bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitroglycerin-Augmented
201
Tl Reinjection Enhances Detection of Reversible Myocardial Hypoperfusion
Authors: He Zuo-Xiang , Medrano Rafael , Hays John T. , Mahmarian John J. , Verani Mario S.
Published: June 2012

Background
Recent observations suggest that administration of nitrates before
201
Tl reinjection enhances the detection of reversible myocardial hypoperfusion.

Methods and Results
Ninety-six patients who underwent exercise-redistribution
201
Tl single photon emission computed tomography (SPECT) and had persistent defects at 4-hour redistribution imaging were prospectively randomized into a double-blind protocol in which they received a reinjection of
201
Tl (1.0 mCi) 5 minutes after either placebo or 0.8 mg sublingual nitroglycerin administration, followed by repeat SPECT imaging. Of the 69 patients who had coronary angiography, all except one had significant coronary stenoses. The overall extent of perfusion defect and the reversible component assessed by polar maps of the stress-redistribution images were similar in patients who received nitroglycerin or placebo. Among the 66 patients with persistent defects in the redistribution images, 58% of those receiving nitroglycerin showed improved reversibility after reinjection, compared with 33% of patients receiving placebo (
P
<.05). Among 68 patients with significant coronary stenoses, those who received nitroglycerin and had coronary collateral circulation were more likely to exhibit improved reversibility after reinjection than the remaining patients (50% versus 21%,
P
<.05). Moreover, the ratio of reversible to total defect in the vascular territories supplied by collaterals was ≥0.50 after reinjection in 80% of patients who received nitroglycerin (n=20) compared with 40% of the patients who received placebo (n=15) (
P
<.05).

Conclusions
Nitrate-augmented
201
Tl reinjection significantly, albeit modestly, improves detection of defect reversibility, especially in patients with coronary collateral circulation.
Verapamil Reduces Tachycardia-Induced Electrical Remodeling of the Atria
Authors: Tieleman Robert G. , De Langen Cees D. J. , Van Gelder Isabelle C. , de Kam Pieter J. , Grandjean Jan , Bel Klaas J. , Wijffels Maurits C. E. F. , Allessie Maurits A. , Crijns Harry J. G. M.
Published: June 2012

Background
Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time.

Methods and Results
To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms,
P
<.001,
P
<.01, and
P
<.01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments,
P
=.03).

Conclusions
Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.
Histopathology of In-Stent Restenosis in Patients With Peripheral Artery Disease
Authors: Kearney Marianne , Pieczek Ann , Haley Laura , Losordo Douglas W. , Andres Vicente , Schainfeld Robert , Rosenfield Kenneth , Isner Jeffrey M.
Published: June 2012

Background
Clinical studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of in-stent restenosis. However, pathological data regarding this issue are limited. Specifically, direct evidence of proliferative activity in tissues excised from stenotic stents has not been previously reported.

Methods and Results
Tissue specimens were retrieved by directional atherectomy from 10 patients in whom in-stent restenosis complicated percutaneous revascularization of peripheral artery disease. Analysis of cellular composition was performed quantitatively after cell-specific immunostaining. For specimens preserved in methanol (7 of 10), cellular proliferation was evaluated by use of antibodies to proliferating cell nuclear antigen (PCNA), cyclin E, and cdk2. TUNEL staining for apoptosis was performed on 8 paraformaldehyde-preserved specimens. Each of the 10 specimens contained extensive foci of hypercellularity composed predominantly of SMCs (mean±SEM, 59.3±3.0%). Evidence of ongoing proliferative activity was documented in all 7 methanol-preserved specimens: 24.6±2.3% of SMCs were PCNA-positive, 24.8±3.1% were cyclin E–positive, and 22.5±2.2% were cdk2-positive. Apoptotic cells were detected in all 8 specimens that had been appropriately preserved to permit DNA nick-end labeling. Macrophages and leukocytes were identified in each of the 10 specimens but accounted for a proportionately smaller number of cells (14.5±1.9% and 9.5±1.4%, respectively). Organized thrombus was observed in 6 of the 10 specimens.

Conclusions
These findings support the notion that in-stent restenosis results from SMC hyperplasia and suggest that adjunctive therapies designed to inhibit SMC proliferation may further enhance the utility of endovascular stents.
Prediction of Restenosis After Coronary Balloon Angioplasty
Authors: Peters Ron J.G. , Kok Wouter E.M. , Di Mario Carlo , Serruys Patrick W. , Bär Frits W.H.M. , Pasterkamp Gerard , Borst Cornelis , Kamp Otto , Bronzwaer Jean G.F. , Visser Cees A. , Piek Jan J. , Panday Radjan N. , Jaarsma Wiebe , Savalle Lucas , Bom Nicolaas
Published: June 2012

Background
Intracoronary ultrasound (ICUS) imaging is potentially suitable to identify lesions at high risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA), but it has not been studied systematically.

