bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Cardiac Nerves in the Cardiovascular Response to Cocaine in Conscious Dogs
Authors: Shannon Richard P. , Mathier Michael A. , Shen You-tang
Published: June 2012

Background
—Although the cardiovascular toxicity of cocaine is well recognized, considerable controversy remains as to the relative contribution of local norepinephrine reuptake inhibition versus central stimulatory effects of cocaine in eliciting its cardiovascular actions. The purpose of the present study was to determine the role of cardiac nerves in mediating the left ventricular (LV) and coronary hemodynamic responses to cocaine.

Methods and Results
—We studied the cardiovascular response to acute cocaine administration (1 mg/kg) in 10 intact, conscious dogs and 6 dogs with ventricular denervation (VD). There were no significant differences in baseline hemodynamic parameters or plasma catecholamines between the 2 groups. In response to acute cocaine, LV and coronary hemodynamic responses were enhanced in the VD dogs. The enhanced systemic pressor and heart rate responses in VD dogs suggest that cardiac nerves mitigate the response to cocaine through ventricular mechanoreceptors rather than mediating the responses.

Conclusions
—These data suggest that peripheral blockade of norepinephrine reuptake is not the principal mechanism of the acute cardiac effects of cocaine. Rather, cardiac nerves modulate the effects of cocaine through baroreflex mechanisms. Thus, individual differences in baroreflex sensitivity may explain the hemodynamic variability observed in response to cocaine.
Liquid-Filled Balloon Brachytherapy Using
68
Ga Is Effective and Safe Because of the Short 68-Minute Half-Life
Authors: Stoll Hans-Peter , Hutchins Gary D. , Winkle Wendy L. , Nguyen Anne T. , Hou Dongming , Appledorn C. Robert , Romeike Bernd , March Keith L.
Published: June 2012

Background
—Liquid-filled balloons for coronary brachytherapy provide significant advantages over solid sources in dose homogeneity but carry the risk of life-threatening radiointoxication after balloon rupture and laboratory contamination in case of a spill. We hypothesized that the positron emitter
68
Ga, with a half-life of only 68 minutes, was well suited to overcome these safety obstacles while providing full therapeutic efficacy.

Methods and Results
—The feasibility, efficacy, and safety of
68
Ga liquid-filled balloon brachytherapy were investigated in the porcine coronary overstretch model. Four groups of 5 balloon-induced coronary lesions were irradiated with 8, 12, 16, and 24 Gy targeted to the adventitia. Ten unirradiated lesions served as controls. Segments treated with 16 or 24 Gy exhibited marked suppression of neointimal proliferation at 28-day follow-up, with quantitative parameters of intraluminal proliferation reduced to <20%. This beneficial effect was not compromised by untoward edge effects. Uninjured but irradiated vessels did not show histological signs of radiation damage. The
68
Ga whole-body dose due to balloon rupture was estimated to be 5 rem/50 mCi treatment activity and compared favorably with that of
188
Re (78 rem/50 mCi).

Conclusions
—
68
Ga positron radiation suppresses neointimal proliferation at doses of 16 and 24 Gy. This biological efficacy, coupled with the attractive safety profile, suggests the selection of
68
Ga as an attractive isotope for liquid-filled balloon brachytherapy.
Intravascular Sonotherapy Decreases Neointimal Hyperplasia After Stent Implantation in Swine
Authors: Fitzgerald Peter J. , Takagi Atsushi , Moore M. Pauliina , Hayase Motoya , Kolodgie Frank D. , Corl Doug , Nassi Menahem , Virmani Renu , Yock Paul G.
Published: June 2012

Background
—Intimal hyperplasia and subsequent in-stent restenosis remain a major limitation after stent implantation. In vitro cell culture studies show that low-frequency, noncavitational ultrasound energy may impact smooth muscle cell proliferation. Accordingly, we assessed the efficacy of intravascular sonotherapy treatment on intimal hyperplasia in a swine stent model.

Methods and Results
—After balloon injury, biliary stents (Johnson & Johnson) were implanted in the femoral arteries of 14 swine. A total of 48 stented sites were randomized to sonotherapy or sham treatment using a custom-built, 8-French catheter intravascular sonotherapy system (
URX
, PharmaSonics Inc). After stent deployment, ultrasound energy (700 KHz) was applied to the treatment group for up to 5 minutes. Smooth muscle cell proliferation was assessed using bromodeoxyuridine histology preparation (BrdU) at 7 days in 28 stented sites. At 28 days, the neointimal thickness and the ratio of neointimal/stent area (percent stenosis) was calculated by histomorphometric quantification in 20 stented sites. At 7 days, percent of BrdU staining was significantly reduced in the sonotherapy group compared with the sham group (24.1±7.0% versus 31.2±3.0%,
P
<0.05). At 28 days, percent stenosis was significantly less in the sonotherapy group than in the sham group (36±24% versus 44±27%,
P
<0.05), and the mean neointimal thickness in the sonotherapy group was less than in the sham group (417±461 μm versus 643±869 μm,
P
=0.06).

Conclusions
—In this swine peripheral model, intravascular sonotherapy seemed to decelerate cellular proliferation and decrease in-stent hyperplasia. Therefore, intravascular sonotherapy may be an effective form of nonionizing energy to reduce in-stent restenosis.
Late Arterial Responses (6 and 12 Months) After
32
P β-Emitting Stent Placement
Authors: Farb Andrew , Shroff Sweta , John Michael , Sweet William , Virmani Renu
Published: June 2012

pick;5248p1-foo;0;;clb/clb>Background
—Three-month studies of stent-delivered brachytherapy in the rabbit model show reduced neointimal growth. However, intimal healing is delayed, raising the possibility that intimal inhibition is merely delayed rather than prevented. The purpose of this study was to explore the long-term histological changes after placement of β-emitting radioactive stents in normal rabbit iliac arteries.

