bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart
Authors: MacCarthy Philip A. , Grocott-Mason Richard , Prendergast Bernard D. , Shah Ajay M.
Published: June 2012

Background
—Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its physiological effects on intrinsic myocardial contractile function in humans in vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the failing human heart are also unknown.

Methods and Results
—A specific ET
A
receptor antagonist, BQ123, was infused (40 nmol/min, 16 minutes) into the left coronary artery in 8 patients with atypical chest pain (normal left ventricular [LV] function and coronary arteries) and 8 patients with nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic catheterization. In normal subjects, BQ123 rapidly induced a significant reduction in LV dP/dt
max
(−270±71 mm Hg/s after 16 minutes;
P
<0.05) and in LV dP/dt at a developed pressure of 40 mm Hg (LV dP/dt
40
) (−179±54 mm Hg/s;
P
<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dt
max
(62±49 mm Hg/s after 16 minutes) or LV dP/dt
40
(83±51 mm Hg/s;
P
<0.05 compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation, LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either patient group.

Conclusions
—Endogenous ET-1 has a tonic positive inotropic effect in normal subjects, independent of effects on the peripheral vasculature and unmasked by inhibition of ET
A
receptors. However, the effect of short-term ET
A
blockade in DCM patients was opposite to that in normal subjects, which suggests that ET-1 may cause negative inotropic effects in the failing heart.
Stable Microreentrant Sources as a Mechanism of Atrial Fibrillation in the Isolated Sheep Heart
Authors: Mandapati Ravi , Skanes Allan , Chen Jay , Berenfeld Omer , Jalife José
Published: June 2012

Background
—Atrial fibrillation (AF) has traditionally been described as aperiodic or random. Yet, ongoing sources of high-frequency periodic activity have recently been suggested to underlie AF in the sheep heart. Our objective was to use a combination of optical and bipolar electrode recordings to identify sites of periodic activity during AF and elucidate their mechanism.

Methods and Results
—AF was induced by rapid pacing in the presence of 0.1 to 0.5 μmol/L acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous optical mapping of the right and left atria (RA and LA) and frequency sampling of optical and bipolar electrode recordings (including a roving electrode) to identify sites having the highest dominant frequency (DF). Rotors were identified from optical recordings, and their rotation period, core area, and perimeter were measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7±3.8 and 10.3±2.1 Hz, respectively. Spatiotemporal periodicity was seen in the LA during all episodes. In 5 of 7 experiments, a single site having periodic activity at the highest DF was localized. The highest DF was most often (80%) localized to the posterior LA, near or at the pulmonary vein ostium. Rotors (n=14) were localized on the LA. The mean core perimeter and area were 10.4±2.8 mm and 3.8±2.8 mm
2
, respectively.

Conclusions
—Frequency sampling allows rapid identification of discrete sites of high-frequency periodic activity during AF. Stable microreentrant sources are the most likely underlying mechanism of AF in this model.
Effect of Verapamil on Long-Term Tachycardia-Induced Atrial Electrical Remodeling
Authors: Lee Shih-Huang , Yu Wen-Chung , Cheng Jun-Jack , Hung Chi-Ren , Ding Yu-An , Chang Mau-Song , Chen Shih-Ann
Published: June 2012

Background
—The effect of verapamil on long-term tachycardia-induced atrial electrical remodeling has not been reported.

Methods and Results
—Forty-eight dogs were randomly divided into verapamil and control groups. The dogs in the verapamil group received verapamil 120 mg every day, those in the control group did not receive verapamil. Atrial effective refractory period (AERP), inducibility of atrial fibrillation (AF), and duration of AF were assessed before and after complete atrioventricular junction ablation with 1-day, 1-week, or 6-week rapid atrial pacing (780 bpm). AERP shortening, AERP dispersion, AERP maladaptation, and inducibility of AF after 1-day pacing was significantly attenuated by verapamil. However, verapamil did not have any significant effect on these parameters in the dogs with 1-week or 6-week pacing. Verapamil did not have any significant effect on the conduction velocity in the dogs with 1-day, 1-week, or 6-week pacing. Before rapid atrial pacing, verapamil significantly prolonged the duration of AF. In the dogs with 1-day pacing, the duration of AF measured immediately after termination of pacing was similar between the control and verapamil groups. However, in the dogs with 1-week or 6-week pacing, the duration of AF after pacing was significantly longer in the verapamil group.

