bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for a Central Origin of the Low-Frequency Oscillation in RR-Interval Variability
Authors: Cooley Ryan L. , Montano Nicola , Cogliati Chiara , van de Borne Philippe , Richenbacher Wayne , Oren Ron , Somers Virend K.
Published: June 2012

Background
—Short-term variability of RR interval and blood pressure occurs predominantly at low frequency (LF; ≈0.1 Hz) and high frequency (≈0.25 Hz). The arterial baroreflex is thought to be the predominant determinant of the LF component of RR variability. Patients with severe congestive heart failure (CHF) have an attenuated or absent LF oscillation in RR variability. The left ventricular assist device (LVAD) offers a unique possibility for analysis of spectral oscillations in RR interval independent of any effects of blood pressure that influence these oscillations via the baroreflex.

Methods and Results
—We performed spectral analysis of RR, blood pressure, and respiration in 2 patients with CHF before and after LVAD implantation. LF components of the RR-interval and blood pressure variability were absent in both CHF patients before LVAD implantation. After LVAD implantation, spectral analysis of the RR interval showed restoration of a clear and predominant LF oscillation in the native hearts of both patients, with no such oscillation evident in the blood pressure profile.

Conclusions
—During total circulatory support with the LVAD, the LF oscillation in RR interval of the native heart, absent in CHF, is restored. This LF oscillation in RR interval occurs in the absence of LF oscillations in blood pressure and thus is unlikely to be explained by baroreflex mechanisms. Hence, the absence of LF oscillation in the RR interval in CHF is functional and is reversible by LVAD circulation. The presence of a predominant LF oscillation in RR interval independent of any oscillation in blood pressure suggests that the LF oscillation is a fundamental property of central autonomic outflow.
A
2A
-Adenosine Receptor Reserve for Coronary Vasodilation
Authors: Shryock John C. , Snowdy Stephen , Baraldi Pier Giovanni , Cacciari Barbara , Spalluto Giampiero , Monopoli Angela , Ongini Ennio , Baker Stephen P. , Belardinelli Luiz
Published: June 2012

Background
—Adenosine is a potent coronary vasodilator and causes an increase of coronary blood flow by activation of A
2A
-adenosine receptors (A
2A
-AdoRs). The purpose of this study was to test the hypothesis that the high potency of adenosine and adenosine analogues to cause coronary vasodilation is explained by the presence of a large A
2A
-AdoR reserve (“spare receptors”).

Methods and Results
—A novel, irreversible antagonist of A
2A
-AdoRs was used to inactivate receptors and reduce the response to agonist. Agonist-induced increases of coronary conductance before and after exposure of hearts to the irreversible antagonist were compared. Three agonists were studied: 2-
p
-(2-carboxyethyl)-phenethylamino-5′-
N
-ethylcarboxamidoadenosine (
CGS21680
), adenosine, and 2-chloro-
N
6
-cyclopentyladenosine (CCPA). Data were analyzed to determine agonist
K
A
(equilibrium dissociation constant) and EC
50
values. Values of
K
A
for activation of A
2A
-AdoRs by
CGS21680
, adenosine, and CCPA were 105, 1800, and 2630 nmol/L, respectively. In contrast, values of EC
50
for
CGS21680
, adenosine, and CCPA to increase coronary conductance were 1.5, 85, and 243 nmol/L, respectively. By use of the law of mass action, it was calculated that half-maximal responses to
CGS21680
, adenosine, and CCPA occurred when only 1.3%, 5%, and 9%, respectively, of A
2A
-AdoRs were occupied by agonist.

Conclusions
—Receptor reserves for 3 A
2A
-AdoR agonists were large. The receptor reserve for A
2A
-AdoRs to cause an increase of coronary conductance can explain both the high potency of adenosine to cause coronary vasodilation and the observation that an A
2A
-AdoR agonist can cause coronary vasodilation without systemic effects.
Acute Hemodynamic Interaction of Aspirin and Ticlopidine With Enalapril
Authors: Spaulding Christian , Charbonnier Bernard , Cohen-Solal Alain , Juillière Yves , Kromer Eckhard Peter , Benhamda Khaldoun , Cador Romain , Weber Simon
Published: June 2012

Background
—Coprescription of aspirin and ACE inhibitors is frequent in heart failure caused by coronary artery disease. Negative interaction between aspirin and enalapril has been reported, presumably through inhibition by aspirin of ACE inhibitor–induced prostaglandin synthesis. Ticlopidine is a potent antiplatelet agent without interaction with prostaglandin synthesis.

Methods and Results
—The objective of this study was to compare the influence of a coadministration of ticlopidine or aspirin on the hemodynamic effects of an ACE inhibitor (enalapril) in patients with chronic heart failure. Twenty patients with severe heart failure were enrolled in a double-blind comparative trial and allocated to ticlopidine (500 mg daily, 12 patients) or aspirin (325 mg daily, 8 patients). Hemodynamic evaluation was performed after 7 days of treatment, every hour for 4 hours after an oral administration of 10 mg of enalapril. Significant reductions in systemic vascular resistance were observed in the ticlopidine group, in contrast to no significant decrease in the aspirin group. A significant (
P
=0.03) time-by-treatment interaction indicated significant aspirin-enalapril drug interaction. Total pulmonary resistance decreased significantly in both groups, with no difference between patients assigned to aspirin or ticlopidine.