Methods and Results
—Three-millimeter β-emitting
32
P stents (6, 24, and 48 μCi) were placed in normal rabbit iliac arteries with nonradioactive stents as controls. Animals were euthanatized at 6 and 12 months, and histological assessment, morphometry, and analysis of endothelialization were performed. Morphometric measurements demonstrated a >50% reduction in intimal growth and percent lumen stenosis within 24- and 48-μCi stents versus control nonradioactive stents at both 6 and 12 months. However, the 24- and 48-μCi stents also showed delayed healing of the intimal surface, characterized by persistent fibrin thrombus with nonconfluent areas of matrix, incomplete endothelialization, and increased intimal cellular proliferation. Stent edge stenosis was present at 12 months in the 24- and 48-μCi stent groups, characterized by both intimal thickening and negative arterial remodeling.

Conclusions
—Inhibition of intimal growth is maintained 6 and 12 months after
32
P β-emitting stent placement. However, delayed arterial healing, incomplete endothelialization, and edge effects are present.
Nonpharmacological Approaches to Atrial Fibrillation
Authors: Scheinman Melvin M. , Morady Fred
Published: June 2012

The mainstay of managing atrial fibrillation (AF) is drug therapy. In some patients, drug therapy is ineffective or not tolerated. This article reviews the current status of various nonpharmacological options for the treatment of AF.
Interleukin-6 (
IL-6
) and the Prognosis of Abdominal Aortic Aneurysms
Authors: Jones K.G. , Brull D.J. , Brown L.C. , Sian M. , Greenhalgh R.M. , Humphries S.E. , Powell J.T.
Published: June 2012

Background
—Abdominal aortic aneurysm is a multifactorial disorder in which inflammation is an important pathophysiological feature. In explant culture, aneurysm biopsies secrete large amounts of interleukin-6 (IL-6), and among aneurysm patients, the circulating concentration of IL-6 appears to be increased.

Methods and Results
—We investigated, in 19 patients, whether aneurysm wall was an important source of circulating IL-6. We also tested the hypotheses, in 466 patients with a small aneurysm, that (1) high concentrations of circulating IL-6 signaled rapid aneurysm growth and (2) the −174 G→C polymorphism in the
IL-6
promoter predicted survival. For 19 patients with large or inflammatory aneurysms, the concentration of IL-6 was higher in the iliac arteries than the brachial arteries (median difference 26.5 pg/mL, this difference increasing with aneurysm diameter,
P
=0.01). In 466 patients with small aneurysms, the frequency of the −174 C allele (0.40) was similar to that in a normal healthy population. Patients of GG genotype had lower plasma concentrations of IL-6 than patients of GC and CC genotypes (medians 1.9, 4.8, and 15.6 pg/mL, respectively, Kruskal-Wallis
P
=0.047). Cardiovascular and all-cause mortalities were lower for patients of GG genotype than for patients of GC and CC genotype: hazard ratios 0.32 (95% CI 0.12 to 0.93),
P
=0.036, and 0.51 (95% CI 0.25 to 1.00),
P
=0.05, respectively. There was no association between plasma IL-6 or
IL-6
genotype and aneurysm growth.

Conclusions
—Aortic aneurysms appear to be an important source of circulating IL-6, the concentration being influenced by genotype. For patients with small aneurysms, the −174 G→C
IL-6
genotype predicts future cardiovascular mortality.
High-Density Lipoprotein Loses Its Anti-Inflammatory Properties During Acute Influenza A Infection
Authors: Van Lenten Brian J. , Wagner Alan C. , Nayak Debi P. , Hama Susan , Navab Mohamad , Fogelman Alan M.
Published: June 2012

Background
—Viruses have been identified as one of a variety of potential agents that are implicated in atherogenesis.

Methods and Results
—C57BL/6J mice were killed before or 2, 3, 5, 7, or 9 days after intranasal infection with 10
5
plaque-forming units (pfu) of Influenza A strain WSN/33. Peak infectivity in lungs was reached by 72 hours, and it returned to baseline by 9 days. No viremia was observed at any time. The activities of paraoxonase and platelet-activating factor acetylhydrolase in HDL decreased after infection and reached their lowest levels 7 days after inoculation. The ability of HDL from infected mice to inhibit LDL oxidation and LDL-induced monocyte chemotactic activity in human artery wall cell cocultures decreased with time after inoculation. Moreover, as the infection progressed, LDL more readily induced monocyte chemotaxis. Peak interleukin-6 and serum amyloid A plasma levels were observed at 2 and 7 days after inoculation. HDL apoA-I levels did not change. ApoJ and ceruloplasmin levels in HDL peaked 3 days after infection. Ceruloplasmin remained elevated throughout the time course, whereas apoJ levels decreased toward baseline after the third day.