Conclusions
—Verapamil cannot prevent long-term (1 and 6 weeks, respectively) tachycardia-induced changes of atrial electrophysiological properties. Furthermore, verapamil increases the duration of AF in the dogs either before or after long-term rapid atrial pacing.
Current Perspectives on Statins
Authors: Maron David J. , Fazio Sergio , Linton MacRae F.
Published: June 2012

Abstract
—Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Statins are well tolerated and have an excellent safety record. Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by ≈30% and produce a greater absolute benefit in patients with higher baseline risk. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an important role in the clinical benefits conferred by these drugs and may ultimately broaden their indication from lipid-lowering to antiatherogenic agents.
Chronic β-Adrenergic Stimulation Induces Myocardial Proinflammatory Cytokine Expression
Authors: Murray David R. , Prabhu Sumanth D. , Chandrasekar Bysani
Published: June 2012

Background
—The sympathetic nervous system and proinflammatory cytokines are believed to play key roles in the pathophysiology of congestive heart failure. To evaluate a possible relationship between these neurohormonal systems, we studied the effects of chronic β-adrenergic stimulation on the myocardial and systemic elaboration of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6.

Methods and Results
—Male rats received either L-isoproterenol (2.4 mg · kg
−1
· d
−1
, n=8) or saline (n=7) via miniosmotic pumps for 7 days. Myocardial cytokine expression was analyzed by both Northern and Western blotting and localized in the tissue using immunohistochemistry. ELISA was performed to measure circulating levels of cytokines. In myocardium from control animals, neither TNF-α nor IL-1β were detected, whereas IL-6 was present at very low levels. Isoproterenol led to a significant (
P
<0.01) increase in mRNA and protein expression of all 3 cytokines. Immunohistochemistry did not detect immunoreactivity for either cytokine in myocardium from controls; however, all 3 cytokines were readily detected (
P
<0.05) throughout the myocardium, localized to resident cells and vessels, in animals treated with isoproterenol. Neither treatment group had detectable levels of cytokines in the serum.

Conclusions
—Chronic β-adrenergic stimulation induces myocardial, but not systemic, elaboration of TNF-α, IL-1β, and IL-6.
Intracoronary β-Irradiation With a Liquid
188
Re-Filled Balloon
Authors: Höher Martin , Wöhrle Jochen , Wohlfrom Markus , Hanke Hartmut , Voisard Rainer , Osterhues Hans H. , Kochs Matthias , Reske Sven N. , Hombach Vinzenz , Kotzerke Jörg
Published: June 2012

Background
—Coronary irradiation is a new concept to reduce restenosis. We evaluated the feasibility and safety of intracoronary irradiation with a balloon catheter filled with
188
Re, a liquid, high-energy β-emitter.

Methods and Results
—Irradiation with 15 Gy at 0.5-mm tissue depth was performed in 28 lesions after balloon dilation (n=9) or stenting (n=19). Lesions included 19 de novo stenoses, 4 occlusions, and 5 restenoses. Irradiation time was 515±199 seconds in 1 to 4 fractions. There were no procedural complications. One patient died of noncardiac causes at day 23. One asymptomatic patient refused 6-month angiography. Quantitative angiography after intervention showed a reference diameter of 2.77±0.35 mm and a minimal lumen diameter of 2.36±0.43 mm. At 6-month follow-up, minimal lumen diameter was 1.45±0.88 mm (late loss index 0.57). Target lesion restenosis rate (>50% in diameter) was low (12%; 3 of 26). In addition, we observed 9 stenoses at the proximal or distal end of the irradiation zone, potentially caused by the short irradiation segment and the decreasing irradiation dose at its borders (“edge” stenoses). The total restenosis rate was 46% and was significantly lower (29% vs 70%,
P
=0.042) when the length of the irradiated segment was more than twice the lesion length.

Conclusions
—Coronary irradiation with a
188
Re-filled balloon is technically feasible and safe, requiring only standard percutaneous transluminal coronary angioplasty techniques. The target lesion restenosis rate was low. The observed edge stenoses appear to be avoidable by increasing the length of the irradiated segment.
Assessment of Coronary Arterial Restenosis With Phase-Contrast Magnetic Resonance Imaging Measurements of Coronary Flow Reserve
Authors: Hundley W. Gregory , Hillis L. David , Hamilton Craig A. , Applegate Robert J. , Herrington David M. , Clarke Geoffrey D. , Braden Gregory A. , Thomas Mark S. , Lange Richard A. , Peshock Ronald M. , Link Kerry M.
Published: June 2012

Background
—After successful percutaneous coronary arterial revascularization, 25% to 60% of subjects have restenosis, a recurrent coronary arterial narrowing at the site of the intervention. At present, restenosis is usually detected invasively with contrast coronary angiography. This study was performed to determine if phase-contrast MRI (PC-MRI) could be used to detect restenosis noninvasively in patients with recurrent chest pain after percutaneous revascularization.