Conclusions
—Enalapril reduced systemic vascular resistance more effectively when given in combination with ticlopidine than with aspirin. In contrast, the reduction in total pulmonary resistance is similar when enalapril is administered in combination with aspirin or ticlopidine. Negative aspirin-enalapril interaction on prostaglandin synthesis presumably alters vasodilatation in systemic vessels, whereas prostaglandin-independent actions of ACE inhibition such as pulmonary arterial vasodilatation are maintained.
Successful Irrigated-Tip Catheter Ablation of Atrial Flutter Resistant to Conventional Radiofrequency Ablation
Authors: Jaïs Pierre , Haïssaguerre Michel , Shah Dipen C. , Takahashi Atsushi , Hocini Mélèze , Lavergne Thomas , Lafitte Stéphane , Le Mouroux Alain , Fischer Bruno , Clémenty Jacques
Published: June 2012

Background
—Catheter ablation of typical right atrial flutter is now widely performed. The best end point has been demonstrated to be bidirectional isthmus block. We investigated the use of irrigated-tip catheters in a small subset of patients who failed isthmus ablation with conventional radiofrequency (RF) ablation.

Methods and Results
—Of 170 patients referred for ablation of common atrial flutter, conventional ablation of the cavotricuspid isthmus with >21 applications failed to create a bidirectional block in 13 (7.6%). An irrigated-tip catheter ablation was performed on identified gaps in the ablation line according to a protocol found to be safe in animals: a moderate flow rate of 17 mL/min and temperature-controlled (target, 50°C) RF delivery with a power limit of 50 W. Bidirectional isthmus block was achieved in 12 patients by use of a mean delivered power of 40±6 W with a single application in 6 patients and 2 to 6 applications in the other 6. No side effects occurred during or after the procedure.

Conclusions
—Irrigated-tip catheter ablation is safe and effective for achieving cavotricuspid isthmus block when conventional RF energy has failed.
Local Adenovirus-Mediated Transfer of Human Endothelial Nitric Oxide Synthase Reduces Luminal Narrowing After Coronary Angioplasty in Pigs
Authors: Varenne Olivier , Pislaru Sorin , Gillijns Hilde , Van Pelt Natascha , Gerard Robert D. , Zoldhelyi Pierre , Van de Werf Frans , Collen Désiré , Janssens Stefan P.
Published: June 2012

Background
—Nitric oxide, synthesized from
l
-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local
NOS
gene transfer on restenosis after experimental balloon angioplasty were investigated.

Methods and Results
—Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5×10
9
pfu) carrying either the
NOS
cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg protein (
P
<0.05) but were restored after constitutive endothelial (ce)
NOS
gene transfer to 1.82±0.98 pmol/mg (
P
<0.05 versus injured group and
P
=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm,
P
=0.02; 0.75±0.21 versus 1.04±0.25 mm,
P
=0.019; and 53±15% versus 75±11%,
P
=0.006, respectively). Lumen area was significantly larger (0.70±0.35 mm
2
in AdCMVceNOS versus 0.32±0.18 mm
2
in AdRR5,
P
=0.007).

Conclusions
—Percutaneous adenovirus-mediated
NOS
gene transfer resulted in efficient local overexpression of functional
NOS
after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.
Restraining Infarct Expansion Preserves Left Ventricular Geometry and Function After Acute Anteroapical Infarction
Authors: Kelley Scott T. , Malekan Ramin , Gorman Joseph H. , Jackson Benjamin M. , Gorman Robert C. , Suzuki Yasuyuki , Plappert Theodore , Bogen Daniel K. , Sutton Martin G. St. John , Edmunds L. Henry
Published: June 2012

Background
—Expansion of an acute myocardial infarction predicts progressive left ventricular (LV) dilatation, functional deterioration, and early death. This study tests the hypothesis that restraining expansion of an acute infarction preserves LV geometry and resting function.

Methods and Results
—In 23 sheep, snares were placed around the distal left anterior descending and second diagonal coronary arteries. In 12 sheep, infarct deformation was prevented by Marlex mesh placed over the anticipated myocardial infarct. Snared arteries were occluded 10 to 14 days later. Serial hemodynamic measurements and transdiaphragmatic quantitative echocardiograms were obtained up to 8 weeks after anteroapical infarction of 0.23 of LV mass. In sheep with mesh, circulatory hemodynamics, stroke work, and end-systolic elastance return to preinfarction values 1 week after infarction and do not change subsequently. Ventricular volumes and ejection fraction do not change after the first week postinfarction. Control animals develop large anteroapical ventricular aneurysms, increasing LV dilatation, and progressive deterioration in circulatory hemodynamics and ventricular function. At week 8, differences in LV end-diastolic pressure, cardiac output, end-diastolic and end-systolic volumes, ejection fraction, stroke work, and end-systolic elastance are significant (
P
<0.01) between groups.