Conclusions
—We conclude that alterations in the relative levels of paraoxonase, platelet-activating factor acetylhydrolase, ceruloplasmin, and apoJ in HDL occur during acute influenza infection, causing HDL to lose its anti-inflammatory properties.
Serial Intravascular Ultrasound Analysis of the Impact of Lesion Length on the Efficacy of Intracoronary γ-Irradiation for Preventing Recurrent In-Stent Restenosis
Authors: Ahmed Javed M. , Mintz Gary S. , Waksman Ron , Weissman Neil J. , Leiboff Borjanka , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Leon Martin B.
Published: June 2012

Background
—The relation between lesion length and effectiveness of brachytherapy is not well studied.

Methods and Results
—We compared serial (postintervention and follow-up) intravascular ultrasound findings in 66 patients with native coronary artery in-stent restenosis (ISR) who were treated with
192
Ir (15 Gy delivered 2 mm away from the radiation source). Patients were enrolled in the Washington Radiation for In-Stent Restenosis Trial (WRIST; ISR length, 10 to 47 mm; n=36) or Long WRIST (ISR length, 36 to 80 mm; n=30). External elastic membrane, stent, lumen, and intimal hyperplasia (IH; stent minus lumen) areas and source-to-target (intravascular ultrasound catheter to external elastic membrane) distances were measured. Postintervention stent areas were larger in WRIST and smaller in Long WRIST patients (
P
<0.0001). At follow-up, maximum IH area significantly increased in both WRIST and Long WRIST patients (
P
<0.0001 for both), but this increase was greater in Long WRIST patients (
P
=0.0006). Similarly, minimum lumen cross-sectional area significantly decreased in both WRIST and Long WRIST patients (
P
<0.05 and
P
<0.0001, respectively), but this decrease was more pronounced in Long WRIST patients (
P
=0.0567). The maximum source-to-target distance was longer in Long WRIST than in WRIST, and it correlated directly with ISR length (
r
=0.547,
P
<0.0001). Overall, the change in minimum lumen area and the change in maximum IH area correlated with the maximum source-to-target distance (
r
=0.352,
P
=0.0038 and
r
=0.523,
P
<0.0001 for WRIST and Long WRIST, respectively). The variability (maximum/minimum) in IH area at follow-up also correlated with the maximum source-to-target distance (
r
=0.378,
P
<0.0001).

Conclusions
—Brachytherapy may be less effective in longer ISR lesions because of the greater variability and longer source-to-target distances in diffuse ISR.
Regulation of Plasma Endothelin by Salt in Salt-Sensitive Hypertension
Authors: Elijovich Fernando , Laffer Cheryl L. , Amador Elias , Gavras Haralambos , Bresnahan Margaret R. , Schiffrin Ernesto L.
Published: June 2012

Background
—Salt dependency of blood pressure (BP) characterizes most models of experimental hypertension in which endothelins play a significant vasoconstrictor role. Despite this, there are no data on the regulation of plasma endothelin by salt balance in human hypertension.

Methods and Results
—Plasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (↓Na) were assessed in 29 of these patients. Endothelin was higher in hypertensive patients (4.6±0.2 fmol/mL) than in 20 control subjects (3.3±0.3 fmol/mL,
P
<0.002), was correlated with BP, and was negatively associated with PRA (
P
<0.04). Salt-sensitive, salt-resistant, and indeterminate groups were defined by the tertiles of the
t
statistic for the difference in BP before and after ↓Na. Systolic BP falls were −15±1, −2±2, and −9±1 mm Hg, respectively. PRA, its response to ↓Na, and its level after ↓Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to ↓Na, catecholamines increased more significantly in salt-sensitive patients (+2.4±0.9 nmol/L) than in the other groups (0.4±0.2 and 0.7±0.2 nmol/L for indeterminate and salt-resistant groups, respectively;
P
<0.03), whereas endothelin increased in the salt-sensitive group (0.8±0.3 fmol/mL), decreased in the salt-resistant group (−0.4±0.3 fmol/mL), and sustained minimal change in the indeterminate group (0.2±0.3 fmol/mL) (
P
<0.04). Thus, endothelin levels in the salt-depleted state were highest in salt-sensitive patients (5.2±0.4 fmol/mL) versus the other groups (3.4±0.4 and 4.4±0.4 fmol/mL for salt-resistant and indeterminate groups, respectively) (
P
<0.02). Changes in endothelin during ↓Na and levels after ↓Na were correlated with changes in catecholamines (
P
<0.02).

Conclusions
—Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.
Oral Matrix Metalloproteinase Inhibition and Arterial Remodeling After Balloon Dilation
Authors: Sierevogel Marion J. , Pasterkamp Gerard , Velema Evelyn , de Jaegere Peter P. T. , de Smet Bart J. G. L. , Verheijen Jan H. , de Kleijn Dominique P. V. , Borst Cornelius
Published: June 2012

Background
—Inhibition of matrix metalloproteinase (MMP) activity after balloon angioplasty by intraperitoneal injection of batimastat reduces late lumen loss by inhibition of constrictive remodeling. In the present study, we investigated whether the oral MMP inhibitor marimastat inhibits constrictive remodeling in favor of neutral or expansive remodeling.

Methods and Results
—In 26 pigs, balloon dilation was performed in 101 peripheral arteries. Pigs were treated with marimastat or served as controls and were euthanized 42 days after intervention. Intravascular ultrasound was performed at all time points. Vessel area (VA) loss was assessed by calculating the change in VA at termination relative to after intervention. Arteries were divided in 3 categories: expansive remodeling (VA loss < −5%), neutral (−5% ≤ VA loss ≤ +5%), and constrictive remodeling (VA loss > +5%). In the marimastat group, a significant reduction (53%) of late lumen loss was observed that was fully explained by impaired constrictive remodeling. In the marimastat group, the prevalence of constrictive remodeling was reduced (38% versus 75% in the control group) in favor of not only neutral but also expansive remodeling (21% and 42% versus 4% and 21% in the control group, respectively,
P
<0.01). In contrast to the control group, acute luminal gain in the marimastat group did not correlate with late VA loss.