Methods and Results
—Seventeen patients (15 men, 2 women, age 36 to 77 years) with recurrent chest pain >3 months after successful percutaneous intervention underwent PC-MRI measurements of coronary artery flow reserve followed by assessments of stenosis severity with computer-assisted quantitative coronary angiography. The intervention was performed in the left anterior descending coronary artery in 15 patients, one of its diagonal branches in 2 patients, and the right coronary artery in 1 patient. A PC-MRI coronary flow reserve value ≤2.0 was 100% and 82% sensitive and 89% and 100% specific for detecting a luminal diameter narrowing of ≥70% and ≥50%, respectively.

Conclusions
—Assessments of coronary flow reserve with PC-MRI can be used to identify flow-limiting stenoses (luminal diameter narrowings >70%) in patients with recurrent chest pain in the months after a successful percutaneous intervention.
Effects of Iloprost Inhalation on Exercise Capacity and Ventilatory Efficiency in Patients With Primary Pulmonary Hypertension
Authors: Wensel Roland , Opitz Christian F. , Ewert Ralf , Bruch Leonhard , Kleber Franz X.
Published: June 2012

Background
—The continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH.

Methods and Results
—In 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 μg of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne · s
−1
· cm
−5
,
P
<0.05). Arterial blood gases remained unchanged (Pa
o
2
69.3 versus 66.8 mm Hg; Pa
co
2
29.6 versus 28.8 mm Hg). Iloprost significantly (
P
<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL · kg
−1
· min
−1
), and V̇
e
-versus-V̇
co
2
slope (58 versus 51.4).

Conclusions
—The present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.
Residual Plaque Burden, Delivered Dose, and Tissue Composition Predict 6-Month Outcome After Balloon Angioplasty and β-Radiation Therapy
Authors: Sabaté Manel , Marijnissen Johannes P. A. , Carlier Stéphane G. , Kay I. Patrick , van der Giessen Willem J. , Coen Veronique L. M. A. , Ligthart Jurgen M. R. , Boersma Eric , Costa Marco A. , Levendag Peter C. , Serruys Patrick W.
Published: June 2012

Background
—Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with β-radiation after BA.

Methods and Results
—Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a β-emitting
90
Sr/
90
Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D
v90
Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (
P
<0.0001). D
v90
Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (
r
=0.71;
P
=0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D
v90
Adv, and type of plaque.

Conclusions
—Residual plaque burden, delivered dose, and tissue composition play a fundamental role in the volumetric outcome at 6-month follow-up after β-radiation therapy and BA.
Increased Risk of Restenosis After Placement of Gold-Coated Stents
Authors: Kastrati Adnan , Schömig Albert , Dirschinger Josef , Mehilli Julinda , von Welser Nicola , Pache Jürgen , Schühlen Helmut , Schilling Tassilo , Schmitt Claus , Neumann Franz-Josef
Published: June 2012

Background
—Gold is a highly biocompatible material. Experimental evidence suggests that coating the stent with a gold layer may have a beneficial influence. In this randomized trial, we assessed whether gold-coated stents were associated with a better clinical and angiographic outcome after coronary placement.

Methods and Results
—Patients with symptomatic coronary artery disease were randomly assigned to receive either a gold-coated Inflow stent (n=367) or an uncoated Inflow stainless steel stent (n=364) of identical design. Follow-up angiography was routinely performed at 6 months. The primary end point of the study was the occurrence of any adverse clinical event (death, myocardial infarction, or target-vessel revascularization) during the first year after stenting. At 30 days, there was no significant difference in the combined incidence of adverse events, with 7.9% in the gold-stent group versus 5.8% in the steel-stent group (
P
=0.25). The incidence of angiographic restenosis (≥50% diameter stenosis) was 49.7% in the gold-stent group and 38.1% in the steel-stent group (
P
=0.003). One-year survival free of myocardial infarction was 88.6% in the gold-stent group and 91.8% in the steel-stent group (
P
=0.14). One-year event-free survival was significantly less favorable in the gold-stent group (62.9% versus 73.9% in the steel-stent group;
P
=0.001).

Conclusions
—Coating steel stents with gold had no significant influence on the thrombotic events observed during the first 30 days after the intervention. However, gold-coated stents were associated with a considerable increase in the risk of restenosis over the first year after stenting.
New Insights Into the Progression of Aortic Stenosis
Authors: Palta Sanjeev , Pai Anita M. , Gill Kanwaljit S. , Pai Ramdas G.
Published: June 2012

Background
—The risk factors affecting aortic stenosis (AS) progression are not clearly defined. Insights into this may allow for its secondary prevention.