Conclusions
—Preventing expansion of acute myocardial infarctions preserves LV geometry and function.
Effects of Probucol on Vascular Remodeling After Coronary Angioplasty
Authors: Côté Gilles , Tardif Jean-Claude , Lespérance Jacques , Lambert Jean , Bourassa Martial , Bonan Raoul , Gosselin Gilbert , Joyal Michel , Tanguay Jean-François , Nattel Stanley , Gallo Richard , Crépeau Jacques
Published: June 2012

Background
—We have shown that probucol reduces restenosis after balloon angioplasty. Whether probucol acted via prevention of neointimal formation or improvement in vascular remodeling could not be addressed by angiography and required the use of intravascular ultrasound (IVUS).

Methods and Results
—Beginning 30 days before angioplasty, 317 patients were randomly assigned to receive probucol, multivitamins, combined treatment, or placebo. Patients were then treated for 6 months after angioplasty. IVUS examination was performed immediately after angioplasty and at follow-up in 94 patients (111 segments). The cross section selected for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. In the placebo group, lumen area decreased by −1.21±1.88 mm
2
at follow-up, and wall area and external elastic membrane (EEM) area increased by 1.50±2.50 and 0.29±2.93 mm
2
, respectively. Change in lumen area, however, correlated more strongly with the change in EEM area (
r
=0.53,
P
=0.002) than with the change in wall area (
r
=−0.13,
P
=0.49). Lumen loss was −1.21±1.88 mm
2
for placebo, −0.83±1.22 mm
2
for vitamins, −0.25±1.17 mm
2
for combined treatment, and −0.15±1.70 mm
2
for probucol alone (
P
=0.002 for probucol,
P
=0.84 for vitamins). Change in wall area was similar for all groups. EEM area increased by 0.29±2.93 mm
2
for placebo, 0.09±2.33 mm
2
for vitamins only, 1.17±1.61 mm
2
for combined treatment, and 1.74±1.80 mm
2
for probucol only (
P
=0.005 for probucol).

Conclusions
—Lumen loss after balloon angioplasty is due to inadequate vessel remodeling in response to neointimal formation. Probucol exerts its antirestenotic effects by improving vascular remodeling after angioplasty.
Recombinant Hirudin (Lepirudin) Provides Safe and Effective Anticoagulation in Patients With Heparin-Induced Thrombocytopenia
Authors: Greinacher A. , Völpel H. , Janssens U. , Hach-Wunderle V. , Kemkes-Matthes B. , Eichler P. , Mueller-Velten H. G. , Pötzsch B.
Published: June 2012

Background
—The immunological type of heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced thrombocytopenia. This study evaluated the efficacy of recombinant hirudin (r-hirudin or lepirudin), a potent thrombin inhibitor, for anticoagulation in patients with confirmed HIT.

Methods and Results
—Eighty-two patients in this prospective, multicenter study received 1 of 4 intravenous r-hirudin regimens: A1, HIT patients with thrombosis (n=51), 0.4-mg/kg bolus and then 0.15 mg · kg
−1
· h
−1
; A2, HIT patients with thrombosis receiving thrombolysis (n=5), 0.2-mg/kg bolus and then 0.1 mg · kg
−1
· h
−1
; B, HIT patients without thrombosis (n=18), 0.1 mg · kg
−1
· h
−1
; and C, during cardiopulmonary bypass surgery (n=8), 0.25-mg/kg bolus and then 5-mg boluses as needed. Response criteria were increase in platelet count by ≥30% to >10
9
/L and activated partial thromboplastin time (aPTT) values 1.5 to 3.0 times baseline values achieved with a maximum of 2 dose increases. No placebo control was used for ethical reasons. Outcomes of a subset of r-hirudin–treated patients who met predefined inclusion criteria (n=71) were compared with those of a historical control group (n=120) for combined and individual incidences of death, amputations, new thromboembolic complications, and incidences of bleeding. Platelet counts increased rapidly in 88.7% of r-hirudin–treated patients with acute HIT. In regimens A1 and A2, the 25% and 75% quartiles of the aPTT were within the target range at all but 1 time point. The incidence of the combined end point (death, amputation, new thromboembolic complications) was significantly reduced in r-hirudin patients compared with historical control patients (
P
=0.014). During first selected treatment, the adjusted hazard ratio for r-hirudin patients versus historical control was 0.279 (95% CI, 0.112 to 0.699;
P
=0.003). Bleeding rates were similar in both groups.