Conclusions
—Irrespective of the acute luminal gain by balloon dilation, the oral MMP inhibitor marimastat inhibited constrictive arterial remodeling in favor of both neutral and expansive remodeling.
Clinical and Echocardiographic Characteristics of Papillary Fibroelastomas
Authors: Sun Jing Ping , Asher Craig R. , Yang Xing Sheng , Cheng Georgiana G. , Scalia Gregory M. , Massed AnMalek G. , Griffin Brian P. , Ratliff Norman B. , Stewart William J. , Thomas James D.
Published: June 2012

Background
—Cardiac papillary fibroelastoma (CPF) is a primary cardiac neoplasm that is increasingly detected by echocardiography. The clinical manifestations of this entity are not well described.

Methods and Results
—In a 16-year period, we identified patients with CPF from our pathology and echocardiography databases. A total of 162 patients had pathologically confirmed CPF. Echocardiography was performed in 141 patients with 158 CPFs, and 48 patients had CPFs that were not visible by echocardiography (<0.2 cm), leaving an echocardiographic subgroup of 93 patients with 110 CPFs. An additional 45 patients with a presumed diagnosis of CPF were identified. The mean age of the patients was 60±16 years of age, and 46.1% were male. Echocardiographically, the mean size of the CPFs was 9±4.6 mm; 82.7% occurred on valves (aortic more than mitral), 43.6% were mobile, and 91.4% were single. During a follow-up period of 11±22 months, 23 of 26 patients with a prospective diagnosis of CPF that was confirmed by pathological examination had symptoms that could be attributable to embolization. In the group of 45 patients with a presumed diagnosis of CPF, 3 patients had symptoms that were likely due to embolization (incidence, 6.6%) during a follow-up period of 552±706 days.

Conclusions
—CPFs are generally small and single, occur most often on valvular surfaces, and may be mobile, resulting in embolization. Because of the potential for embolic events, symptomatic patients, patients undergoing cardiac surgery for other lesions, and those with highly mobile and large CPFs should be considered for surgical excision.
Comparative Value of Dobutamine and Adenosine Stress in the Detection of Coronary Stenosis With Myocardial Contrast Echocardiography
Authors: Lafitte Stéphane , Matsugata Hisashi , Peters Barry , Togni Mario , Strachan Monet , Kwan Oi Ling , DeMaria Anthony N.
Published: June 2012

Background
—Controversy continues as to whether adenosine or dobutamine is the superior pharmacological stress agent for myocardial contrast echocardiography (MCE).

Methods and Results
—We compared real-time MCE refilling curves and wall thickening during adenosine and dobutamine stress in 14 open-chest dogs with left anterior descending and left circumflex coronary artery stenoses that reduced hyperemia by 40% to 60% and 70% to 90% (mild and severe non–flow-limiting stenosis, NFLS) and resting flow by 10% to 30% and 35% to 50% (mild and severe flow-limiting stenosis, FLS). MCE was performed with low-energy imaging during Optison infusion. After high-energy bubble destruction, time-intensity data from risk beds were fitted for an exponential function as
y
=A(1−
e
−
bt
), from which the rate of intensity increase (b) and maximal plateau intensity (A) were derived. Although severe NFLS and greater stenoses decreased b with both dobutamine and adenosine, with mild NFLS it was reduced in 58% of animals with dobutamine versus 8% with adenosine. The absolute decrease in b, however, was greater for adenosine than dobutamine with FLS. The A parameter was decreased with both adenosine and dobutamine only with the most severe FLS. Wall thickening was decreased with dobutamine in 33% of animals with severe NFLS and in all animals with any FLS; with adenosine, in all with severe FLS.

Conclusions
—Both dobutamine and adenosine significantly reduce MCE refilling rates in the setting of severe stenosis and in the absence of contractile abnormalities. Dobutamine decreases refilling rate and wall thickening at a less reduced flow grade than adenosine, but adenosine produces a greater magnitude of change than dobutamine.
Liposome-Mediated Gene Transfection of Endothelial Nitric Oxide Synthase Reduces Endothelial Activation and Leukocyte Infiltration in Transplanted Hearts
Authors: Iwata Akiko , Sai Sadahiro , Nitta Yoshio , Chen Megan , de Fries-Hallstrand Ricarda , Dalesandro Joy , Thomas Robert , Allen Margaret D.
Published: June 2012

Background
—During cardiac ischemia-reperfusion injury, neutrophilic infiltration of the myocardium is mediated by adhesion molecule expression on activated coronary endothelium. Nitric oxide inhibits neutrophil adhesion to endothelium in vitro by blocking the nuclear factor (NF)-κB–dependent transcription of adhesion molecules. We investigated whether intraoperative gene delivery of endothelial nitric oxide synthase (eNOS) into donor hearts before transplantation would have a similar effect on an entire organ.