Methods and Results
—We investigated predictors of AS progression in 170 consecutive patients with AS who had paired echocardiograms ≥3 months (23±11) apart. Various clinical, echocardiographic, and biochemical variables were related to the change in aortic valve area (AVA). The annual rate of reduction in AVA was 0.10±0.27 cm
2
or 7±18% per year. The reduction in AVA per year was significantly related to initial AVA (
r
=0.46,
P
<0.0001), the mean aortic valve gradient (
r
=0.27,
P
=0.04), left ventricular (LV) outflow tract velocity (
r
=0.26,
P
=0.001), and LV end-diastolic diameter (
r
=0.20,
P
=0.04) and marginally to serum creatinine level (
r
=0.15,
P
=0.08). Patients with a rate of reduction in AVA faster than the mean had higher serum creatinine (
P
=0.04) and calcium (
P
=0.08) levels. Those with a serum cholesterol level >200 mg/dL had a rate of AVA reduction roughly twice that of those with a lower cholesterol level (
P
=0.04). Stepwise multiple regression analysis identified initial AVA, current smoking, and serum calcium level as the independent predictors of amount of AVA reduction per year.

Conclusions
—Absolute and percentage reduction in AVA per year in those with AS is greater in those with milder degrees of stenosis and is accelerated in the presence of smoking, hypercholesterolemia, and elevated serum creatinine and calcium levels. These findings may have important implications in gaining further insights into the mechanism of AS progression and in formulating strategies to retard this process.
Hormone Replacement Therapy and Incidence of Acute Myocardial Infarction
Authors: Varas-Lorenzo Cristina , García-Rodríguez Luis A. , Perez-Gutthann Susanne , Duque-Oliart Alberto
Published: June 2012

Background
—Epidemiological studies suggest a decreased risk of coronary heart disease (CHD) in healthy women taking hormonal replacement therapy (HRT). Whether this effect is shared by oral and transdermal preparations is unknown.

Methods and Results
—We conducted a population-based case-control study nested in a cohort of women 50 to 74 years of age without cardiovascular disease history in the United Kingdom. Among 164 769 women from the General Practice Research Database (January 1, 1991, to December 31, 1995), we identified 1242 first acute myocardial infarctions (AMI) and confirmed 1013 after medical record review. We randomly selected 5000 age-frequency–matched control subjects. AMI incidence was 1.6 per 1000 person-years; 13% and 17% of cases and control subjects used HRT within 6 months before the index date. Risk factor and comorbidity–adjusted OR of AMI for current-recent HRT users compared with nonusers was 0.72 (95% CI 0.59 to 0.89). The OR was similar within 30 days before the index date. The beneficial effect was present after 1 year of use (OR 0. 68; 95% CI 0.53 to 0.86), with no increase in risk within the first year. ORs for unopposed and opposed therapy were 0.52 (95% CI 0.35 to 0.78) and 0.79 (95% CI 0.59 to 1.08); 79% and 21% used oral and transdermal therapy. The protective effect was present at medium-high doses of estrogens with ORs for oral and transdermal therapy of 0.63 (95% CI 0.46 to 0.86) and 0.62 (95% CI 0.37 to 1.06) and ceased after 2 to 3 years since stopping HRT.

Conclusions
—Results are consistent with those previously reported in women without CHD who were taking oral HRT and, although based on few users, suggest that transdermal therapy might have similar cardioprotective effects.
Left Ventricular Concentric Remodeling Rather Than Left Ventricular Hypertrophy Is Related to the Insulin Resistance Syndrome in Elderly Men
Authors: Sundström Johan , Lind Lars , Nyström Niklas , Zethelius Björn , Andrén Bertil , Hales C. Nicholas , Lithell Hans O.
Published: June 2012

Background
—Associations between left ventricular (LV) geometry and the insulin resistance syndrome have been found, mostly in small studies of middle-aged hypertensives. The purpose of this study was to elucidate these associations through the use of a large sample of elderly men.

Methods and Results
—We investigated 475 men (157 hypertensives) 71 years of age who were attending a population-based health survey in Uppsala County with echocardiography, oral glucose tolerance test (OGTT), hyperinsulinemic euglycemic clamp, and lipid and 24-hour ambulatory blood pressure monitoring. LV relative wall thickness was significantly related to clamp insulin sensitivity index (
r
=−0.14), fasting insulin, 32-33 split proinsulin, triglycerides, nonesterified fatty acids, OGTT glucose and insulin levels, waist-to-hip ratio, body mass index, 24-hour blood pressure, and heart rate (
r
=0.10 to 0.22). Only 24-hour systolic pressure (
r
=0.15), OGTT 2-hour insulin (
r
=−0.10), and heart rate (
r
=−0.14) were significantly related to LV mass index. Comparing subjects with various LV geometry (normal, concentric remodeling and concentric and eccentric hypertrophy) showed that 24-hour heart rate, OGTT glucose and insulin levels, waist-to-hip ratio, and body mass index were significantly higher (
P
<0.001 to 0.05) and clamp insulin sensitivity index was significantly lower (
P
<0.01) in the concentric remodeling geometry group than in the normal LV geometry group. The 24-hour blood pressure was significantly higher in the concentric hypertrophy group than in the normal LV geometry group (
P
<0.001).