Conclusions
—r-Hirudin treatment is associated with a rapid and sustained recovery of platelet counts, sufficient aPTT prolongations, and true clinical benefits for patients with HIT.
Death of Smooth Muscle Cells and Expression of Mediators of Apoptosis by T Lymphocytes in Human Abdominal Aortic Aneurysms
Authors: Henderson E. Lynne , Geng Yong-Jian , Sukhova Galina K. , Whittemore Anthony D. , Knox James , Libby Peter
Published: June 2012

Background
—Thinning of the tunica media and rarefaction of smooth muscle cells (SMCs) characterize aneurysmal aortas. Apoptosis determines the cellularity and morphogenesis of tissue. Macrophages and T lymphocytes infiltrate the wall of abdominal aortic aneurysms (AAAs) and produce death-promoting proteins (perforin, Fas, and FasL). This study investigated whether apoptosis occurs in association with the expression of these proteins.

Methods and Results
—We examined signs of apoptosis and expression of death-promoting mediators in segments of AAAs from patients undergoing elective repair (n=20). Anti–α-actin immunostaining showed a reduced number of SMCs in AAAs. In situ terminal transferase-mediated dUTP nick end-labeling (TUNEL) showed higher levels of DNA fragmentation in AAAs than in controls (n=5). The AAA walls contained more cells bearing markers of apoptosis than normal aorta (
P
<0.05, Student’s
t
test). Double immunostaining identified SMCs and macrophages as the principal cell types displaying fragmented DNA. Immunohistochemistry revealed that AAAs but not normal aorta contained CD4
+
and CD8
+
T cells that expressed well-characterized cytotoxic mediators: perforin, which produces membrane damage, and Fas, which acts by ligand-receptor interaction. Double immunostaining also identified SMCs that expressed Fas. Immunoblotting confirmed the presence and, in the case of Fas, activation of these proteins in aneurysmal tissue.

Conclusions
—Many medial SMCs in AAAs bear markers of apoptosis and signals capable of initiating cell death. Apoptotic death may contribute to the reduction of cellularity and to the impaired repair and maintenance of the arterial extracellular matrix in AAAs. Macrophages and T lymphocytes infiltrate the wall of AAAs, where they can produce cytotoxic mediators such as cytokines, perforin, and Fas/FasL. These death-promoting products of activated immune cells may contribute to elimination of SMCs, a source of elastin and collagen, during the pathogenesis of AAAs.
Tenascin-C Is Expressed in Macrophage-Rich Human Coronary Atherosclerotic Plaque
Authors: Wallner Kurt , Li Chen , Shah Prediman K. , Fishbein Michael C. , Forrester James S. , Kaul Sanjay , Sharifi Behrooz G.
Published: June 2012

Background
—Tenascin is a large extracellular matrix glycoprotein generally found in adult tissues undergoing active remodeling such as healing wounds and tumors. To determine the potential role of tenascin-C (TN-C) in the pathophysiology of atherosclerosis, we investigated the pattern of expression of TN-C in human coronary atherosclerotic plaques.

Methods and Results
—Immunohistochemical staining and in situ hybridization demonstrated minimal and random expression of TN-C in fibrotic but lipid-poor atherosclerotic plaques. In contrast, all plaques with an organized lipid core or ruptured intimal surface strongly expressed TN-C, which was preferentially concentrated around the lipid core, shoulder regions, and ruptured area of the plaques but not in the fibrous cap. TN-C was not detected in normal arterial tissue. To identify the cellular source of TN-C, the plaques were stained with smooth muscle cell– and macrophage-specific antibodies. TN-C expression correlated with the infiltration of macrophages. Northern blot and immunoprecipitation analysis showed that macrophages expressed 7.0-kb TN-C mRNA and 220-kDa protein. Reverse transcription–polymerase chain reaction of total RNA derived from macrophages showed that they express the small isoform of TN-C. Zymogram analysis revealed that macrophages markedly increased MMP-9 expression.

Conclusions
—This study demonstrates that the level of TN-C expression correlates with the degree of inflammation present, not with plaque size. In addition, cultured macrophages have the capacity to express the TN-C gene. These findings suggest the significance of macrophages in the remodeling of atherosclerotic plaque matrix composition.
Prior Cytomegalovirus Infection and the Risk of Restenosis After Percutaneous Transluminal Coronary Balloon Angioplasty
Authors: Manegold Christoph , Alwazzeh Marwan , Jablonowski Helmut , Adams Ortwin , Medve Martin , Seidlitz Beate , Heidland Ulrich , Häussinger Dieter , Strauer Bodo-Eckehard , Heintzen Matthias P.
Published: June 2012

Background
—Restenosis is a common problem after all revascularization procedures in atherosclerotic coronary arteries. Reactivated human cytomegalovirus (CMV) has been detected in tissues of restenotic vascular lesions and was hypothesized to be a contributing pathogenic factor. Recent data suggest an association of restenosis after optimal coronary atherectomy with CMV serostatus, and a possible role of antiviral therapy was discussed. We therefore tested the hypothesis that prior CMV infection might be a risk factor for restenosis after conventional coronary balloon angioplasty (PTCA).