Methods and Results
—In an allogeneic rabbit heart transplant model, liposomes complexed to the gene encoding eNOS were infused into the donor coronary circulation before transplantation. By 24 hours after transplantation, calcium-dependent nitrite production was significantly higher in eNOS-transfected donor hearts than in the 3 control groups: donor hearts transfected with empty plasmids alone, donor hearts treated with diluent only, and untransplanted native hearts. Intramyocardial neutrophil and T-lymphocyte populations were halved in eNOS-transfected hearts compared with control donor hearts (
P
<0.05). Moreover, the prevalence of NF-κB activation in microvascular endothelial cells and surrounding cardiac myocytes as well as endothelial vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression were all significantly reduced in eNOS-transfected hearts compared with control donor hearts (
P
<0.01). Without immunosuppression, eNOS-transfected hearts survived longer than controls.

Conclusions
—Intraoperative liposome-mediated gene delivery of eNOS to donor hearts can result in early gene expression sufficient to reduce ischemia-reperfusion injury by inhibiting NF-κB activation, adhesion molecule expression, and the early infiltration of leukocytes, all of which may improve graft survival.
Marine n-3 Fatty Acids, Wine Intake, and Heart Rate Variability in Patients Referred for Coronary Angiography
Authors: Christensen Jeppe Hagstrup , Skou Helle Aarup , Fog Lars , Hansen Vibeke Ellegaard , Vesterlund Thomas , Dyerberg Jørn , Toft Egon , Schmidt Erik Berg
Published: June 2012

Background
—Dietary n-3 polyunsaturated fatty acids (PUFAs) derived from fish may reduce the incidence of sudden cardiac death (SCD). In addition, wine drinking is suggested to have a protective effect against cardiovascular death.

Methods and Results
—We included 291 patients referred for coronary angiography in whom ischemic heart disease was suspected and all of whom completed a food questionnaire regarding fish and wine intake. The n-3 PUFA composition of granulocyte membranes and of adipose tissue was measured. In addition, 24-hour heart rate variability (HRV) was analyzed. Fish intake was positively associated with the level of n-3 PUFAs in adipose tissue. Significant positive correlation coefficients were found between HRV indices and the levels of n-3 PUFAs in granulocytes. Wine intake was also significantly positively related to HRV, but the patients with the highest wine intake also had the highest intake of fish, as documented by a high n-3 PUFA content in adipose tissue. Multiple linear regression analysis revealed that traditional factors such as treatment with β-blockers, smoking, age, and previous myocardial infarction were independently related to HRV, and furthermore that n-3 PUFAs (but not wine intake) were significantly independently associated with HRV.

Conclusions
—The close positive association between n-3 PUFAs and HRV in patients suspected of having ischemic heart disease may indicate a protective effect of n-3 PUFAs against SCD. This may partly explain the reduction in SCD observed in humans with a modest intake of n-3 PUFA. Wine intake was also positively correlated with HRV, but this correlation was no longer significant after controlling for the cellular level of n-3 PUFA.
Inhibition of the Na
+
/H
+
Exchanger Delays the Development of Rapid Pacing–Induced Atrial Contractile Dysfunction
Authors: Altemose Gregory T. , Zipes Douglas P. , Weksler Juan , Miller John M. , Olgin Jeffrey E.
Published: June 2012

Background
—Atrial mechanical stunning due to atrial fibrillation may persist after restoration of sinus rhythm. Although the mechanism of rapid rate–related contractile dysfunction remains unknown, ischemia, pH changes, and calcium overload have been postulated as potential mechanisms. We hypothesized that blockade of the Na
+
/H
+
exchanger (NHE) would alter atrial contractile dysfunction from rapid rates.

Methods and Results
—Twenty-three anesthetized dogs were studied and subjected to 5 hours of rapid right atrial pacing. Ten received an inhibitor of the NHE, 10 received saline, and 3 received nifedipine. All animals underwent placement of 2 sonomicrometers on the left atrium, transesophageal echocardiography, and invasive hemodynamic monitoring. All measurements were made in sinus rhythm. Except for baseline and postdrug measurements, reduction in left atrial fractional shortening was significantly less at all time points in the NHEI group than in the control and nifedipine groups (
P
=0.05). The percent change from baseline of left atrial function at all time intervals as assessed by left atrial appendage contraction velocity (LAACV) was significantly less in the NHEI group than in the control (
P
=0.05) group. LAACV was significantly preserved at all time intervals (except 300 minutes) in the NHEI group compared with the nifedipine group (
P
=0.05). The only significant difference in hemodynamics among the groups was between the control and the nifedipine groups at 30 minutes after drug (
P
=0.05).

Conclusions
—Treatment with HOE642 significantly blunts the decline in left atrial mechanical function from rapid atrial rates compared with both control and nifedipine-treated groups.
QT Dispersion Has No Prognostic Information for Patients With Advanced Congestive Heart Failure and Reduced Left Ventricular Systolic Function
Authors: Brendorp Bente , Elming Hanne , Jun Li , Køber Lars , Malik Marek , Jensen Gorm Boje , Torp-Pedersen Christian
Published: June 2012

Background
—QT dispersion is a potential prognostic marker of tachyarrhythmic events and death, but it is unclear whether this applies to patients with congestive heart failure (CHF).

Methods and Results
—Of the 1518 patients with advanced CHF and left ventricular dysfunction enrolled in the Danish Investigations of Arrhythmia and Mortality on Dofetilide-CHF (Diamond-CHF) study, a baseline ECG was available in 1319 patients. Of these, QT dispersion could be measured in 703 patients. During a median follow-up of 18 months (minimum 1 year), 285 patients (41%) died. The median QT dispersion was 70 ms (34/155 ms [5%/95% percentiles]), with no difference between survivors and nonsurvivors. Survival analysis revealed no prognostic information derived from QT dispersion regarding all-cause mortality (risk ratio 1.00, 95% CI 1.00 to 1.00;
P
=0.74), cardiac mortality (risk ratio 1.00, 95% CI 1.00 to 1.01;
P
=0.55), or cardiac arrhythmic mortality (risk ratio 1.00, 95% CI 0.99 to 1.01;
P
=0.38).