Conclusions
—Several components of the insulin resistance syndrome were related to thick LV walls and concentric remodeling but less to LV hypertrophy in this population-based sample of elderly men.
Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation
Authors: Nakashima Hideko , Kumagai Koichiro , Urata Hidenori , Gondo Naoki , Ideishi Munehito , Arakawa Kikuo
Published: June 2012

Background
—The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling.

Methods and Results
—In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149±11 to 132±16 ms,
P
<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142±9 to 147±12 ms with candesartan, from 153±15 to 153±14 ms with captopril,
P
=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups.

Conclusions
—The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.
Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology
Authors: Li Danshi , Melnyk Peter , Feng Jianlin , Wang Zhiguo , Petrecca Kevin , Shrier Alvin , Nattel Stanley
Published: June 2012

Background
—Congestive heart failure (CHF) is frequently associated with atrial fibrillation (AF), but little is known about the effects of CHF on atrial cellular electrophysiology.

Methods and Results
—We studied action potential (AP) properties and ionic currents in atrial myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5 weeks. Atrial myocytes from CHF dogs were hypertrophied (mean±SEM capacitance, 89±2 pF versus 71±2 pF in control, n=160 cells per group,
P
<0.001). CHF significantly reduced the density of L-type Ca
2+
current (
I
Ca
) by ≈30%, of transient outward K
+
current (
I
to
) by ≈50%, and of slow delayed rectifier current (
I
Ks
) by ≈30% without altering their voltage dependencies or kinetics. The inward rectifier, ultrarapid and rapid delayed rectifier, and T-type Ca
2+
currents were not altered by CHF. CHF increased transient inward Na
+
/Ca
2+
exchanger (NCX) current by ≈45%. The AP duration of atrial myocytes was not altered by CHF at slow rates but was increased at faster rates, paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging mean AF duration from 8±4 to 535±82 seconds (
P
<0.01).

Conclusions
—Experimental CHF selectively decreases atrial
I
to
,
I
Ca
, and
I
Ks
, increases NCX current, and leaves other currents unchanged. The cellular electrophysiological remodeling caused by CHF is quite distinct from that caused by atrial tachycardia, highlighting important differences in the cellular milieu characterizing different clinically relevant AF substrates.
Predictors of Systolic Augmentation From Left Ventricular Preexcitation in Patients With Dilated Cardiomyopathy and Intraventricular Conduction Delay
Authors: Nelson Gregory S. , Curry Cecilia W. , Wyman Bradley T. , Kramer Andrew , Declerck Jerome , Talbot Maurice , Douglas Margaret R. , Berger Ronald D. , McVeigh Elliot R. , Kass David A.
Published: June 2012

Background
—VDD pacing can enhance systolic function in patients with dilated cardiomyopathy and discoordinate contraction; however, identification of patients likely to benefit is unclear. We tested predictors of systolic responsiveness on the basis of global parameters as well as directly assessed mechanical dyssynchrony.

Methods and Results
—Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt
max
) and ejection-phase (pulse pressure, PP) systolic function by 35±21% and 16.4±11%, respectively, and these changes correlated directly (
r
=0.7,
P
=0.001). %ΔdP/dt
max
was weakly predicted by baseline QRS (
r
=0.6,
P
<0.02), more strongly by baseline dP/dt
max
(
r
=0.7,
P
=0.001), and best by bidiscriminate analysis combining baseline dP/dt
max
≤700 mm Hg/s and QRS ≥155 ms to predict %ΔdP/dt
max
≥25% and %ΔPP ≥10% (
P
<0.0005, χ
2
), with no false-positives. Benefit could not be predicted by %ΔQRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at ≈80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0±7.1% in normal subjects versus 201.4±84.3% in DCM patients (
P
=0.001). Mechanical dyssynchrony also correlated directly with %ΔdP/dt
max
(
r
=0.85,
P
=0.008).

Conclusions
—These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt
max
provides an excellent tool to identify maximal responders.
Sympathetic Denervation of the Upper Limb Improves Forearm Exercise Performance and Skeletal Muscle Bioenergetics
Authors: Kardos Attila , Taylor Doris J. , Thompson Campbell , Styles Peter , Hands Linda , Collin Jack , Casadei Barbara
Published: June 2012

Background
—Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis.