Methods and Results
—We analyzed 92 consecutive patients who had been admitted for control angiography after previous PTCA within a mean interval of 6 months. Anti-CMV antibodies were measured as an indicator of prior CMV infection and latency. The coronary angiograms before PTCA, directly after, and 6 months later were analyzed quantitatively. Sixty-five percent of the patients were CMV-positive. Before PTCA, the degree (mean±SD) of stenosis was 69±10% in CMV-positive and 68±8.3% in CMV-negative subjects. PTCA resulted in a residual stenosis of 39% in both groups. After 6 months, the late losses of luminal diameter in the CMV-positive and -negative groups were 11±13% and 12±15%, respectively (
P
=0.658). In an ANCOVA with 25 potential risk factors for restenosis, CMV serostatus was not significantly associated with restenosis development.

Conclusions
—Our data indicate that prior CMV infection, in contrast to optimal atherectomy, is not associated with chronic restenosis after conventional coronary balloon angioplasty. The results do not support a possible benefit from antiviral therapy.
Repeated Administration of Vasopressin but Not Epinephrine Maintains Coronary Perfusion Pressure After Early and Late Administration During Prolonged Cardiopulmonary Resuscitation in Pigs
Authors: Wenzel Volker , Lindner Karl H. , Krismer Anette C. , Miller Egfried A. , Voelckel Wolfgang G. , Lingnau Werner
Published: June 2012

Background
—It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold between 20 and 30 mm Hg that renders defibrillation successful.

Methods and Results
—After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg, respectively; n=6) or epinephrine (early epinephrine: 45, 45, and 200 μg/kg, respectively; n=6). Another 12 animals were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive, every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n=6), or epinephrine (late epinephrine: 45 and 200 μg/kg, respectively; n=6). Defibrillation was attempted after 22 minutes of cardiac arrest. Mean±SEM coronary perfusion pressure was significantly higher 90 seconds after early vasopressin compared with early epinephrine (50±4 versus 34±3 mm Hg,
P
<0.02; 42±5 versus 15±3 mm Hg,
P
<0.0008; and 37±5 versus 11±3 mm Hg,
P
<0.002, respectively). Mean±SEM coronary perfusion pressure was significantly higher 90 seconds after late vasopressin compared with late epinephrine (40±3 versus 22±4 mm Hg,
P
<0.004, and 32±4 versus 15±4 mm Hg,
P
<0.01, respectively). All vasopressin animals survived 60 minutes, whereas no epinephrine pig had return of spontaneous circulation (
P
<0.05).

Conclusions
—Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.
Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation
Authors: Pastore Joseph M. , Girouard Steven D. , Laurita Kenneth R. , Akar Fadi G. , Rosenbaum David S.
Published: June 2012

Background
—Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear.

Methods and Results
—T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation.

Conclusions
—Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.
C-terminal
HERG
Mutations
Authors: Berthet Myriam , Denjoy Isabelle , Donger Claire , Demay Laurence , Hammoude Hicham , Klug Didier , Schulze-Bahr Eric , Richard Pascale , Funke Harald , Schwartz Ketty , Coumel Philippe , Hainque Bernard , Guicheney Pascale
Published: June 2012

Background
—The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes
KCNQ1
and
HERG
. In this study, we investigated the 3′ part of
HERG
for mutations.

Methods and Results
—New specific primers allowed the amplification of the 3′ part of
HERG
, the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of
HERG
, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in
KCNQ1
. The 2 more severely affected sisters bore both mutations.

Conclusions
—The discovery of mutations in the C-terminal part of
HERG
emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.
Randomized Secondary Prevention Trial of Azithromycin in Patients With Coronary Artery Disease and Serological Evidence for
Chlamydia pneumoniae
Infection
Authors: Anderson Jeffrey L. , Muhlestein Joseph B. , Carlquist John , Allen Ann , Trehan Sanjeev , Nielson Cindy , Hall Staci , Brady John , Egger Marlene , Horne Benjamin , Lim Tobin
Published: June 2012

Background
—
Chlamydia pneumoniae
commonly causes respiratory infection, is vasotropic, causes atherosclerosis in animal models, and has been found in human atheromas. Whether it plays a causal role in clinical coronary artery disease (CAD) and is amenable to antibiotic therapy is uncertain.

Methods and Results
—CAD patients (n=302) who had a seropositive reaction to
C pneumoniae
(IgG titers ≥1:16) were randomized to receive placebo or azithromycin, 500 mg/d for 3 days, then 500 mg/wk for 3 months. Circulating markers of inflammation (C-reactive protein [CRP], interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-α),
C pneumoniae
antibody titers, and cardiovascular events were assessed at 3 and 6 months. Treatment groups were balanced, with age averaging 64 (SD=10) years; 89% of the patients were male. Azithromycin reduced a global rank sum score of the 4 inflammatory markers at 6 (but not 3) months (
P
=0.011) as well as the mean global rank sum change score: 531 (SD=201) for active drug and 587 (SD=190) for placebo (
P
=0.027). Specifically, change-score ranks were significantly lower for CRP (
P
=0.011) and IL-6 (
P
=0.043). Antibody titers were unchanged, and number of clinical cardiovascular events at 6 months did not differ by therapy (9 for active drug, 7 for placebo). Azithromycin decreased infections requiring antibiotics (1 versus 12 at 3 months,
P
=0.002) but caused more mild, primarily gastrointestinal, adverse effects (36 versus 17,
P
=0.003).