Methods and Results
We recruited 200 patients in whom ICUS studies were performed after successful PTCA and related their ICUS parameters to 6-month follow-up quantitative coronary angiography. This was performed in 164 patients (82%), yielding 170 lesions for analysis. The overall incidence of a ≥50% diameter stenosis at follow-up (categorical restenosis) was 29.4%. Quantitative ICUS parameters were weakly but significantly related to follow-up minimal luminal diameter on quantitative coronary angiography (lumen area:
R
2
=.36,
P
=.0001; vessel area:
R
2
=.29,
P
=.0002; plaque area:
R
2
=−.18,
P
=.021; percent obstruction:
R
2
=−.15,
P
=.05), but categorical restenosis was not significantly related to these parameters (
P
=.63, .77, .38, and .08, respectively). There were no significant predictors of restenosis in ICUS parameters of plaque morphology: eccentric versus concentric (
P
=1.0), plaque type (hard, soft, or calcific,
P
=.98), or the number of calcified quadrants (
P
=.41). There were no significant predictors of restenosis in two predefined types of vessel-wall disruptions: (1) rupture: presence (
P
=.79), depth (partial versus complete,
P
=.85), or extent in quadrants (
P
=.6), and (2) dissection: presence (
P
=.31), depth (
P
=.82), or extent (
P
=.38).

Conclusions
Qualitative ICUS parameters after PTCA did not predict restenosis. A larger lumen and vessel area and a smaller plaque area by ICUS were associated with a larger angiographic minimal lumen diameter at follow-up, but these parameters were not significantly related to categorical restenosis.
Effects of Inhibition of the
l
-Arginine/Nitric Oxide Pathway on Vasodilation Caused by β-Adrenergic Agonists in Human Forearm
Authors: Dawes Matthew , Chowienczyk Philip J. , Ritter James M.
Published: June 2012

Background
We examined whether vasodilator responses to β-agonists in human forearm vasculature are mediated in part through the nitric oxide pathway.

Methods and Results
We measured forearm blood flow responses to brachial artery infusions of β-adrenergic agonists in healthy men. Salbutamol was more than 100 times as potent as dobutamine. Cumulative doses of salbutamol (0.3 to 3.5 nmol·min
−1
) did not cause tachyphylaxis to an identical repeated infusion after a 24-minute recovery period. Vasodilators were infused with this sequence during coinfusion of saline and
N
G
-monomethyl-
l
-arginine (L-NMMA, 4 μmol·min
−1
), an inhibitor of nitric oxide synthase. L-NMMA coinfusion inhibited responses (area under the dose-response curve) to isoproterenol (0.01 to 0.1 nmol·min
−1
) by 59±7% (n=5) and inhibited those to salbutamol (0.3 to 3.5 nmol·min
−1
) by 52±6% (n=8). L-NMMA had no significant effect on vasodilator responses to nitroprusside (2.7 to 11.0 nmol·min
−1
, n=8), verapamil (20 to 80 nmol·min
−1
, n=8), or prostacyclin (0.08 to 0.24 nmol·min
−1
, n=8).

Conclusions
These results suggest that β-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through β
2
-adrenergic receptors and are dependent on nitric oxide synthesis.
Intracoronary Angiotensin II Potentiates Coronary Sympathetic Vasoconstriction in Humans
Authors: Saino Antonio , Pomidossi Guido , Perondi Rodolfo , Valentini Romano , Rimini Alberto , Di Francesco Lucia , Mancia Giuseppe
Published: June 2012

Background
In humans with coronary artery disease, ACE inhibition attenuates coronary sympathetic vasoconstriction. Whether this is due to removal of angiotensin (Ang) II production or to a reduced bradykinin breakdown, however, is unknown.

Methods and Results
In eight normotensive patients with angiographic evidence of mild left coronary artery lesions (≤50%), mean arterial pressure (MAP, intra-arterial catheter), heart rate (HR, ECG lead), coronary sinus blood flow (CBF, thermodilution method), and coronary vascular resistance (CVR, ratio between MAP and CBF) were measured before and during a 15-minute left intracoronary infusion of Ang II at a dose that had no direct coronary or systemic vasomotor effects. The same measurements were made before and during a 15-minute infusion of saline. A 2-minute cold pressor test (CPT) and a 45-second diving were performed at the end of either infusion period. These maneuvers were used because their coronary vasomotor effects are abolished by phentolamine and thus depend on sympathetic activation. During saline infusion, both CPT and diving caused a marked increase in MAP. HR increased with CPT and fell with diving. CBF increased in parallel to the MAP increase, with little change in CVR. The MAP and HR responses were similar during Ang II infusion, which, however, caused either no change or a reduction in CBF with a consequent marked increase in CVR with both CPT and diving. In four additional patients, the diameter of the stenotic vessels remained unchanged during the CPT performed under saline and Ang II infusion.

Conclusions
Ang II markedly enhances sympathetic influences on coronary circulation in humans, presumably by acting at the arteriolar level. This may explain the blunting effect of ACE inhibition on sympathetic coronary vasoconstriction in patients with coronary artery disease.
Evaluation of Different Ventricular Pacing Sites in Patients With Severe Heart Failure
Authors: Blanc Jean-Jacques , Etienne Yves , Gilard Martine , Mansourati Jacques , Munier Stéphane , Boschat Jacques , Benditt David G. , Lurie Keith G.
Published: June 2012

Background
Multisite ventricular pacing has recently been proposed as an additional treatment for patients with severe congestive heart failure. To further assess the potential value of this technique, we compared the acute hemodynamic changes associated with pacing the right ventricular apex (RVA) or outflow tract (RVOT) alone, the left ventricle (LV) alone, or biventricular (BIV) pacing of the RVA and LV together.

