Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for ≥30 days had higher central venous pressures (11±6 versus 8±5 mm Hg,
P
=0.04), lower pulmonary artery diastolic pressures (14±9 versus 21±9 mm Hg,
P
=0.01), and higher cardiac outputs (5.1±1.6 versus 3.7±1.0 L/min,
P
<0.001). In LVAD versus transplantation hearts, V
30
(ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179±75 versus 261±118 mL,
P
=0.005) but not in the right ventricle (RV) (140±59 versus 148±52 mL,
P
=NS). LV myocyte diameter decreased more significantly after LVAD support (17%,
P
=0.05) than in the RV (11%,
P
=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51±0.26 versus 1.04±0.34,
P
<0.001) but not in the RV (0.48±34 versus 0.67±0.55,
P
=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (
P
=0.01) but not RV trabeculae.

Conclusions

—

Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.
Phased Chest and Abdominal Compression-Decompression Versus Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
Authors: Arntz Hans-Richard , Agrawal Rahul , Richter Hans , Schmidt Stefan , Rescheleit Tanja , Menges Marlies , Burbach Hubert , Schröder Joachim , Schultheiss Heinz-Peter
Published: September 2007

Background

Several methods have been developed to improve the efficacy of mechanical resuscitation, because organ perfusion achieved with conventional manual resuscitation is often insufficient. In animal studies, phased chest and abdominal compression-decompression resuscitation by use of the Lifestick device has resulted in a better outcome compared with that of conventional resuscitation. In end-of-life patients, an increased coronary perfusion pressure was achieved. The aim of the present study was to determine the feasibility, safety, and efficacy of the Lifestick compared with conventional resuscitation in patients with sudden nontraumatic out-of-hospital cardiac arrest.

Methods and Results

The crews of 4 mobile intensive care units, staffed by an emergency physician and a paramedic, were trained to use the device. Fifty patients were randomized by sealed envelopes to either Lifestick (n=24) or conventional (n=26) resuscitation. No differences were found regarding demographic and logistical conditions between the groups. Nineteen of the patients (73%) with conventional resuscitation had ventricular fibrillation, 13 of whom survived to hospital admission (no survivals with other arrhythmias) and 7 were discharged. In contrast, in the Lifestick-CPR group, only 9 patients had ventricular fibrillation (38%;
P
=<0.02; OR, 2.5; 95% CI, 0.6 to 10.6). Four of these 9 patients and 5 of 15 patients with other arrhythmias survived to hospital admission, but none survived to hospital discharge. Autopsy in a subgroup of patients who died at the scene revealed less injuries with Lifestick than with conventional resuscitation.

Conclusion

Lifestick resuscitation is feasible and safe and may be advantageous in patients with asystole or pulseless electric activity.
Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries
Authors: Richard Vincent , Hurel-Merle Sonia , Scalbert Elizabeth , Ferry Gilles , Lallemand Françoise , Bessou Jean-Paul , Thuillez Christian
Published: September 2007

Background

In human arteries, angiotensin-converting enzyme (ACE) inhibitors incompletely block the production of angiotensin (Ang) II from Ang I. This ACE-independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase. However, several serine proteases may produce Ang II, and the exact role of chymase in the vascular production of Ang II has never been directly evaluated using selective chymase inhibitors.

Methods and Results

Rings of human mammary arteries were subjected to either Ang I or the chymase-selective substrate [pro,
11
D-Ala
12
] Ang I in the absence or the presence of the ACE inhibitor captopril, the serine protease inhibitor chymostatin, or the selective chymase inhibitor C41. Captopril only partially inhibited (by 33%) the response to Ang I. In the absence of captopril, C41 markedly reduced (by 44%) the response to Ang I, and this effect was identical to that of chymostatin. C41 also significantly reduced the response to Ang I in the presence of captopril, although this inhibitory effect was slightly less than that of captopril in combination with chymostatin. [Pro,
11
D-Ala
12
] Ang I induced potent contractions that were not affected by captopril but were abolished by chymostatin and markedly reduced by C41. In addition, we found that prior treatment of the patients with an ACE inhibitor did not affect the in vitro response to Ang I (in the absence or the presence of captopril) or to [Pro,
11
D-Ala
12
] Ang I.

Conclusions

Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACE-independent production of Ang II in human arteries.
Serum Levels of the Antiinflammatory Cytokine Interleukin-10 Are Decreased in Patients With Unstable Angina
Authors: Smith David A. , Irving Sandra D. , Sheldon Joanna , Cole Della , Kaski Juan Carlos
Published: September 2007

Background

Proinflammatory cytokines play a role in acute coronary events. However, the potential role of antiinflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10, which is expressed in human atherosclerotic plaques, has potent deactivating properties in macrophages and T cells. The aim of this study was to assess whether serum concentrations of IL-10 differed between patients with unstable and stable angina pectoris.