Conclusions
—In CAD patients positive for
C pneumoniae
antibodies, global tests of 4 markers of inflammation improved at 6 months with azithromycin. However, unlike another smaller study, no differences in antibody titers and clinical events were observed. Longer-term and larger studies of antichlamydial therapy are indicated.
Clinical and Angiographic Follow-Up After Primary Stenting in Acute Myocardial Infarction
Authors: Stone Gregg W. , Brodie Bruce R. , Griffin John J. , Costantini Costantino , Morice Marie Claude , St. Goar Frederick G. , Overlie Paul A. , Popma Jeffrey J. , McDonnell JoAnn , Jones Denise , O’Neill William W. , Grines Cindy L.
Published: June 2012

Background
—Restenosis has been reported in as many as 50% of patients within 6 months after PTCA in acute myocardial infarction (AMI), which necessitates repeat target-vessel revascularization (TVR) in ≈20% of patients during this time period. Routine (primary) stent implantation after PTCA has the potential to further improve late outcomes.

Methods and Results
—Primary stenting was performed as part of a prospective study in 236 consecutive patients without contraindications who presented with AMI of <12 hours’ duration at 9 international centers. A mean of 1.4±0.7 stents were implanted per patient (97% Palmaz-Schatz) at 17.3±2.4 atm. During a clinical follow-up period of 7.4±2.6 months, death occurred in 4 patients (1.7%), reinfarction occurred in 5 patients (2.1%), and TVR was required in 26 patients (11.1%). By Cox regression analysis, small reference-vessel diameter and the number of stents implanted were the strongest determinants of TVR. Angiographic restenosis occurred in 27.5% of lesions. By multiple logistic regression analysis, the number of stents implanted and the absence of thrombus on the baseline angiogram were independent determinants of binary restenosis.

Conclusions
—A strategy of routine stent implantation during mechanical reperfusion of AMI is safe and is associated with favorable event-free survival and low rates of restenosis compared with primary PTCA alone.
Improved Left Ventricular Mechanics From Acute VDD Pacing in Patients With Dilated Cardiomyopathy and Ventricular Conduction Delay
Authors: Kass David A. , Chen Chen-Huan , Curry Cecilia , Talbot Maurice , Berger Ronald , Fetics Barry , Nevo Erez
Published: June 2012

Background
—Ventricular pacing can improve hemodynamics in heart failure patients, but direct effects on left ventricular (LV) function from varying pacing site and atrioventricular (AV) delay remain unknown. We hypothesized that the magnitude and location of basal intraventricular conduction delay critically influences pacing responses and that single-site pacing in the delay-activated region yields similar or better responses to biventricular pacing.

Methods and Results
—Aortic and LV pressures were measured in 18 heart failure patients (mean±SD: LV ejection fraction, 19±7%; LV end-diastolic pressure, 25±8 mm Hg; QRS duration, 157±36 ms). Data under normal sinus rhythm were compared with ventricular pacing (VDD) at varying sites and AV delays (randomized order). Right ventricular (RV) apical or midseptal pacing had negligible contractile/systolic effects. However, LV free-wall pacing raised dP/dt
max
by 23.7±19.0% and pulse-pressure by 18.0±18.4% (
P
<0.01). Biventricular pacing yielded less change (+12.8±9.3% in dP/dt
max
,
P
<0.05 versus LV). Pressure-volume analysis performed in 11 patients consistently revealed minimal changes with RV pacing but increased stroke work and lower end-systolic volumes with LV pacing. Optimal AV intervals averaged 125±49 ms, and within this range, AV delay had less influence on LV function than pacing site. Basal QRS duration positively correlated with %ΔdP/dt
max
(
P
<0.005), but pacing efficacy was not associated with QRS narrowing. Conduction delay pattern generally predicted pacing sites with most effect.

Conclusions
—VDD pacing acutely enhances contractile function in heart failure patients with intraventricular conduction delay. Single-site pacing at the site of greatest delay achieves similar or greater benefits to biventricular pacing in such patients. These data clarify pacing-effect mechanisms and should help in candidate identification for future studies.
Influence of Pulmonary Capillary Wedge Pressure on Central Apnea in Heart Failure
Authors: Solin Peter , Bergin Peter , Richardson Meroula , Kaye David M. , Walters E. Haydn , Naughton Matthew T.
Published: June 2012

Background
—Recent studies suggest that acute pulmonary congestion induces hyperventilation and that hyperventilation-related hypocapnia leads to ventilatory control instability and central sleep apnea. Whether chronic pulmonary congestion due to congestive heart failure (CHF) is associated with central apnea is unknown. We hypothesized that CHF patients with central apnea would have greater pulmonary capillary wedge pressure (PCWP) than patients without central apnea and that PCWP would correlate with central apnea severity.