Methods and Results
Acute hemodynamic findings were measured in 27 patients with severe heart failure despite optimal therapy and either first-degree AV block and/or an intraventricular conduction defect. In the 23 patients with a high pulmonary capillary wedge pressure (PCWP) (>15 mm Hg), data were collected after transvenous pacing at different ventricular sites in either the VDD mode (AV delay=100 ms) or the VVI mode in patients with atrial fibrillation (n=6). The mean baseline cardiac index was 1.82 L · min
−1
· m
−2
. Mean±SD baseline systolic blood pressure (SBP) (118.5±15.2 mm Hg), PCWP (26.4±6.6 mm Hg), and V-wave amplitude (39.1±14.6 mm Hg) were similar before and after either RVA or RVOT pacing. In contrast, LV-based pacing (either LV alone or BIV pacing) resulted in higher SBP (
P
<.03) and lower PCWP (
P
<.01) and V-wave amplitude (
P
<.001) than either baseline or RV pacing measurements. With LV pacing alone, SBP, PCWP, and V waves were 126.5±15.1, 20.7±5.9, and 25.5±8.1 mm Hg, respectively. The results with LV pacing alone were similar to those obtained with BIV pacing.

Conclusions
In patients with severe congestive heart failure, both LV pacing alone and BIV pacing resulted in a similar and significant acute improvement in SBP, PCWP, and V-wave amplitude compared with baseline measurements and RV pacing alone. These results provide a strong basis for initiating long-term studies examining the chronic effects of LV-based pacing in patients with medically refractory congestive heart failure.
Absence of Parasympathetic Control of Heart Rate After Human Orthotopic Cardiac Transplantation
Authors: Arrowood James A. , Minisi Anthony J. , Goudreau Evelyne , Davis Annette B. , King Anne L.
Published: June 2012

Background
Partial reinnervation of cardiac sympathetic nerves has been observed after heart transplantation; we hypothesized that parasympathetic control to the heart after transplantation may return as well. To test this hypothesis, we examined heart rate responses produced by two cardiovascular reflexes whose efferent limbs are subserved by vagal fibers to the heart: (1) trigeminal reflex (simulated diving reflex) and (2) arterial baroreflex with phenylephrine injection.

Methods and Results
An “early” group (n=31, <24 months after transplantation) and a “late group” (n=27, >45 months after transplantation) were studied and compared with a control group with intact cardiac innervation (n=32) and a renal transplant group with similar transplant immunosuppressive regimen (n=11). For trigeminal reflex testing, responses of the donor sinus node (DSN) (sinus node controlling heart rate) and recipient sinus node (RSN) in the innervated remnant right atrium in cardiac transplant patients were compared with heart rate responses in the control groups. For arterial baroreflex testing, baroreflex gains for the DSN and RSN in the cardiac transplant groups were compared with those of the control group. With engagement of the trigeminal reflex, the DSN rate of both transplant groups changed minimally (early, 1.2±1.2 bpm; late, 1.8±2.5 bpm) compared with the expected decrease in control subjects (−19.8±3.0 bpm) and renal transplant patients (−23.9±4.9 bpm) (
P
<.001 versus cardiac transplants). Changes in the RSN rate of both cardiac transplant groups (early, −13.0±4.0 bpm; late, −10.0±3.7 bpm) were similar to the control groups. Arterial baroreflex gains for the DSN were also depressed (early, 0.1±0.2 ms/mm Hg; late, 0.2±0.2 ms/mm Hg) compared with control (14.9±1.8 ms/mm Hg) and RSN (early, 9.9±1.3 ms/mm Hg; late, 10.9±1.3 ms/mm Hg;
P
<.001 versus DSN transplant).

Conclusions
These data suggest that parasympathetic influences on donor heart rate are absent in the majority of patients up to 96 months after cardiac transplantation.
Primate Smooth Muscle Cell Migration From Aortic Explants Is Mediated by Endogenous Platelet-Derived Growth Factor and Basic Fibroblast Growth Factor Acting Through Matrix Metalloproteinases 2 and 9
Authors: Kenagy R. D. , Hart C. E. , Stetler-Stevenson W. G. , Clowes A. W.
Published: June 2012

Background
Migration of arterial smooth muscle cells (SMCs) is regulated by basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and matrix metalloproteinases (MMPs) in the injured rat carotid artery. We have recently shown that migration of SMCs from baboon aortic explants depends on the activity of MMPs, but the identity of the stimulatory MMPs and the role of bFGF and PDGF in this primate system are not known.

Methods and Results
These experiments were designed to determine whether MMP2, MMP9, bFGF, or PDGF plays a role in SMC migration from medial explants of baboon aorta. Explants were cultured in serum-free medium with insulin, transferrin, and ovalbumin. Neutralizing antibodies to MMP2 and antibodies that inhibit activation of proMMP9 decreased SMC migration from the aortic explants. Antibodies to bFGF and to the α- and β-subunits of the PDGF receptor also inhibited migration from the explants. Addition of bFGF and PDGF-BB but not PDGF-AA increased migration. The antibodies to bFGF but not the antibodies to the PDGF receptor subunits decreased the levels of MMP9, whereas all the antibodies decreased activated MMP2.

Conclusions
These data demonstrate that SMC migration from primate aortic explants is dependent on endogenous MMP2, MMP9, PDGF, and bFGF. The data also suggest that PDGF-induced (PDGF-BB or possibly PDGF-AB) migration is dependent on MMP2, whereas bFGF-induced migration depends on both MMP2 and MMP9.
Intimal Hyperplasia After Balloon Injury Is Attenuated by Blocking Selectins
Authors: Barron Michael K. , Lake R. Scott , Buda Andrew J. , Tenaglia Alan N.
Published: June 2012

Background
Cell adhesion molecules facilitate the adherence of platelets and leukocytes to the vascular endothelium in response to injury. Restenosis after balloon angioplasty is thought to represent the response to vascular injury. The role of cell adhesion in this process is unclear.

