bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Sympathetic Dysinnervation in Diabetes
Authors: Stevens Martin J. , Raffel David M. , Allman Kevin C. , Dayanikli Firat , Ficaro Edward , Sandford Tracy , Wieland Donald M. , Pfeifer Michael A. , Schwaiger Markus
Published: June 2012

Background
—Regional cardiac sympathetic hyperactivity predisposes to malignant arrhythmias in nondiabetic cardiac disease. Conversely, however, cardiac sympathetic denervation predicts increased morbidity and mortality in severe diabetic autonomic neuropathy (DAN). To unite these divergent observations, we propose that in diabetes regional cardiac denervation may elsewhere induce regional sympathetic hyperactivity, which may in turn act as a focus for chemical and electrical instability. Therefore, the aim of this study was to explore regional changes in sympathetic neuronal density and tone in diabetic patients with and without DAN.

Methods and Results
—PET using the sympathetic neurotransmitter analogue
11
C-labeled hydroxyephedrine ([
11
C]-HED) was used to characterize left ventricular sympathetic innervation in diabetic patients by assessing regional disturbances in myocardial tracer retention and washout. The subject groups comprised 10 diabetic subjects without DAN, 10 diabetic subjects with mild DAN, 9 diabetic subjects with severe DAN, and 10 healthy subjects. Abnormalities of cardiac [
11
C]-HED retention were detected in 40% of DAN-free diabetic subjects. In subjects with mild neuropathy, tracer defects were observed only in the distal inferior wall of the left ventricle, whereas with more severe neuropathy, defects extended to involve the distal and proximal anterolateral and inferior walls. Absolute [
11
C]-HED retention was found to be increased by 33% (
P
<0.01) in the proximal segments of the severe DAN subjects compared with the same regions in the DAN-free subjects (30%;
P
<0.01 greater than the proximal segments of the mild DAN subjects). Despite the increased tracer retention, no appreciable washout of tracer was observed in the proximal segments, consistent with normal regional tone but increased sympathetic innervation. Distally, [
11
C]-HED retention was decreased in severe DAN by 33% (
P
<0.01) compared with the DAN-free diabetic subjects (21%;
P
<0.05 lower than the distal segments of the mild DAN subjects).

Conclusions
—Diabetes may result in left ventricular sympathetic dysinnervation with proximal hyperinnervation complicating distal denervation. This combination could result in potentially life-threatening myocardial electrical instability and explain the enhanced cardioprotection from β-blockade in these subjects.
Intake of Potassium, Magnesium, Calcium, and Fiber and Risk of Stroke Among US Men
Authors: Ascherio A. , Rimm E. B. , Hernán M. A. , Giovannucci E. L. , Kawachi I. , Stampfer M. J. , Willett W. C.
Published: June 2012

Background
—Animal experiments and epidemiological studies have suggested that high potassium intake may reduce the risk of stroke, but the evidence is inconclusive, and the role of other nutrients in potassium-rich foods remains unknown.

Methods and Results
—We examined the association of potassium and related nutrients with risk of stroke among 43 738 US men, 40 to 75 years old, without diagnosed cardiovascular diseases or diabetes, who completed a semiquantitative food frequency questionnaire in 1986. During 8 years of follow-up, 328 strokes (210 ischemic, 70 hemorrhagic, 48 unspecified) were documented. The multivariate relative risk of stroke of any type for men in the top fifth of potassium intake (median intake, 4.3 g/d) versus those in the bottom (median, 2.4 g/d) was 0.62 (95% CI, 0.43, 0.88;
P
for trend=0.007). Results for ischemic stroke alone were similar. Intakes of cereal fiber and magnesium, but not of calcium, were also inversely associated with risk of total stroke. These inverse associations were all stronger in hypertensive than normotensive men and were not materially altered by adjustment for blood pressure levels. Use of potassium supplements was also inversely related to risk of stroke, particularly among men taking diuretics (relative risk, 0.36; 95% CI, 0.18, 0.72).