Methods and Results
—Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by
31
phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9±1.4 to 13.4±1.8 minutes (
P
<0.0001) with the right forearm and from 5.7±0.4 to 7.6±0.9 minutes (
P
<0.05) with the left (
P
<0.05 for the interaction between treatment and side). Right forearm blood flow at rest was 66% higher (
P
<0.01) after right TST, but this difference decreased as the exercise progressed. After right TST, a significant reduction occurred in muscle acidification and phosphocreatine depletion during ipsilateral forearm exercise. This was associated with a significantly reduced mean arterial pressure response to right handgrip, whereas the pressor response to left handgrip did not change.

Conclusions
—Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.
Design of a New Surgical Approach for Ventricular Remodeling to Relieve Ischemic Mitral Regurgitation
Authors: Liel-Cohen Noah , Guerrero J. Luis , Otsuji Yutaka , Handschumacher Mark D. , Rudski Lawrence G. , Hunziker Patrick R. , Tanabe Hiroaki , Scherrer-Crosbie Marielle , Sullivan Suzanne , Levine Robert A.
Published: June 2012

Background
—Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings.

Methods and Results
—We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus (
P
<0.0001). To counteract these shifts, the LV was remodeled by plication of the infarct region to reduce myocardial bulging, without muscle excision or cardiopulmonary bypass. Immediately and up to 2 months after plication, MR was reduced to trace-to-mild as tethering distance was decreased (
P
<0.0001). LV ejection fraction, global LV end-systolic volume, and mitral annular area were relatively unchanged. By multiple regression, the only independent predictor of MR was tethering distance (
r
2
=0.81).

Conclusions
—Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering.
Cardiac Hypertrophy Is Not a Required Compensatory Response to Short-Term Pressure Overload
Authors: Hill Joseph A. , Karimi Mohsen , Kutschke William , Davisson Robin L. , Zimmerman Kathy , Wang Zhengyi , Kerber Richard E. , Weiss Robert M.
Published: June 2012

Background
—Cardiac hypertrophy is considered a necessary compensatory response to sustained elevations of left ventricular (LV) wall stress.

Methods and Results
—To test this, we inhibited calcineurin with cyclosporine (CsA) in the setting of surgically induced pressure overload in mice and examined in vivo parameters of ventricular volume and function using echocardiography. Normalized heart mass increased 45% by 5 weeks after thoracic aortic banding (TAB; heart weight/body weight, 8.3±0.9 mg/g [mean±SEM] versus 5.7±0.1 mg/g unbanded,
P
<0.05). Similar increases were documented in the cell-surface area of isolated LV myocytes. In mice subjected to TAB+CsA treatment, we observed complete inhibition of hypertrophy (heart weight/body weight, 5.2±0.3 mg/g at 5 weeks) and myocyte surface area (endocardial and epicardial fractions). The mice tolerated abolition of hypertrophy with no signs of cardiovascular compromise, and 5-week mortality was not different from that of banded mice injected with vehicle (TAB+Veh). Despite abolition of hypertrophy by CsA (LV mass by echo, 83±5 mg versus 83±2 mg unbanded), chamber size (end-diastolic volume, 33±6 μL versus 37±1 μL unbanded), and systolic ejection performance (ejection fraction, 97±2% versus 97±1% unbanded) were normal. LV mass differed significantly in TAB+Veh animals (103±5 mg,
P
<0.05), but chamber volume (end-diastolic volume, 44±6 μL), ejection fraction (92±2%), and transstenotic pressure gradients (70±14 mm Hg in TAB+Veh versus 77±11 mm Hg in TAB+CsA) were not different.

Conclusions
—In this experimental setting, calcineurin blockade with CsA prevented LV hypertrophy due to pressure overload. TAB mice treated with CsA maintain normal LV size and systolic function.
Prolonged Antibiotic Prophylaxis After Cardiovascular Surgery and Its Effect on Surgical Site Infections and Antimicrobial Resistance
Authors: Harbarth Stephan , Samore Matthew H. , Lichtenberg Debi , Carmeli Yehuda
Published: June 2012

Background
—Despite evidence supporting short antibiotic prophylaxis (ABP), it is still common practice to continue ABP for more than 48 hours after coronary artery bypass graft (CABG) surgery.