Conclusions
—QT dispersion has no prognostic value regarding all-cause mortality, cardiac mortality, or cardiac arrhythmic mortality for patients with advanced CHF and reduced left ventricular systolic function.
Supplementation of Atherogenic Diet With B Vitamins Does Not Prevent Atherosclerosis or Vascular Dysfunction in Monkeys
Authors: Lentz Steven R. , Piegors Donald J. , Malinow M. René , Heistad Donald D.
Published: June 2012

Background
—Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven.

Methods and Results
—Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B
12
, and vitamin B
6
) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6±0.3 to 11.8±1.7 μmol/L in monkeys fed an unsupplemented atherogenic diet (
P
<0.01) but did not increase in monkeys fed an atherogenic diet supplemented with B vitamins (3.8±0.3 μmol/L). Serum cholesterol increased from 122±7 to 550±59 mg/dL in the unsupplemented group (
P
<0.001) and from 118±5 to 492±55 mg/dL in the supplemented group (
P
<0.001). Responses to endothelium-dependent vasodilators, both in resistance vessels in vivo and in the carotid artery ex vivo, were impaired to a similar extent in groups that did and did not receive vitamin supplements. Anticoagulant responses to the infusion of thrombin were also impaired to a similar extent in both groups. Vitamin supplementation failed to prevent intimal thickening in the carotid or iliac arteries.

Conclusions
—These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis.
Treatment of Reinfarction After Thrombolytic Therapy for Acute Myocardial Infarction
Authors: Barbash Gabriel I. , Birnbaum Yochai , Bogaerts Kris , Hudson Michael , Lesaffre Emmanuel , Fu Yuling , Goodman Shaun , Houbracken Katrijn , Munsters Kurt , Granger Chris B. , Pieper Karen , Califf Robert M. , Topol Eric J. , Van de Werf Frans
Published: June 2012

Background
—Early reinfarction after thrombolytic therapy is associated with adverse outcomes and increased mortality. Among patients with reinfarction in the 1992 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and the 1998 Assessment of the Safety of a New Thrombolytic (ASSENT 2) trials, we investigated temporal and regional differences in the use of repeat thrombolysis, revascularization (angioplasty and/or bypass surgery), or conservative measures and the outcomes of each management strategy.

Methods and Results
—Data from the 4% of patients (n=2301) who experienced reinfarction after thrombolytic therapy were studied. Baseline characteristics, 30-day mortality, and incidence of total and hemorrhagic strokes were compared among the 3 treatment groups. The 30-day mortality did not differ between the repeat thrombolysis and revascularization groups (
P
=0.72), and it was significantly lower among patients treated by these 2 strategies than in those treated conservatively (11% and 11% versus 28%, respectively;
P
<0.001). Stroke rates did not differ significantly between the 3 treatment strategies (
P
=0.49). From 1992 to 1998, the percentage of reinfarction patients treated with repeat thrombolysis decreased from 29.3% to 18.5% in US centers and from 51.4% to 41.9% in all other centers (
P
<0.001). In contrast, use of revascularization procedures increased from 33.5% to 47.9% in US centers and from 8.1% to 23.0% in all other centers (
P
<0.001).

Conclusions
—Repeat thrombolysis and revascularization are associated with significantly lower mortality among reinfarction patients. Randomized trials are necessary to assess the exact risks and benefits of rethrombolysis versus interventional revascularization in this subset of high-risk patients presenting with reinfarction after thrombolytic therapy.
Similarity of Ventricular Function in Patients Alive 5 Years After Randomization to Surgery or Angioplasty in the BARI Trial
Authors: Gibbons Raymond J. , Miller D. Douglas , Liu Peter , Guo Ping , Brooks Maria Mori , Schwaiger Markus
Published: June 2012

Background
—Left ventricular ejection fraction (LVEF) is a recognized determinant of survival in patients with coronary artery disease. In major trials comparing surgical and percutaneous revascularization approaches, the long-term effect of the coronary revascularization strategy on LVEF has not been reported.

Methods and Results
—In the NHLBI-sponsored Bypass and Angioplasty Revascularization Investigation (BARI) randomized trial comparing angioplasty and bypass surgery as initial treatment strategies, 1220 (75%) of the 1617 surviving randomized patients had their EF measured by radionuclide ventriculography 5 years after study entry. For the total study group, the 5-year EF in the CABG group (n=623) was 55.8±12.3, compared with 55.7±12.7 in PTCA group (n=597,
P
=0.82). There was no significant difference in measured EF between the CABG group and the PTCA group within multiple subgroups determined by the presence or absence of diabetes, 3-vessel disease, complete revascularization, or prior myocardial infarction. In a multiple linear regression model developed to predict 5-year EF, treatment assignment to PTCA or CABG was not significant (
P
=0.95). If an EF of 0 was imputed for patients who were dead and missing EF data, however, there was a higher EF in the CABG group (
P
=0.0018) among diabetic patients only.