Conclusions
—Although these data do not prove a causal relationship, they are consistent with the hypothesis that diets rich in potassium, magnesium, and cereal fiber reduce the risk of stroke, particularly among hypertensive men. Potassium supplements may also be beneficial, but because of potential risks, use should be carefully monitored and restricted to men taking potassium-losing diuretics.
all-
Trans
-Retinoic Acid Reduces Neointimal Formation and Promotes Favorable Geometric Remodeling of the Rat Carotid Artery After Balloon Withdrawal Injury
Authors: Miano Joseph M. , Kelly Louise A. , Artacho Cecilia A. , Nuckolls Tammy A. , Piantedosi Roseann , Blaner William S.
Published: June 2012

Background
—The multifactorial and unpredictable nature of human restenosis will probably necessitate interventional strategies that target multiple processes involved in acute vascular narrowing. Retinoids (eg, all-
trans
-retinoic acid, atRA) represent a growing class of pleiotropic biological response modifiers with demonstrable efficacy in managing several pathological conditions. In this report, we have initiated studies to examine the hypothesis that atRA limits neointimal formation after experimental vascular injury.

Methods and Results
—Rats were predosed with atRA (30 mg · kg
−1
· d
−1
PO) or corn oil 4 days before balloon withdrawal injury (BWI) of the left common carotid artery and continued on this drug regimen for an additional 14 days. High-performance liquid chromatographic analysis documented therapeutic levels of atRA in serum and vascular tissue. atRA depressed peak DNA synthesis in the tunica media of BWI vessels (
P
<0.05). Histomorphometry revealed atRA-mediated reductions in neointimal area, neointimal cell number, and intimal/medial area ratio as well as significant increases in vessel wall perimeter (
P
<0.05). Such changes in vascular architecture contributed to a 35% to 37% increase in the luminal area of BWI vessels exposed to atRA (
P
<0.005 compared with controls).

Conclusions
—atRA reduces neointimal mass and elicits favorable geometric remodeling of the injured rat carotid artery.
Better Outcome for Women Compared With Men Undergoing Coronary Revascularization
Authors: Jacobs Alice K. , Kelsey Sheryl F. , Brooks Maria Mori , Faxon David P. , Chaitman Bernard R. , Bittner Vera , Mock Michael B. , Weiner Bonnie H. , Dean Larry , Winston Carla , Drew Laura , Sopko George
Published: June 2012

Background
—Numerous studies have shown that women undergoing coronary revascularization procedures do so at a higher risk for an adverse outcome compared with men. However, the impact of advances in technology and improvements in techniques on in-hospital and long-term outcome after revascularization in women is unclear.

Methods and Results
—We evaluated 1829 patients with symptomatic multivessel coronary disease randomized to CABG or PTCA in the Bypass Angioplasty Revascularization Investigation (BARI), of whom 27% were women. As expected, women were older (64.0 versus 60.5 years), with more congestive heart failure (14% versus 7%), hypertension (68% versus 42%), treated diabetes mellitus (31% versus 15%), and unstable angina (67% versus 61%) than men but had similar preservation of left ventricular function and extent of multivessel disease. Women assigned to surgery received the same number of total grafts but fewer internal mammary artery grafts (72% versus 85%,
P
<0.01), and those assigned to angioplasty had more intended lesions (76% versus 71%,
P
<0.01) successfully dilated than men. At an average of 5.4 years’ follow-up, crude mortality rates were similar in women (12.8%) and men (12.0%). The Cox regression model adjusting for baseline differences revealed that women had a significantly lower risk of death (relative risk, 0.60; 95% CI, 0.43 to 0.84;
P
=0.003) but not a significantly lower risk of death plus myocardial infarction (relative risk, 0.84; 95% CI, 0.66 to 1.07;
P
=0.16) than men.