Methods and Results
This study was performed in New Zealand White rabbits that underwent balloon angioplasty of the iliac artery. Expression of the cell adhesion molecule E-selectin on endothelium was determined by immunohistochemistry and increased at 6 hours with a peak expression 24 to 48 hours after balloon injury, returning to baseline by 1 week. The expression of L-selectin on circulating leukocytes, measured by flow cytometry, was significantly increased at 48 hours, with return to baseline by 1 week. In seven animals, the selectins were blocked with an analogue of sialyl-Lewis
X
given as an IV bolus of 10 mg/kg followed by 2 mg · kg
−1
· h
−1
IP infusion for 7 days. After 4 weeks, compared with control animals, the study group had a larger lumen area (57.7 versus 44.7 mm
2
,
P
<.05), smaller intima area (9.0 versus 19.2 mm
2
,
P
<.01), smaller intima/media ratio (0.4 versus 1.0,
P
<.01), and a smaller percent area stenosis (15.6% versus 34.3%,
P
<.01).

Conclusions
The cell adhesion molecules E-selectin and L-selectin are expressed after balloon injury. Blockade of the selectins has a favorable effect on the response to vascular injury.
Impaired Nitric Oxide–Mediated Renal Vasodilation in Rats With Experimental Heart Failure
Authors: Abassi Zaid A. , Gurbanov Konstantin , Mulroney Susan E. , Potlog Clariss , Opgenorth Terry J. , Hoffman Aaron , Haramati Aviad , Winaver Joseph
Published: June 2012

Background
Congestive heart failure (CHF) is associated with a decrease in renal perfusion. Because endothelium-derived NO is important in the regulation of renal blood flow (RBF), we tested the hypothesis that an impairment in the NO system may contribute to the decrease in RBF in rats with experimental CHF.

Methods and Results
Studies were performed in rats with experimental high-output CHF induced by aortocaval (AV) fistula and sham-operated controls. In controls, incremental doses of acetylcholine (ACh, 1 to 100 μg · kg
−1
· min
−1
) increased RBF and caused a dose-related decrease in renal vascular resistance (RVR). However, the increase in RBF and decrease in RVR were markedly attenuated in rats with CHF. Likewise, the effects of ACh on urinary sodium and cGMP excretion were also diminished in CHF rats, as was the renal vasodilatory effect of the NO donor
S
-nitroso-
N
-acetylpenicillamine (SNAP). These attenuated responses to endothelium-dependent and -independent renal vasodilators in CHF rats occurred despite a normal baseline and stimulated NO
2
+NO
3
excretion and normal expression of renal endothelial NO synthase (eNOS), as determined by eNOS mRNA levels and immunoreactive protein. Infusion of the NO precursor
l
-arginine did not affect baseline RBF or the response to ACh in rats with CHF. However, administration of the nonpeptide angiotensin II receptor antagonist
A81988
before ACh completely restored the renal vasodilatory response to ACh in CHF rats.

Conclusions
This study demonstrates that despite a significant attenuation in the NO-related renal vasodilatory responses, the integrity of the renal NO system is preserved in rats with chronic AV fistula. This impairment in NO-mediated renal vasodilation in experimental CHF appears to be related to increased activity of the renin-angiotensin system and may contribute further to the decrease in renal perfusion seen in CHF.
Significance of Ventricular Myocytes and Nonmyocytes Interaction During Cardiocyte Hypertrophy
Authors: Harada Masaki , Itoh Hiroshi , Nakagawa Osamu , Ogawa Yoshihiro , Miyamoto Yoshihiro , Kuwahara Koichiro , Ogawa Emiko , Igaki Toshio , Yamashita Jun , Masuda Izuru , Yoshimasa Takaaki , Tanaka Issei , Saito Yoshihiko , Nakao Kazuwa
Published: June 2012

Background
In cardiac hypertrophy, both excessive enlargement of cardiac myocytes and progressive interstitial fibrosis are well known to occur simultaneously. In the present study, to investigate the interaction between ventricular myocytes (MCs) and cardiac nonmyocytes (NMCs), mostly fibroblasts, during cardiocytes hypertrophy, we examined the change in cell size and gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cultured MCs as markers for hypertrophy in the neonatal rat ventricular cardiac cell culture system.

Methods and Results
The size of cultured MCs significantly increased in the MC-NMC coculture. Concomitantly, secretions of ANP and BNP into culture media were significantly increased in the MC-NMC coculture compared with in the MC culture (with the possible contamination of NMC <1% of MC). Moreover, in the MC culture, enlargement of MC and an increase in ANP and BNP secretions were induced by treatment with conditioned media of the NMC culture. A considerable amount of endothelin (ET)-1 production was detected in the NMC-conditioned media. BQ-123, an ET-A receptor antagonist, and bosentan, a nonselective ET receptor antagonist, significantly blocked the hypertrophic response of MCs induced by treatment with NMC-conditioned media. Angiotensin II (Ang II) (10
−10
to 10
−6
mol/L) and transforming growth factor-β1 (TGF-β1) (10
−13
to 10
−9
mol/L), both of which are known to be cardiac hypertrophic factors, did not induce hypertrophy in MC culture, but both Ang II and TGF-β1 increased the size of MCs and augmented ANP and BNP productions in the MC-NMC coculture. This hypertrophic activity of Ang II and TGF-β1 was associated with the potentiation of ET-1 production in the MC-NMC coculture, and the effect of Ang II or TGF-β1 on the secretions of ANP and BNP in the coculture was significantly suppressed by pretreatment with BQ-123.