Methods and Results

A total of 95 patients with angina pectoris and angiographically documented coronary artery disease were studied. Of these, 50 patients had chronic stable angina (with stable symptoms over 3 months), and 45 patients had Braunwald class IIIB unstable angina with ST-segment changes. Serum IL-10 and IL-6 concentrations were measured on admission using commercially available immunoassays. Serum IL-10 concentrations were lower in unstable angina patients compared with those who had chronic stable angina (28.4 versus 14.0 pg/mL; 95% CI, 9.8 to 19.0;
P
<0.0001), even after adjustment for variables that were significantly different on univariate analysis. IL-6 concentrations were higher in the unstable angina group (20.9 versus 11.4 pg/mL; 95% CI, 1.0 to 12.6;
P
=0.04).

Conclusions

Patients with unstable angina had significantly lower serum IL-10 concentrations than did patients with chronic stable angina. This important finding is in keeping with previous data from animal model studies that suggest that IL-10 has a protective role in atherosclerosis.
His Electrogram Alternans Reveal Dual-Wavefront Inputs Into and Longitudinal Dissociation Within the Bundle of His
Authors: Zhang Youhua , Bharati Saroja , Mowrey Kent A. , Zhuang Shaowei , Tchou Patrick J. , Mazgalev Todor N.
Published: September 2007

Background

His electrogram (HE) amplitude and morphology changes were observed in our previous studies during transition from “fast” to “slow” atrioventricular nodal (AVN) conduction. This phenomenon and its significance for the dual-AVN electrophysiology are not well recognized and have not been studied.

Methods and Results

Experiments were performed on 17 healthy rabbit atrial-AVN preparations during standard programmed electrical pacing. HEs were mapped along the His bundle with roving surface electrodes, along with recording of cellular action potentials (APs). HEs recorded from the superior margin of the His bundle were of greater amplitude during basic beats and decreased substantially, by 42±19% (
P
<0.01), when premature A
1
A
2
shortened to 178±20 ms. In contrast, the HEs from the inferior margin increased dramatically, 2.9±1.7 times (
P
<0.01), during short A
1
A
2
and remained high until AVN block occurred. In addition, during long A
1
A
2
, the superior HEs consistently preceded the inferior by 1.9±0.7 ms. In contrast, at short A
1
A
2
, the superior HEs occurred 2.7±0.8 ms after the inferior. Cellular AP recordings demonstrated clearly the presence of and the transition between early (fast) and late (slow) excitation wavefronts that accompanied HE alternans.

Conclusions

The morphological-electrophysiological evidence from the AV junction suggests that fast and slow wavefronts reach the His bundle differently, producing functional longitudinal dissociation into 2 domains. The characteristic HE alternans recorded from these domains are a new sensitive tool to determine the presence of distinctly different wavefronts and their participation in the conduction during reentrant or other arrhythmias. These findings provide further understanding of the mechanisms of dual-AVN electrophysiology.
Development of A Noninvasive Ultrasound Color M-Mode Means of Estimating Pulmonary Vascular Resistance in Pediatric Pulmonary Hypertension
Authors: Shandas Robin , Weinberg Craig , Ivy D.Dunbar , Nicol Ewen , DeGroff Curt G. , Hertzberg Jean , Valdes-Cruz Lilliam
Published: September 2007

Background
—

Accurate determination of pulmonary vascular resistance (PVR) is an important component in the evaluation and treatment of pediatric patients with pulmonary hypertension. We developed a novel technique, based on the concept of flow propagation, to estimate PVR noninvasively. The hypothesis is that changes in PVR cause changes in the velocity propagation (Vel
prop
) within the main pulmonary artery and that Vel
prop
can be quantified using color M-mode imaging.

Methods and Results
—

We tested the hypothesis using mathematical modeling, in vitro experiments, and preliminary clinical studies. The mathematical model showed that pressure and velocity tracings are closely correlated in time and that 6 to 18 ms time resolution was needed to resolve propagation times within typical main pulmonary artery lengths (2 to 5 cm). The in vitro experiments demonstrated that it was feasible to use color M-mode to measure Vel
prop
and that Vel
prop
correlated well with downstream resistance [y=(−1.01x)+22.77;
R
=0.96]. The method was then evaluated on patients undergoing acute pulmonary reactivity testing (n=22 measurements). Good correlation between Vel
prop
and PVR was found [y=(−1.71x)+26.0;
R
=0.90; SEE=2.41].