Conclusions
—Although the unadjusted mortality rate suggests that women and men undergoing CABG and PTCA have a similar 5-year mortality, women have higher risk profiles; consequently, contrary to previous reports, female sex is an independent predictor of improved 5-year survival after we control for multiple risk factors.
Norepinephrine Stimulates Apoptosis in Adult Rat Ventricular Myocytes by Activation of the β-Adrenergic Pathway
Authors: Communal Catherine , Singh Krishna , Pimentel David R. , Colucci Wilson S.
Published: June 2012

Background
—Myocardial sympathetic activity is increased in heart failure. We tested the hypothesis that norepinephrine (NE) stimulates apoptosis in adult rat ventricular myocytes in vitro.

Methods and Results
—Myocytes were exposed to NE alone (10 μmol/L), NE+propranolol (2 μmol/L), NE+prazosin (0.1 μmol/L), or isoproterenol (ISO, 10 μmol/L) for 24 hours. NE and ISO decreased the number of viable myocytes by ≈35%. This effect was completely blocked by the β-adrenergic antagonist propranolol but was not affected by the α
1
-adrenergic antagonist prazosin. NE increased DNA laddering on agarose gel electrophoresis and increased the percentage of cells that were stained by terminal deoxynucleotidyl transferase–mediated nick end-labeling from 5.8±1.0% to 21.0±2.3% (
P
<0.01; n=4). NE likewise increased the percentage of apoptotic cells with hypodiploid DNA content as assessed by flow cytometry from 7.8±0.7% to 16.7±2.2% (
P
<0.01; n=6), and this effect was abolished by propranolol but not prazosin. ISO and forskolin (10 μmol/L) mimicked the effect of NE, increasing the percentage of apoptotic cells to 14.7±1.9% and 14.4±2.2%, respectively. NE-stimulated apoptosis was abolished by the protein kinase A inhibitor H-89 (20 μmol/L) or the voltage-dependent calcium channel blockers diltiazem and nifedipine.

Conclusions
—NE, acting via the β-adrenergic pathway, stimulates apoptosis in adult rat cardiac myocytes in vitro. This effect is mediated by protein kinase A and requires calcium entry via voltage-dependent calcium channels. NE-stimulated apoptosis of cardiac myocytes may contribute to the progression of myocardial failure.
Voltage-Dependent Calcium Channel Promoter Restores Baroreflex Sensitivity in Conscious Dogs With Heart Failure
Authors: Uechi Masami , Asai Kuniya , Sato Naoki , Vatner Stephen F.
Published: June 2012

Background
—The aim of this study was to determine the mechanism by which the calcium channel promoter BAY y 5959 affects the control of heart rate and baroreflex sensitivity in conscious dogs with pacing-induced heart failure (HF).

Methods and Results
—We compared responses to BAY y 5959, which increases inotropy and decreases chronotropy, with those to norepinephrine (NE), which coincidentally exerts the same directional effects on inotropy and chronotropy, albeit through different mechanisms, in the presence and absence of ganglionic blockade both in control and in HF. Both BAY y 5959 and NE elicit direct effects on the heart and indirect effects through activation of reflexes, primarily the sinoaortic baroreceptor reflex. BAY y 5959 still reduced heart rate in dogs with arterial baroreceptor denervation, but not after ganglionic blockade. HF induced classic catecholamine desensitization to the inotropic effects of NE and blunted reflex bradycardia. In contrast, inotropic responses to BAY y 5959 were preserved in HF. Surprisingly, the autonomically mediated bradycardia induced by BAY y 5959 was also preserved in HF. Baroreflex sensitivity was assessed in control and in HF by pulse interval–systolic arterial blood pressure (PI/SAP) slopes constructed in response to pharmacological alterations in arterial pressure. HF depressed the PI/SAP slope from 11.5±1.3 to 4.8±0.9 ms/mm Hg, but during BAY y 5959 infusion in HF, the PI/SAP slope was restored to 24.1±5.2 ms/mm Hg. To assess central versus peripheral actions of BAY y 5959, the agent was infused with intra–carotid artery perfusion at a low dose, which acted centrally but did not have an effect peripherally. Under these conditions, it still decreased heart rate and restored baroreflex sensitivity (PI/SAP slope, 12.7±2.8 ms/mm Hg).