Conclusions
These results demonstrate that NMCs regulate MC hypertrophy at least partially via ET-1 secretion and that the interaction between MCs and NMCs plays a critical role during the process of Ang II–or TGF-β1–induced cardiocyte hypertrophy.
Long-term Angiographic and Clinical Outcome of Patients Undergoing Multivessel Coronary Stenting
Authors: Moussa Issam , Reimers Bernhard , Moses Jeffrey , Di Mario Carlo , Di Francesco Lucia , Ferraro Massimo , Colombo Antonio
Published: June 2012

Background
Randomized clinical trials have shown that multivessel coronary angioplasty is feasible and provides similar long-term survival as bypass surgery in selected patients. However, the higher need for repeat intervention, in particular, coronary artery bypass graft surgery, remains a problem. The objective of this study was to test the hypothesis that multivessel stenting is safe and effective in reducing the need for repeat interventions, in particular, the need for bypass surgery.

Methods and Results
Between March 1993 and June 1995, 100 consecutive patients (243 lesions) had multivessel coronary stenting. High-pressure stent optimization was used in all patients. Procedural success was achieved in 97% of lesions; 2 patients (2%) required emergency bypass surgery. Angiographic follow-up was obtained in 89% of patients at 5.2±2.5 months. Angiographic restenosis occurred in 22% of the lesions, but 37% of patients had ≥1 lesion with restenosis. Clinical follow-up was obtained in all patients at 21±10 months: target lesion revascularization was needed in 30 patients (30%), repeat angioplasty in 28 patients (28%) and coronary bypass surgery in 2 patients (2%); the overall survival rate was 96% (2% noncardiac death).

Conclusions
Multivessel coronary stenting can be performed with high success rate and low need for emergency bypass surgery. Compared with historical results with multivessel percutaneous transluminal coronary angioplasty, patients who undergo multivessel stenting need less repeat interventions, in particular, less coronary bypass surgery and have similar long-term survival.
Cardiovascular and Sympathetic Effects of Nitric Oxide Inhibition at Rest and During Static Exercise in Humans
Authors: Owlya Reza , Vollenweider Laurent , Trueb Lionel , Sartori Claudio , Lepori Mattia , Nicod Pascal , Scherrer Urs
Published: June 2012

Background
Nitric oxide (NO) regulates vascular tone and blood pressure, and studies in animals suggest that it does so, at least in part, by modulating sympathetic neural outflow. Loss of NO-induced vasodilator tone and restraint on sympathetic vasoconstrictor outflow could lead to exaggerated vasoconstrictor and pressor responses to physical stress in humans.

Methods and Results
To determine the role of NO in the modulation of central sympathetic outflow and vascular tone at rest and during a physical stress, we tested effects of systemic inhibition of NO synthase by
N
G
-monomethyl-
l
-arginine (L-NMMA) infusion (a stereospecific inhibitor of NO synthase) on sympathetic nerve activity (microneurography), regional vascular resistance, and blood pressure at rest and during static handgrip. The major new findings are that (1) under resting conditions, L-NMMA infusion, which increased mean arterial pressure by ≈10%, did not have any detectable effect on muscle sympathetic nerve activity, whereas a similar increase in arterial pressure evoked by phenylephrine infusion (an NO-independent vasoconstrictor) decreased the rate of sympathetic nerve firing by ≈50%; (2) during static handgrip, the exercise-induced sympathetic nerve responses were preserved during L-NMMA infusion but markedly attenuated during phenylephrine infusion; and (3) the L-NMMA–induced loss of vasodilator tone did not result in exaggerated exercise-induced pressor and calf vasoconstrictor responses.

Conclusions
These findings indicate that NO is involved in the central regulation of sympathetic outflow in humans and suggest that both neuronal and endothelial NO synthesis may contribute to the regulation of vasomotor tone.
Adenosine-Induced Atrioventricular Block in Patients With Unexplained Syncope
Authors: Brignole Michele , Gaggioli Germano , Menozzi Carlo , Gianfranchi Lorella , Bartoletti Angelo , Bottoni Nicola , Lolli Gino , Oddone Daniele , Attilio Del Rosso  , Pellinghelli Giuseppe
Published: June 2012

Background
ATP and its related nucleoside, adenosine, are ubiquitous biological compounds with potent depressant activity on the atrioventricular node. We hypothesized that an increased susceptibility of the atrioventricular node to adenosine may, in some cases, play a role in the genesis of syncope.