Conclusions
—In the BARI randomized trial, initial treatment assignment to angioplasty was not associated with any difference in long-term ventricular function compared with initial treatment assignment to surgery. These results apply, however, only to patients who were alive at 5 years.
Adenosine Enhances Neuroexcitability by Inhibiting a Slow Postspike Afterhyperpolarization in Rabbit Vagal Afferent Neurons
Authors: Middlekauff Holly R. , Doering Andrea , Weiss James N.
Published: June 2012

Background
—Electrophysiological mechanisms by which adenosine may activate cardiac afferent neurons are unknown. Slow afterhyperpolarizations (AHPs) follow action potentials in a subset of vagal C afferents, rendering them inexcitable. The purpose of this study was to test the hypothesis that adenosine increases vagal neuronal excitability by blocking slow AHPs and to determine the adenosine receptor subtype mediating these effects.

Methods and Results
—Using the perforated patch-clamp technique, we identified cultured adult rabbit nodose ganglion cells with slow AHPs in current-clamp mode. Trains of 100 current pulses at 20% above threshold were injected, with an interspike interval of 100 ms, and the number of action potentials triggered were counted and reported as the action potential response rate. During adenosine (10 μmol/L), slow AHPs were suppressed and action potential response rate was augmented from 3.8±0.5% at baseline to 28±7% after adenosine (
P
=0.0009). The selective A
2
-adenosine receptor agonist NECA but not the A
1
-adenosine agonist CCPA replicated the adenosine effect. The selective A
2A
-adenosine antagonist ZM 241385 (10 nmol/L) but not the A
1
adenosine antagonist DPCPX (5 μmol/L) abolished the adenosine effect. We considered two alternative hypotheses: (1) A
2
-receptor–mediated suppression of I
Ca
leading to smaller increases in intracellular Ca during stimulation, resulting in less activation of I
K(Ca)
and consequent suppression of slow AHPs, or (2) A
2
-receptor–mediated elevation of cAMP directly suppressing slow AHPs. Under voltage-clamp conditions, adenosine did not significantly inhibit I
Ca
, making the latter hypothesis more likely.

Conclusions
—Adenosine inhibits slow AHPs in vagal afferent neurons. This effect is most likely caused by A
2A
-receptor–mediated stimulation of cAMP production.
Inflammatory Left Ventricular Microaneurysms as a Cause of Apparently Idiopathic Ventricular Tachyarrhythmias
Authors: Chimenti Cristina , Calabrese Fiorella , Thiene Gaetano , Pieroni Maurizio , Maseri Attilio , Frustaci Andrea
Published: June 2012

Background

—

We sought to investigate the arrhythmogenic role, incidence, treatment, and prognosis of inflammatory left ventricular (LV) microaneurysms in patients with apparently idiopathic ventricular tachyarrhythmias.

Methods and Results

—

We studied 156 consecutive patients (71 men, 85 women; mean age, 44.1±11.8 years) with severe ventricular arrhythmias and normal 2D echo cardiac parameters by coronary and ventricular angiography, biventricular endomyocardial biopsy, and electrophysiological study. Polymerase chain reaction was used to detect genomic sequences of enterovirus, adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex viruses, influenza A and B viruses, and hepatitis C virus in frozen endomyocardial samples. Of these patients, 15 (9.6%) showed angiographic evidence of single or multiple LV microaneurysms. All 15 patients had recurrent episodes of ventricular tachycardia with right bundle-branch block morphology, and the arrhythmias originated within or close to the aneurysms in those patients (n=6) undergoing ventricular mapping. A lymphocytic myocarditis was observed in LV biopsies of all patients and in the right ventricles of 3 patients. Polymerase chain reaction analysis was performed in 12 and viral genomes were found in 5 (42%): hepatitis C virus in 2, enterovirus in 2, and influenza virus A in 1. The patients were treated with antiarrhythmics, and cardiac function was preserved for the next 47±39.5 months of follow-up. No major clinical event was registered, and arrhythmias were successfully treated by antiarrhythmics.

Conclusions

—

Inflammatory LV microaneurysms, often of viral origin, are a consistent cause of apparently idiopathic ventricular arrhythmias. Their prognosis so far has been benign, and aggressive therapeutic strategies have been unnecessary.
Load Versus Humoral Activation in the Genesis of Early Hypertensive Heart Disease
Authors: Hart Chari Y.T. , Meyer Donna M. , Tazelaar Henry D. , Grande Joseph P. , Burnett Jr John C. , Housmans Philippe R. , Redfield Margaret M.
Published: June 2012

Background

—

The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation.

Methods and Results

—

Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (τ) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*
P
<0.05 versus controls: 139±4* versus 123±4 mm Hg), week 5 (174±7* versus 124±4 mm Hg), and week 12 (181±12* versus 124±4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. τ was increased in HTN-5wk (50±3* ms) and HTN-12wk (62±10* ms) dogs compared with sham (41±2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls.

Conclusions

—

Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.
Angiotensin II Type 2 Receptor Is Essential for Left Ventricular Hypertrophy and Cardiac Fibrosis in Chronic Angiotensin II–Induced Hypertension
Authors: Ichihara Sahoko , Senbonmatsu Takaaki , Price Edward , Ichiki Toshihiro , Gaffney F. Andrew , Inagami Tadashi
Published: June 2012

Background

The roles of angiotensin II (Ang II) in the regulation of heart function under normal and pathological conditions have been well documented. Although 2 types of Ang II receptor (AT
1
and AT
2
) are found in various proportions, most studies have focused on AT
1
-coupled events. In the present study, we examined the hypothesis that signaling by AT
2
is important to the development of left ventricular hypertrophy and cardiac fibrosis by Ang II infusion in mice lacking the AT
2
gene (
Agtr
2−/Y).