Conclusion
—

This newly developed method promises to be useful in the noninvasive evaluation of adults and children with pulmonary hypertension.
Methods for Determining the Refractory Period and Excitable Gap During Persistent Atrial Fibrillation in the Goat
Authors: Duytschaever Mattias , Mast Frans , Killian Matthijs , Blaauw Yuri , Wijffels Maurits , Allessie Maurits
Published: September 2007

Background

—

Recently, the temporal excitable gap during atrial fibrillation (AF) has been identified as a vulnerable parameter for cardioversion of AF. In this study, we evaluated 5 methods to measure the refractory period (RP
AF
) and the excitable period (EP
AF
) during persistent AF.

Methods and Results

—

In 11 goats instrumented with 83 epicardial atrial electrodes, persistent AF (43±34 days) was induced with a median AF cycle length (CL) of 98±14 ms. To measure RP
AF
, premature stimuli were applied to the center of the electrode array on the right or left atrium. The RP
AF
measured by mapping of premature stimuli was 70±12 ms (“gold standard”). The RP
AF
determined during entrainment of AF was 77±17 ms (
R
2
=0.88,
P
<0.01). Statistical analysis of the effects of synchronized stimuli (each coupling interval ×100) on the AFCL histogram yielded an RP
AF
of 70±13 ms (
R
2
=0.94,
P
<0.01). A further simplification was to apply slow fixed-rate pacing (1 Hz) during AF. For each stimulus (n=250 to 500), the paced AFCL was plotted against its coupling interval, and capture was determined by statistical shortening of the AFCL (RP
AF
71±17 ms,
R
2
=0.84,
P
<0.01). The 5th percentile of the AFCL histogram as an index of RP
AF
was 77±12 ms (
R
2
=0.90,
P
<0.01).

Conclusions

—

During persistent AF with an AFCL of 98±14 ms, the RP
AF
determined by mapping of synchronized premature stimuli (gold standard) was 70±12 ms, with an excitable period of 28±8 ms. Although the indirect methods to measure RP
AF
all correlated well with the gold standard, slow fixed-rate pacing seems to be the most attractive technique because of the ease of acquiring the data and the clear graphic result.
Atrial Therapies Reduce Atrial Arrhythmia Burden in Defibrillator Patients
Authors: Friedman Paul A. , Dijkman Barbara , Warman Eduardo N. , Xia H. Amy , Mehra Rahul , Stanton Marshall S. , Hammill Stephen C. ,   for the Worldwide Jewel AF Investigators
Published: September 2007

Background

Approximately 25% of patients who receive an implantable cardioverter-defibrillator (ICD) to treat ventricular tachyarrhythmias have documented atrial tachyarrhythmias before implantation. This study assessed the ability of device-based prevention and termination therapies to reduce the burden of spontaneous atrial tachyarrhythmias.

Methods and Results

Patients with a standard indication for the implantation of an ICD and 2 episodes of atrial tachyarrhythmias in the preceding year received a dual-chamber ICD (Medtronic 7250 Jewel AF) that uses pacing and shock therapies for prevention and/or termination of atrial tachyarrhythmias. In a multicenter trial, patients were randomized to 3-month periods with atrial therapies “on” or “off” and subsequently crossed over. Analysis was performed on the 52 of 269 patients who had episodes of atrial tachyarrhythmia and had ≥30 days of follow-up with atrial therapies on and off. The atrial therapies resulted in a reduction of atrial tachyarrhythmia burden from a mean of 58.5 to 7.8 h/mo. A paired analysis (Wilcoxon signed-rank test) showed that the median difference in burden (1.1 h/mo) was highly significant (
P
=0.007). When the subgroup of 41 patients treated only with atrial pacing therapies was analyzed, the reduction in burden persisted (
P
=0.01).

Conclusions

In this study, patients with a standard ICD indication and atrial tachyarrhythmias had a significant reduction in atrial tachyarrhythmia burden with use of atrial pacing and shock therapies.
Incremental Prognostic Value of Elevated Baseline C-Reactive Protein Among Established Markers of Risk in Percutaneous Coronary Intervention
Authors: Chew Derek P. , Bhatt Deepak L. , Robbins Mark A. , Penn Marc S. , Schneider Jakob P. , Lauer Michael S. , Topol Eric J. , Ellis Stephen G.
Published: September 2007

Background

Established methods of risk assessment in percutaneous coronary intervention have focused on clinical and anatomical lesion characteristics. Emerging evidence indicates the substantial contribution of inflammatory processes to short-term and long-term outcomes in coronary artery disease.