Methods and Results
The study was performed in two parts. In part 1, we evaluated the effects of a bolus injection of 20 mg ATP in a group of 60 patients (57±19 years, 31 men) with syncope of unexplained origin and in 90 control subjects without syncope (55±17 years, 46 men). In control subjects, the upper 95th percentile of the maximum RR interval distribution, during ATP-induced atrioventricular block (AVB), was 6000 ms. In the syncope group, 28% of patients had a maximum RR interval above this limit (
P
=.000). The distribution of the maximum RR interval below the 95th percentile was similar in the two groups. In part 2, we validated the ATP test in 24 patients who had the fortuitous ECG recording of a spontaneous syncope caused by a transient asystolic pause (AVB in 15 and sinus arrest in 9). The ATP test caused AVB with an asystolic pause of ≥6000 ms in 53% of the patients with documented AVB but in none (0%) of the patients with documented sinus arrest (
P
=.01). Among the patients with spontaneous AVB, the ATP test was abnormal in 6 of the 7 patients (86%) in whom all conventional investigations for syncope had been negative and in 2 of the 8 patients (25%) who had shown positivity (
P
=.03).

Conclusions
An increased susceptibility to ATP testing is present in patients with SUO and patients with syncope due to paroxysmal AVB. Thus, a logical inference is that ATP testing can be used to identify patients with syncope due to paroxysmal AVB. The results of this study form the necessary background for future prospective studies with an aim to validate this assumption.
Chronic Endothelin Receptor Blockade Attenuates Progressive Ventricular Dilation and Improves Cardiac Function in Rats With Myocardial Infarction
Authors: Fraccarollo Daniela , Hu Kai , Galuppo Paolo , Gaudron Peter , Ertl Georg
Published: June 2012

Background
Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ET
A
and ET
B
receptor blocker (bosentan) on the circulating and cardiac endothelin systems.

Methods and Results
Three hours after coronary ligation or sham operation, bosentan (100 mg · kg body wt
−1
· d
−1
) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116±2 versus 125±3 mm Hg,
P
<.05) and arterial pressure (93±2 versus 103±3 mm Hg,
P
<.05), improved stroke volume index (0.69±0.06 versus 0.52±0.04 mL/kg,
P
<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390±33 versus 475±22 pg/g tissue,
P
<.05) and density of ET-1 receptors (262±24 versus 346±31 fmol/mg protein,
P
<.05) in left ventricular myocardium.

Conclusions
In the present study, a mixed ET
A
and ET
B
receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.
Profibrillatory Effects of Intracoronary Thrombus in Acute Regional Ischemia of the In Situ Porcine Heart
Authors: Coronel Ruben , Wilms-Schopman Francien J. G. , Janse Michiel J.
Published: June 2012

Background
An intracoronary thrombus during regional ischemia is related to life-threatening arrhythmias. The electrophysiological consequences of a thrombus are unknown.

Methods and Results
In open chest pigs, regional ischemia was induced by intracoronary injection of a thrombus (protocol 1). In protocol 2, coronary ligation was followed by injection of heparinized blood. Three consecutive episodes of ischemia (10 minutes) and reperfusion (20 minutes) were studied in protocols 3 and 4 (ligation). During the former, an intracoronary thrombus started the third period of ischemia. Multiple (78) local electrograms were recorded simultaneously, and activation patterns were determined. In a first period of ischemia, ventricular fibrillation (during the first 10 minutes) occurred more often after intracoronary thrombosis than during the other protocols (4/7 versus 2/19,
P
<.05) despite similar size of the ischemic tissue. The incidence of delayed arrhythmias (between 15 and 30 minutes) was not different. Epicardial activation delay was larger 2 to 4 minutes after intracoronary thrombosis compared with ligation. ST elevation was larger with than without a thrombus (2 minutes of ischemia, 12.9±4.1 versus 8.2±3.0 mV; ±SD,
P
<.05). In protocols 3 and 4 the second period and third period of ischemia were similar irrespective of the presence of an intracoronary thrombus.

Conclusions
More conduction slowing underlies the profibrillatory effect of an intracoronary thrombus relative to coronary ligation. After preconditioning with ischemia, the profibrillatory effects are no longer detectable.
Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium
Authors: Sosunov Eugene A. , Anyukhovsky Evgeny P. , Rosen Michael R.
Published: June 2012

Background
The antiarrhythmic action of quinidine is associated with a slowing of conduction and prolongation of repolarization. The latter effect has no consistent correlation with quinidine actions on action potential duration (APD) in isolated tissue experiments. To enhance our understanding of the mechanisms of quinidine action, we studied its effect on APD in canine epicardial, midmyocardial, and endocardial tissues.

Methods and Results
Standard microelectrode techniques were used to study the effects of quinidine 2.5 to 20 μmol/L on APD in ventricular epicardial, endocardial, and transmural (M-cell) slabs at cycle lengths (CLs) from 300 to 4000 ms. Qualitatively different time courses of actions and concentration- and rate-dependent effects were seen in M cells compared with the others. In endocardium and epicardium, quinidine induced monotonic and concentration-dependent APD prolongation at all CLs. In contrast, the effects of quinidine in M cells varied from prolongation to shortening, depending on duration of superfusion, concentration, and CL. Experiments with E4031 and TTX suggested that in M cells, quinidine-induced APD lengthening was attributable to block of delayed rectifier potassium current and APD shortening was due to inhibition of TTX-sensitive steady-state sodium current.