Methods and Results

Male
Agtr
2−/Y and age-matched wild-type (WT) mice were treated long-term with Ang II, infused at a rate of 4.2 ng · kg
−1
· min
−1
for 3 weeks. Ang II elevated systolic blood pressure to comparable levels in
Agtr
2−/Y and WT mice. WT mice developed prominent concentric cardiac hypertrophy, prominent fibrosis, and impaired diastolic relaxation after Ang II infusion. In contrast, there was no cardiac hypertrophy in
Agtr
2−/Y mice.
Agtr
2−/Y mice, however, did not show signs of heart failure or impairment of ventricular relaxation and only negligible fibrosis after Ang II infusion. The absence of fibrosis may be a clue to the absence of impairment in ventricular relaxation and account for the normal left ventricular systolic and diastolic performances in
Agtr
2−/Y mice.

Conclusions

Chronic loss of AT
2
by gene targeting abolished left ventricular hypertrophy and cardiac fibrosis in mice with Ang II–induced hypertension.
Passive smoking and heart disease. Epidemiology, physiology, and biochemistry.
Authors: Glantz S A , Parmley W W
Published: June 2012

The evidence that ETS increases risk of death from heart disease is similar to that which existed in 1986 when the US Surgeon General concluded that ETS caused lung cancer in healthy nonsmokers. There are 10 epidemiological studies, conducted in a variety of locations, that reflect about a 30% increase in risk of death from ischemic heart disease or myocardial infarction among nonsmokers living with smokers. The larger studies also demonstrate a significant dose-response effect, with greater exposure to ETS associated with greater risk of death from heart disease. These epidemiological studies are complemented by a variety of physiological and biochemical data that show that ETS adversely affects platelet function and damages arterial endothelium in a way that increases the risk of heart disease. Moreover, ETS, in realistic exposures, also exerts significant adverse effects on exercise capability of both healthy people and those with heart disease by reducing the body's ability to deliver and utilize oxygen. In animal experiments, ETS also depresses cellular respiration at the level of mitochondria. The polycyclic aromatic hydrocarbons in ETS also accelerate, and may initiate, the development of atherosclerotic plaque. Of note, the cardiovascular effects of ETS appear to be different in nonsmokers and smokers. Nonsmokers appear to be more sensitive to ETS than do smokers, perhaps because some of the affected physiological systems are sensitive to low doses of the compounds in ETS, then saturate, and also perhaps because of physiological adaptions smokers undergo as a result of long-term exposure to the toxins in cigarette smoke. In any event, these findings indicate that, for cardiovascular disease, it is incorrect to compute "cigarette equivalents" for passive exposure to ETS and then to extrapolate the effects of this exposure on nonsmokers from the effects of direct smoking on smokers. These results suggest that heart disease is an important consequence of exposure to ETS. The combination of epidemiological studies with demonstration of physiological changes with exposure to ETS, together with biochemical evidence that elements of ETS have significant adverse effects on the cardiovascular system, leads to the conclusion that ETS causes heart disease. This increase in risk translates into about 10 times as many deaths from ETS-induced heart disease as lung cancer; these deaths contribute greatly to the estimated 53,000 deaths annually from passive smoking. This toll makes passive smoking the third leading preventable cause of death in the United States today, behind active smoking and alcohol.
In vivo technetium-99m S12 antibody imaging of platelet alpha-granules in rabbit endothelial neointimal proliferation after angioplasty.
Authors: Miller D D , Boulet A J , Tio F O , Garcia O J , Guy D M , McEver R P , Palmaz J C , Pak K Y , Neblock D S , Berger H J
Published: June 2012

To examine the specificity of technetium-99m monoclonal antibody (S12) imaging for identifying activated platelets at interventional injury sites in atherosclerotic rabbit arteries, subgroups of unheparinized rabbits (n = 39) underwent serial percutaneous transluminal aortic angioplasty (PTA) procedures (with or without intravascular stent placement) followed by in vivo and then ex vivo gamma camera imaging, scanning, and immunoelectron microscopy to determine the intravascular loci of S12 Fab' antibody binding. Despite angiographic vessel patency, image-derived ratios of in vivo S12 binding in injured versus uninjured vascular segments were significantly increased (p less than 0.05) after one PTA (1.3 +/- 0.17, n = 7), PTA twice at 6-week intervals (1.4 +/- 0.22, n = 7), and PTA plus stent placement (1.6 +/- 0.28, n = 7) compared with control experiments (1.1 +/- 0.13, n = 7). Ex vivo imaging of blood-free excised aortas confirmed S12 localization at PTA (2 +/- 0.4, n = 3) and PTA plus stent placement (5 +/- 3.8, n = 7) sites (both p less than 0.05 versus controls). S12 antibody uptake decreased significantly (p less than 0.05) at 1 week after PTA plus stent placement in vivo (1.1 +/- 0.10, n = 4) and ex vivo (1.6 +/- 0.7, n = 3). Electron microscopic studies confirmed dense platelet, fibrin, and red blood cell deposition in regions of acute injury, with endothelial neointimal proliferation at 1 week after PTA. Immunoelectron microscopic studies confirmed specific in vivo S12 binding (22:1 versus nonrelevant IgG) at sites of alpha-granule GMP-140 expression in activated platelets. Therefore, S12 studies may be useful to localize sites of platelet-derived mitogen release at arterial PTA injury sites.