Methods and Results
—Seventy-five stable CHF patients underwent right heart catheterization and, on the basis of overnight sleep studies, were divided into central apnea (n=33), obstructive apnea (n=20), or nonapnea groups (apnea-hypopnea index [AHI] <5 events per hour). Mean PCWP was significantly greater in the central than in the obstructive and nonapnea groups (mean±SEM [range]: 22.8±1.2 [11 to 38] versus 12.3±1.2 [4 to 21] versus 11.5±1.5 [3 to 28] mm Hg, respectively;
P
<0.001). Within the central apnea group, PCWP correlated with the frequency and severity of central apnea (AHI:
r
=0.47,
P
=0.006) and degree of hypocapnia (Pa
co
2
:
r
=−0.42,
P
=0.017). Intensive medical therapy in 7 patients with initially high PCWP and central apneas reduced both PCWP (29.0±2.6 [20 to 38] to 22.0±1.8 [17 to 27] mm Hg;
P
<0.001) and central apnea frequency (AHI) (38.5±7.7 [7 to 62] to 18.5±5.3 [1 to 31] events per hour;
P
=0.005).

Conclusions
—PCWP is elevated in CHF patients with central apneas compared with those with obstructive apnea or without apnea. Moreover, a highly significant relationship exists between PCWP, hypocapnia, and central apnea frequency and severity.
Long-Term Clinical and Echocardiographic Follow-Up After Percutaneous Mitral Valvuloplasty With the Inoue Balloon
Authors: Hernandez Rosa , Bañuelos Camino , Alfonso Fernando , Goicolea Javier , Fernández-Ortiz Antonio , Escaned Javier , Azcona Luis , Almeria Carlos , Macaya Carlos
Published: June 2012

Background
—The objective of this study was to assess the long-term clinical outcome and valvular changes (area and regurgitation) after percutaneous mitral valvuloplasty (PMV).

Methods and Results
—After PMV, 561 patients were followed up for 39 (±23) months and clinical/echocardiographic data obtained yearly. Kaplan-Meier and Cox regression analyses were performed to estimate event-free survival, its predictors, and the relative risks of several patient subgroups. There were several nonexclusive events: 19 (3.3%) cardiac deaths, 55 (9.8%) mitral replacements, 6 (1%) repeated PMVs, 56 (10%) cases of restenosis, and 108 (19%) cases of clinical impairment. Survival free of major events (cardiac death, mitral surgery, repeat PMV, or functional impairment) was 69% at 7 years, ranging from 88% to 40% in different subgroups of patients. Wilkins score was the best preprocedural predictor of mitral opening, but the procedural result (mitral area and regurgitation) was the only independent predictor of major event-free survival. Mitral area loss, though mild [0.13 (±0.21)cm
2
], increased with time and was ≥0.3 cm
2
in 12%, 22%, and 27% of patients at 3, 5, and 7 years, respectively. Regurgitation did not progress in 81% of patients, and when it occurred it was usually by 1 grade.

Conclusions
—Seven years after PMV, more than two thirds of patients were in good clinical condition and free of any major event. The procedural result was the main determinant of long-term outcome, although a high score had also negative implications. Mitral area decreased progressively over time, whereas regurgitation did not tend to progress.
Intracoronary Flecainide Induces ST Alternans and Reentrant Arrhythmia on Intact Canine Heart
Authors: Tachibana Hidetada , Yamaki Michiyasu , Kubota Isao , Watanabe Tetsu , Yamauchi Sou , Tomoike Hitonobu
Published: June 2012

Background
—The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia.

Methods and Results
—A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (ST
a
) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest ST
a
among 60 leads for evaluation. High-dose flecainide (100 μg · kg
−1
· min
−1
) increased ST
a
and evoked a spontaneous VF. The ST
a
in high-dose flecainide loading (8.7±3.4 mV; mean±SEM) was significantly greater than that in disopyramide or lidocaine (0.9±0.4 and 0.8±0.2 mV,
P
<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in ST
a
and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those.

Conclusions
—Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP–sensitive current such as
I
to
or
I
sus
may play an important role on this phenomenon.
Abnormal Norepinephrine Clearance and Adrenergic Receptor Sensitivity in Idiopathic Orthostatic Intolerance
Authors: Jacob Giris , Shannon John R. , Costa Fernando , Furlan Raffaello , Biaggioni Italo , Mosqueda-Garcia Rogelio , Robertson Rose Marie , Robertson David
Published: June 2012

Background
—Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of ≥30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses.

Methods and Results
—Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55±5% versus 30±7%,
P
<0.02). After tyramine, NE spillover did not change significantly in patients but increased 50±10% in control subjects (
P
<0.001). The dose of isoproterenol required to increase heart rate 25 bpm was lower in patients than in control subjects (0.5±0.05 versus 1.0±0.1 μg,
P
<0.005), and the dose of phenylephrine required to increase systolic blood pressure 25 mm Hg was lower in patients than control subjects (105±11 versus 210±12 μg,
P
<0.001). Baroreflex sensitivity was lower in patients (12±1 versus 18±2 ms/mm Hg,
P
<0.02), but the intrinsic heart rate was similar in both groups.