Conclusions
In vitro, there is a significant difference of quinidine effects in M cells versus epicardial and endocardial cells that appears to reflect differences in the contributions of specific ion channels to the APD at the three sites. The differences may influence the actions of quinidine on repolarization of the heart in situ and determine both the proarrhythmic and antiarrhythmic actions of the drug.
Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium
Authors: Anyukhovsky Evgeny P. , Sosunov Eugene A. , Feinmark Steven J. , Rosen Michael R.
Published: June 2012

Background
In the companion article, we report a significant difference in quinidine effects on the action potential duration between surface (epicardial and endocardial) cells and midmyocardial cells (M cells) of canine left ventricle in vitro. This article considers two questions raised by the previous study: (1) Are the complex quinidine effects in vitro reflected in its actions on the heart in situ? (2) What are the cellular determinants of quinidine effects on QT interval in ECG?

Methods and Results
We used plunge and surface electrodes to measure activation-recovery intervals (ARIs) of bipolar electrograms obtained from epicardium, endocardium, and midmyocardium (3, 5, and 9 mm from epicardium) of canine left ventricle in conditions of AV block and right ventricular pacing. Quinidine was infused continuously; its plasma level increased from 1.6±0.1 μg/mL at 30 minutes to 7.6±0.7 μg/mL at 180 minutes. At cycle lengths (CLs) from 300 to 1500 ms, there was no ARI gradient across the ventricular wall before and during quinidine infusion. At a CL of 300 ms, therapeutic concentrations of quinidine prolonged ARIs and QT intervals. At a CL of 1500 ms, ARIs were significantly prolonged at low quinidine concentrations. With an increase of quinidine concentration, this effect subsided and disappeared.

Conclusions
In situ, quinidine-induced prolongation of repolarization is uniform in all myocardial layers and follows the pattern observed in M cells in vitro. The ability of quinidine in therapeutic concentrations to prolong repolarization at rapid heart rates can contribute to its antiarrhythmic efficacy.
Activation-Repolarization Coupling in the Normal Swine Endocardium
Authors: Gepstein Lior , Hayam Gal , Ben-Haim Shlomo A.
Published: June 2012

Background
While abnormalities of activation and repolarization play an important role in arrhythmogenesis, little information is available on the interaction between their spatial dispersions in the heart. This study examined the effects of activation spread on the spatial distribution of the repolarization properties during different depolarization patterns.

Methods and Results
Left ventricular (LV) endocardial activation and repolarization patterns were mapped in 13 healthy pigs. LV local activation, repolarization, and activation-recovery interval (ARI) times were determined from the intracardiac unipolar electrograms, color-coded, and superimposed on a three-dimensional anatomic map of the ventricle generated with a nonfluoroscopic mapping system. ARI values correlated with the duration of monophasic activation potential recorded from onset of activation to time of 90% repolarization (
r
=.97,
P
<.01). Activation time range of the left ventricle was 42±5 ms (mean±SEM) during sinus rhythm and 54±5 ms during right ventricular septal pacing. ARI inversely correlated with the corresponding activation times during both sinus (
r
2
=.76±.03) and paced (
r
2
=.77±.02) rhythms. The longest ARIs were located at the sites of earliest activation and shortest at the latest activation areas, with gradual shortening between them.

Conclusions
The spatial distribution of repolarization is dependent on the activation pattern. Repolarization dispersion in the healthy swine heart is relatively small as the result of tight coupling of the action potential duration to the activation process, assigning longer ARIs to sites activated earlier. This coupling reduces global and regional dispersion of repolarization and may serve as an important antiarrhythmic mechanism present in normal myocardium.
Nonuniform Heating During Radiofrequency Catheter Ablation With Long Electrodes
Authors: McRury Ian D. , Panescu Dorin , Mitchell Mark A. , Haines David E.
Published: June 2012

Background
Long, narrow electrodes are being considered for radiofrequency ablation of atrial fibrillation; however, preliminary work revealed coagulum formation on the electrodes and lack of lesion continuity. This may be due to the “edge effect,” which concentrates radiated energy at sharp geometric gradients. It is proposed that temperature sensors at electrode edges are preferable to a single centered sensor for temperature feedback and monitoring of long electrode geometries.

Methods and Results
A finite element model was used to predict the heating properties of new long electrode geometries. Sixteen dogs with atrial fibrillation underwent left and right atrial ablation using catheters with multiple 12.5-mm coil electrodes. Electrodes with a single thermistor were compared with electrodes with dual thermocouples placed at opposite ends and on opposing sides of the electrode. Power, temperature, and impedance were recorded for all lesions, and coagulum adhesion and magnitude were noted in a subset of lesions. Finite element analysis shows uneven heating, with the main heating concentrated at the electrode edges and a propensity toward temperatures >100°C with single-thermistor feedback control. Ablations with dual thermocouple electrodes achieved higher measured temperatures at lower power levels than those that used single-thermistor electrodes. Impedance rises and coagulum adherence occurred less frequently with dual thermocouple electrodes than with single, centered thermistor electrodes (176 of 395 versus 9 of 425 lesions;
P
<.0001; 46 of 98 versus 7 of 150 lesions;
P
<.0001, respectively).

Conclusions
Maximum heating from radiofrequency energy occurs at the electrode edges, particularly with long electrodes. The safety of temperature-feedback atrial ablation with these electrodes is significantly improved by monitoring temperatures at the edges.
Exaggerated Reactivity to Mental Stress Is Associated With Exercise-Induced Myocardial Ischemia in an Asymptomatic High-Risk Population
Authors: Kral Brian G. , Becker Lewis C. , Blumenthal Roger S. , Aversano Thomas , Fleisher Lee A. , Yook Raphael M. , Becker Diane M.
Published: June 2012

Background
This study was done to determine whether cardiovascular reactivity to mental stress is associated with exercise-induced occult ischemia in an asymptomatic population at high risk for premature coronary heart disease (CHD).