Methods and Results
—To compare the effect of short (<48 hours) versus prolonged (>48 hours) ABP on surgical site infections (SSIs) and acquired antimicrobial resistance, we conducted an observational 4-year cohort study at a tertiary-care center. An experienced infection control nurse performed prospective surveillance of 2641 patients undergoing CABG surgery. The main exposure was the duration of ABP, and main outcomes were the adjusted rate of SSI and the isolation of cephalosporin-resistant enterobacteriaceae and vancomycin-resistant enterococci (acquired antibiotic resistance). Adjustment for confounding was performed by multivariable modeling. A total of 231 SSIs (8.7%) occurred after a median of 16 days, including 93 chest-wound infections (3.5%) and 13 deep-organ-space infections (0.5%). After 1502 procedures using short ABP, 131 SSIs were recorded, compared with 100 SSIs after 1139 operations with prolonged ABP (crude OR, 1.0; CI, 0.8 to 1.3). After adjustment for possible confounding, prolonged ABP was not associated with a decreased risk of SSI (adjusted OR, 1.2; CI, 0.8 to 1.6) and was correlated with an increased risk of acquired antibiotic resistance (adjusted OR, 1.6; CI, 1.1 to 2.6).

Conclusions
—Our findings confirm that continuing ABP beyond 48 hours after CABG surgery is still widespread; however, this practice is ineffective in reducing SSI, increases antimicrobial resistance, and should therefore be avoided.
Metalloproteinase Inhibition Reduces Constrictive Arterial Remodeling After Balloon Angioplasty
Authors: de Smet Bart J. G. L. , de Kleijn Dominique , Hanemaaijer Roeland , Verheijen Jan H. , Robertus Lukas , van der Helm Yvonne J. M. , Borst Cornelius , Post Mark J.
Published: June 2012

Background
—Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation.

Methods and Results
—In atherosclerotic iliac arteries of 12 Yucatan micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3±0.1 versus 0.8±0.1 mm (
P
=0.01) and 2.2±0.5 versus 4.9±0.7 mm
2
(
P
=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9±0.6 mm
2
in the Batimastat group compared with 3.8±0.8 mm
2
in the vehicle group (
P
=0.003, mixed model analysis
P
=0.01). Neointima formation was 1.3±0.3 mm
2
in the Batimastat group and 1.0±0.2 mm
2
in the vehicle group (
P
=0.542).

Conclusions
—Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition.
Severity of Coronary Artery Calcification by Electron Beam Computed Tomography Predicts Silent Myocardial Ischemia
Authors: He Zuo-Xiang , Hedrick Thomas D. , Pratt Craig M. , Verani Mario S. , Aquino Vincent , Roberts Robert , Mahmarian John J.
Published: June 2012

Background
—Detection of subclinical coronary artery disease (CAD) before the development of life-threatening cardiac complications has great potential clinical relevance. Electron beam computed tomography (EBCT) is currently the only noninvasive test that can detect CAD in all stages of its development and thus has the potential to be an excellent screening technique for identifying asymptomatic subjects with underlying myocardial ischemia.

Methods and Results
—Over 2.5 years, we prospectively studied 3895 generally asymptomatic subjects with EBCT, 411 of whom had stress myocardial perfusion tomography (SPECT) within a close (median, 17 days) time period. SPECT and exercise treadmill results were compared with the coronary artery calcium score (CACS) as assessed by EBCT. The total CACS identified a population at high risk for having myocardial ischemia by SPECT although only a minority of subjects (22%) with an abnormal EBCT had an abnormal SPECT. No subject with CACS <10 had an abnormal SPECT compared with 2.6% of those with scores from 11 to 100, 11.3% of those with scores from 101 to 399, and 46% of those with scores ≥400 (
P
<0.0001). CACS predicted an abnormal SPECT regardless of subject age or sex.

Conclusions
—CACS identifies a high-risk group of asymptomatic subjects who have clinically important silent myocardial ischemia. Our results support the role of EBCT as the initial screening tool for identifying individuals at various stages of CAD development for whom therapeutic decision making may differ considerably.
Immunoglobulin Adsorption in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Müller Johannes , Wallukat Gerd , Dandel Michael , Bieda Heidrun , Brandes Kersten , Spiegelsberger Susanne , Nissen Eberhard , Kunze Rudolf , Hetzer Roland
Published: June 2012

Background
—Idiopathic dilated cardiomyopathy (IDC) frequently is a progressive disease without causative therapy options. Following the hypothesis that in certain patients autoantibodies against cardiac structures may induce, maintain, or promote the progression of the disease, we investigated whether the elimination of these autoantibodies through immunoadsorption would improve cardiac function.