Methods and Results

Within a single-center registry of contemporary percutaneous coronary revascularization strategies with postprocedural creatine kinase and clinical events routinely recorded, we assessed the association of baseline C-reactive protein with death or myocardial infarction within the first 30 days. Predictive usefulness of baseline C-reactive protein within the context of established clinical and angiographic predictors of risk was also examined. Among 727 consecutive patients, elevated baseline C-reactive protein before percutaneous coronary intervention was associated with progressive increase in death or myocardial infarction at 30 days (lowest quartile, 3.9%, versus highest quartile, 14.2%;
P
=0.002). Among clinical and procedural characteristics, baseline C-reactive protein remained independently predictive of adverse events, with the highest quartile of C-reactive protein associated with an odds ratio for excess 30-day death or myocardial infarction of 3.68 (95% CI, 1.51 to 8.99;
P
=0.004). A predictive model that included baseline C-reactive protein quartiles, American College of Cardiology/American Heart Association lesion score, acute coronary syndrome presentation, and coronary stenting appears strongly predictive of 30-day death or myocardial infarction within this population (C-statistic, 0.735) and among individual patients (Brier score, 0.006).

Conclusions

Elevated baseline C-reactive protein portends heightened risk of 30-day death or myocardial infarction after coronary intervention. Coupled anatomic, clinical, and inflammatory risk stratification demonstrates strong predictive utility among patients undergoing percutaneous coronary intervention and may be useful for guiding future strategies.
Reduced Sarco/Endoplasmic Reticulum Ca
2+
Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta
Authors: Adachi Takeshi , Matsui Reiko , Weisbrod Robert M. , Najibi Soheil , Cohen Richard A.
Published: September 2007

Background

Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca
2+
) store refilling via the sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta.

Methods and Results

A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by
45
Ca
2+
uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly.

Conclusions

These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMP-independent Ca
2+
uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca
2+
pump function can account for the impaired response to NO in HC.
Long-QT Syndrome-Associated Missense Mutations in the Pore Helix of the HERG Potassium Channel
Authors: Huang Fu-De , Chen Jun , Lin Monica , Keating Mark T. , Sanguinetti Michael C.
Published: September 2007

Background

Mutations in the human ether-à-go-go-related gene (
HERG
) cause chromosome 7-linked long-QT syndrome (LQTS), an inherited disorder of cardiac repolarization that predisposes affected individuals to arrhythmia and sudden death.

Methods and Results

Here, we characterize the physiological consequences of 3 LQTS-associated missense mutations (V612L, T613M, and L615V) located in the pore helix of the HERG channel subunit. Mutant HERG subunits were heterologously expressed in
Xenopus
oocytes alone or in combination with wild-type HERG subunits. Two-microelectrode voltage-clamp techniques were used to record currents, and a single oocyte chemiluminescence assay was used to assay surface expression of epitope-tagged subunits. When expressed alone, V612L and T613M HERG subunits did not induce detectable currents, and L615V induced very small currents. Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect that varied for each mutation.

Conclusions

These findings define the physiological consequences of mutations in
HERG
that cause LQTS and indicate the importance of the pore helix of HERG for normal channel function.
Right Atrial Septal Electrode for Reducing the Atrial Defibrillation Threshold
Authors: Zheng Xiangsheng , Benser Michael E. , Walcott Gregory P. , Ideker Raymond E.
Published: September 2007

Background

The atrial defibrillation threshold (ADFT) energy of the standard lead configuration, right atrial appendage (RAA) to coronary sinus (CS), was reduced by >50% with the addition of a third electrode traversing the atrial septum in a previous study. This study determined whether the ADFT would be lowered by a more clinically practical third electrode placed in the right atrium along the atrial septum (RSP).

Methods and Results

Sustained atrial fibrillation was induced in 8 closed-chest sheep with burst pacing and maintained with pericardial infusion of acetyl-β-methylcholine chloride. A custom-made, dual-defibrillation catheter was placed with electrodes in the lateral RA, CS, and RSP. A separate defibrillation catheter was also placed in the RAA. ADFT characteristics of RAA→CS and 6 other single- or sequential-shock configurations were determined in random order by using biphasic, truncated-exponential waveforms in a multiple-reversal protocol. The delivered-energy, peak-voltage, and peak-current ADFTs for the sequential-shock configuration CS→RSP/RA→RSP (0.53±0.31 J, 86±22 V, and 1.6±0.6 A, respectively) were significantly lower than those of RAA→CS (1.14±0.64 J, 157±34 V, and 2.5±1.1 A, respectively). The ADFT characteristics of RAA→CS and RA→CS were not significantly different, nor were those of CS→RSP/RA→RSP and CS→RSP/RAA→ RSP.

Conclusions

The ADFT of the standard RAA→CS configuration may be markedly reduced with an additional electrode situated at the RSP.