Methods and Results
One hundred fifty-two siblings of persons with premature CHD underwent mental stress testing. Exercise thallium tomography and 24-hour Holter monitoring were also performed. Hemodynamic changes were monitored during both stressors. Siblings positive for exercise-induced ischemia were offered cardiac catheterization. During mental stress, siblings with an abnormal exercise ECG and/or thallium scan (n=15) had greater maximal increases in systolic blood pressure (SBP,
P
=.0004) and diastolic blood pressure (DBP,
P
=.05) and had greater heart rate variability in the normalized low frequency domain of an analysis of Holter monitor recordings, compared with siblings without exercise-induced ischemia. Coronary arteriography confirmed coronary atherosclerosis in 85% of siblings with exercise-induced ischemia. Regression analyses showed that occult ischemia during exercise was a strong independent predictor of maximal change in SBP and DBP during mental stress. A multivariate logistic model demonstrated that siblings with exercise-induced occult ischemia were 21 times more likely to be “hot” responders (top quartile of change in SBP and DBP) during mental stress.

Conclusions
An exaggerated cardiovascular response to mental stress is associated with exercise-induced myocardial ischemia in persons with preclinical coronary heart disease.
Direct Intracoronary Evidence of Collateral Steal in Humans
Authors: Seiler Christian , Fleisch Martin , Meier Bernhard
Published: June 2012

Background
Coronary steal is defined as a fall in blood flow toward a certain vascular region in favor of another area during arteriolar vasodilatation, ie, a coronary flow velocity reserve (CFVR) <1. The purpose of this study was to determine the frequency of steal in patients with a wide range of collateral supply to a vascular area of interest and to assess whether steal is associated with the amount of collateral flow.

Methods and Results
One hundred patients 57±9 years old with a coronary artery stenosis to be dilated were examined with intracoronary (IC) Doppler guidewires. IC adenosine–induced CFVR<1 obtained distal to the stenosis was defined as steal. An index for collateral flow was determined by positioning the Doppler guidewire in the collateral-dependent vessel distal to the stenosis and measuring the flow velocity time integral during (Vi
occl
, cm) and after (Vi
ø-occl
) balloon occlusion. Vi
occl
/Vi
ø-occl
was determined without and with intravenous adenosine (140 μg · kg
−1
· min
−1
). Coronary steal occurred in 10 of 100 patients. Patients with steal showed superior collaterals compared with those without steal: Vi
occl
/Vi
ø-occl
=0.65±0.24 in patients with steal versus 0.29±0.18 in those without steal (
P
=.0001). In all patients with steal, there was a reduction in collateral flow during intravenous adenosine–induced hyperemia, whereas in the majority (70%) of patients without steal, collateral flow increased or remained unchanged during hyperemia.

Conclusions
Coronary steal assessed by intracoronary Doppler flow velocity measurements occurs in 10% of patients with a wide range of coronary collaterals to the vascular area from which blood flow is redistributed. There is a direct association between the presence of steal away from and the amount of collateral flow toward the region under investigation. Collateral flow to the vascular region studied decreases during adenosine-induced hyperemia, which indicates a mechanism of steal via the extensive collaterals.
Dipyridamole-Induced Ischemia as a Prognostic Marker of Future Adverse Cardiac Events in Adult Patients With Hypertrophic Cardiomyopathy
Authors: Lazzeroni Ettore , Picano Eugenio , Morozzi Letizia , Maurizio Anna Rita , Palma Giampaolo , Ceriati Roberta , Iori Emilio , Barilli Angela , (EPIC) Study Group, Subproject Hypertrophic Cardiomyopathy ;
Published: June 2012

Background
Myocardial ischemia may play a role in the natural history of hypertrophic cardiomyopathy (HCM). To assess the relative prevalence and the prognostic value of dipyridamole-induced ischemia, 79 patients with HCM and without concomitant coronary artery disease (53 men; mean age, 46±15 years) underwent a high-dose (up to 0.84 mg/kg over 10 minutes) dipyridamole test with 12-lead ECG and two-dimensional echo monitoring and were followed up for a mean of 6 years.

Methods and Results
Twenty-nine patients (37%) showed ECG (ie, ST depression ≥2 mV) signs of myocardial ischemia during dipyridamole test (group 1), whereas 50 (63%) had a negative test (group 2). No patient had transient wall motion abnormalities during the dipyridamole test. During the follow-up, 16 events (ie, left ventricular or atrial enlargement, unstable angina, syncope, atrial fibrillation, and bundle-branch block) occurred in 29 patients in group 1 and 5 in 50 patients in group 2 (55% versus 10%,
P
<.001). Patients with a positive dipyridamole test showed worse 72-month event-free survival rates compared with patients with a negative test (36.2% versus 84.2%,
P
<.001). A forward stepwise event-free survival analysis identified dipyridamole test positivity by ECG criteria (χ
2
=19.7,
P
=.0001), rest gradient (χ
2
=11.3,
P
=.0008), and age (χ
2
=4.1;
P
=.0413) as independent and additive predictors of subsequent events.

Conclusions
ECG signs of myocardial ischemia elicited by dipyridamole are frequent in patients with HCM and identify patients at higher risk of cardiac events, suggesting a potentially important pathogenetic role of inducible myocardial ischemia in determining adverse cardiac events in these patients.