Methods and Results
—This prospective case-control study included 34 patients with IDC. Each patient presented with moderate to severe heart failure and evidence of autoantibodies directed against β
1
-adrenoceptors (β
1
-AABs). Seventeen patients received standard medical therapy (control group), whereas 17 were also treated with immunoadsorption (treatment group) to eliminate β
1
-AABs. A 1-year follow-up included echocardiographic assessment of left ventricular ejection fraction and internal diameters, β
1
-AAB levels, and clinical status every 3 months. Within 1 year, the mean±SD left ventricular ejection fraction rose from 22.3±3.3% to 37.9±7.9% (
P
=0.0001) in the treatment group, with a relative increase of 69.9%. However, in the control group, no overall increase was seen (from 23.8±3.0% to 25.2±5.9%,
P
=0.3154). Left ventricular diameter in diastole decreased by 14.5% from 74.5±7.1 to 63.7±6.0 mm in the treatment group (
P
=0.0001) and by 3.8% (
P
=0.2342) in the control group. In the treatment group, the NYHA functional rating improved after immunoadsorption (
P
=0.0001). β
1
-AABs did not increase anew.

Conclusions
—In IDC, the use of immunoadsorption is superior to the use of standard medical therapy. It significantly improves cardiac performance and clinical status.
Effects of Continuous Positive Airway Pressure on Sleep Apnea and Ventricular Irritability in Patients With Heart Failure
Authors: Javaheri S.
Published: June 2012

Background
—Patients with heart failure and systolic dysfunction may develop disordered breathing during sleep. Repeated episodes of apnea and hypopnea may result in desaturation and arousals, which could adversely affect left ventricular function. The purpose of this study was to determine the short-term effects of continuous positive airway pressure (CPAP) on sleep-disordered breathing and its consequences in heart failure patients.

Methods and Results
—The author prospectively studied 29 male patients whose initial polysomnograms showed 15 or more episodes of apnea and hypopnea per hour (apnea-hypopnea index, AHI). Twenty-one patients had predominately central and 8 patients obstructive sleep apnea. All were treated with CPAP during the subsequent night. In 16 patients, CPAP resulted in virtual elimination of disordered breathing. In these patients, the mean AHI (36±12 [SD] versus 4±3 per hour,
P
=0.0001), arousal index due to disordered breathing (16±9 versus 2±2 per hour,
P
=0.0001), and percent of total sleep time below saturation of 90% (20±23% to 0.3±0.7%,
P
=0.0001) decreased, and lowest saturation (76±8% versus 90±3%,
P
=0.0001) increased with CPAP. In 13 patients who did not respond to CPAP, these values did not change significantly. In patients whose sleep apnea responded to CPAP, the number of hourly episodes of nocturnal premature ventricular contractions (66±117 versus 18±20,
P
=0.055) and couplets (3.2±6 versus 0.2±0.21,
P
=0.031) decreased. In contrast, in patients whose sleep apnea did not respond to CPAP, ventricular arrhythmias did not change significantly.

Conclusions
—In 55% of patients with heart failure and sleep apnea, first-night nasal CPAP eliminates disordered breathing and reduces ventricular irritability.
Upregulation of COX-2 During Cardiac Allograft Rejection
Authors: Yang Xiaochun , Ma Ninsheng , Szabolcs Matthias J. , Zhong Jing , Athan Eleni , Sciacca Robert R. , Michler Robert E. , Anderson Gary D. , Wiese Joseph F. , Leahy Kathleen M. , Gregory Susan , Cannon Paul J.
Published: June 2012

Background
—The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model.

Methods and Results
—COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (n=3,
P
<0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-
l
-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764±337 versus 5110±141 arbitrary units, n=3,
P
<0.05) and iNOS enzymatic activity (1.7±0.4 versus 22.8±14.4 nmol/mg protein, n=3,
P
<0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (
P
<0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts.

Conclusions
—The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection.
Delivery Strategies to Achieve Therapeutic Myocardial Angiogenesis
Authors: Kornowski Ran , Fuchs Shmuel , Leon Martin B. , Epstein Stephen E.
Published: June 2012

Abstract
—The use of recombinant genes or growth factors to enhance myocardial collateral blood vessel function may represent a new approach to the treatment of cardiovascular disease. Proof of concept has been demonstrated in animal models of myocardial ischemia, and clinical trials are underway. Currently, it is unknown which is the safest and most effective delivery strategy to induce clinically important therapeutic angiogenic responses in ischemic myocardium. Most strategies for transcatheter delivery of angiogenic factors have used an intracoronary route, which may have limitations because of imprecise localization of genes or proteins and systemic delivery to noncardiac tissue. The effect of direct intraoperative intramyocardial injection of angiogenic factors on collateral function has been reported in experimental models, and angiogenesis is being studied after direct intramyocardial injection of angiogenic peptides or plasmid vectors during open heart surgery in patients. Catheter-based transendocardial injection of angiogenic factors may provide equivalent benefit without the need for surgery. Intrapericardial delivery of angiogenic factors may offer a theoretical advantage of prolonged exposure of either coronary or myocardial tissue to the administered drug as result of a reservoir function of the pericardium. In this article, we review the different modes of administration for therapeutic myocardial angiogenesis therapy.