Conclusions
—The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.
Intraperitoneal Administration of Anti–c-
fms
Monoclonal Antibody Prevents Initial Events of Atherogenesis but Does Not Reduce the Size of Advanced Lesions in Apolipoprotein E–Deficient Mice
Authors: Murayama Toshinori , Yokode Masayuki , Kataoka Hiroshi , Imabayashi Takeshi , Yoshida Hiroyuki , Sano Hideto , Nishikawa Satomi , Nishikawa Shin-Ichi , Kita Toru
Published: June 2012

Background
—Atherosclerosis results from complex inflammatory-fibroproliferative responses. To elucidate the central role of macrophage and macrophage-colony stimulating factor (M-CSF) during atherogenesis, we used a new strategy to administer to adult apolipoprotein E (apoE)-deficient mice a monoclonal antibody (AFS98) raised against c-
fms
, the receptor of M-CSF.

Methods and Results
—When 6-week-old apoE-deficient mice were fed a high-fat diet and injected with 2 mg of AFS98 intraperitoneally on alternate days for 6 weeks, accumulation of macrophage-derived foam cells in the aortic root was suppressed by 70% compared with that in controls. This preventive effect was associated with neither remarkable decrease of the number of circulating monocytes nor systemic growth retardation. In contrast, when apoE-deficient mice that had been fed a high-fat diet from 6 weeks of age were given AFS98 from 12 to 18 weeks of age, a minimal protective effect on lesion size was observed.

Conclusions
—These results suggest that (1) macrophage and M-CSF/c-
fms
play an essential role in the arterial wall during development of the fatty streak lesion and (2) blockade of the M-CSF/c-
fms
pathway could act as protection from at least early atherogenesis but could have a less preventive effect on maintenance of the advanced lesions.
Functional Polymorphism in the Regulatory Region of Gelatinase B Gene in Relation to Severity of Coronary Atherosclerosis
Authors: Zhang Baiping , Ye Shu , Herrmann Stefan-Martin , Eriksson Per , de Maat Moniek , Evans Alun , Arveiler Dominique , Luc Gérald , Cambien François , Hamsten Anders , Watkins Hugh , Henney Adriano M.
Published: June 2012

Background
—Gelatinase B
,
a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis.

Methods and Results
—Single-strand conformation polymorphism analysis was carried out to search the promoter region of the gene encoding gelatinase B for naturally occurring genetic variation. As a result, an unreported common polymorphism was detected, which arose from a cytosine (C) to thymidine (T) transition at position −1562 relative to the start of transcription. Transient transfection experiments and DNA-protein interaction assays indicated that the T allele had a higher promoter activity than the C allele, which appeared to be due to preferential binding of a putative transcription repressor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects were genotyped. The allele frequencies were not significantly different between the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying 1 or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of
C/C
homozygotes had triple-vessel disease.

Conclusions
—These data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.
Long-Term Prostacyclin for Pulmonary Hypertension With Associated Congenital Heart Defects
Authors: Rosenzweig Erika Berman , Kerstein Diane , Barst Robyn J
Published: June 2012

Background
—Although long-term prostacyclin (PGI2) has been shown to improve hemodynamics, quality of life, and survival in patients with primary pulmonary hypertension, its use in patients with pulmonary hypertension (PHT) and associated congenital heart defects (CHD) has not been evaluated.

Methods and Results
—Twenty patients (15±14 years) with PHT and associated CHD (9 atrial septal defect, 7 ventricular septal defect, 4 transposition of the great vessels, 3 patient ductus arteriosus, 3 partial anomalous pulmonary venous return, and 1 aortopulmonary window) who failed conventional therapy (including digitalis; diuretics; oxygen; warfarin; calcium channel blockade, if indicated; and surgery, if operable) were treated with chronic PGI2. Eleven patients had previous cardiac surgery at a median age of 3 years (range, 5 days to 47 years). Eleven of 20 patients had residual systemic to pulmonary shunts. Hemodynamics, NYHA functional class, and exercise capacity were measured at baseline and after 1 year of PGI2 therapy. None of the patients acutely responded to PGI2 administration. Despite lack of an acute response, mean pulmonary artery pressure decreased 21% on chronic PGI2: 77±20 to 61±15 mm Hg (
P
<0.01, n=16). Cardiac index and pulmonary vascular resistance also improved on long-term PGI2: 3.5±2.0 to 5.9±2.7 L · min
−1
· m
−2
(
P
<0.01, n=16), and 25±13 to 12±7 U · m
2
(
P
<0.01, n=16), respectively. NYHA functional class improved from 3.2±0.7 to 2.0±0.9 (
P
<0.0001, n=19). Exercise capacity increased from 408±149 to 460±99 m (
P
=0.13, n=14) on long-term PGI2.

Conclusions
—Chronic PGI2 improves hemodynamics and quality of life in patients with PHT and associated CHD who fail conventional therapy. As previously demonstrated in patients with primary pulmonary hypertension, long-term PGI2 may have an important role in the treatment of patients with PHT and associated CHD.