Conclusions
—Thus, the calcium promoter restores arterial baroreflex sensitivity in HF. Based on intra–carotid artery experiments, this occurs through a central nervous system and vagal mechanism.
Estimation of Oxygen Delivery in Newborns With a Univentricular Circulation
Authors: Barnea Ofer , Santamore William P. , Rossi Anthony , Salloum Ellis , Chien Sufan , Austin Erle H.
Published: June 2012

Background
—The management of neonates with complex congenital anomalies depends on careful interpretation of arterial blood gas values. Improved interpretation of these oxygen parameters may allow clinicians to avoid unexpected cardiovascular events. This study examined whether systemic oxygen delivery (D
o
2
) can be maximized by the use of indices derived from oxygen saturation measurements in neonates with hypoplastic left heart syndrome.

Methods and Results
—For the single-ventricle heart with both circulations in parallel, we used a previously developed computer simulation to obtain D
o
2
as a function of systemic arterial (Sa
o
2
) and venous (Sv
o
2
) oxygen saturation, arteriovenous oxygen difference (Sa-v
o
2
), or pulmonary-to-systemic flow ratio (Qp/Qs). We also examined the oxygen excess factor, Sa
o
2
/Sa-v
o
2
(Ω). We found that (1) slight increases in Sa
o
2
may be associated with large decreases in D
o
2
. (2) Low values for Sv
o
2
indicate low values for D
o
2
. (3) Curves for Sa-v
o
2
and Qp/Qs are redundant in the data provided. (Qp/Qs, however, provides these data in more physiologically relevant terms.) (4) High values for Qp/Qs (>4) are associated with low D
o
2
. (5) Estimating Qp/Qs from oxygen saturation measurements may result in errors when pulmonary venous oxygen saturation is not available. (6) Maximizing D
o
2
is extremely difficult using Sa
o
2
, Sv
o
2
, and Qp/Qs. (7) A linear relationship exists between Ω and D
o
2
, and this linear relationship is not altered by changes in cardiac output.

Conclusions
—Patients with low Sv
o
2
values require attention. Ideally, after reducing Qp/Qs to <1.5, Ω might be a better index to guide further therapy and maximize D
o
2
. Interventions that increased Ω would be considered beneficial, whereas interventions that decreased Ω would be considered detrimental.
Oxidized LDL and Malondialdehyde-Modified LDL in Patients With Acute Coronary Syndromes and Stable Coronary Artery Disease
Authors: Holvoet Paul , Vanhaecke Johan , Janssens Stefaan , Van de Werf Frans , Collen Désiré
Published: June 2012

Background
—The association between oxidative modifications of LDL and coronary artery disease (CAD) is suspected but not established. Therefore, the association between plasma levels of oxidized LDL and malondialdehyde (MDA)-modified LDL and acute coronary syndromes and stable CAD was investigated.

Methods and Results
—The study population contained 63 patients with acute coronary syndromes (45 with acute myocardial infarction and 18 with unstable angina pectoris), 35 nontransplanted patients with angiographically confirmed stable angina, 28 heart transplant patients with posttransplant CAD, 79 heart transplant patients without CAD, and 65 control subjects. After correction for age, sex, and LDL and HDL cholesterol, plasma levels of oxidized LDL and MDA-modified LDL were significantly higher in patients with CAD than in individuals without CAD (
r
2
=0.57 and
r
2
=0.26, respectively; both
P
=0.0001). Plasma levels of MDA-modified LDL were significantly higher in patients with acute coronary syndromes than in individuals with stable CAD (
r
2
=0.65;
P
=0.0001) and were associated with increased levels of troponin I and C-reactive protein (
r
2
=0.39 and
r
2
=0.34, respectively; both
P
=0.0001). Plasma levels of oxidized LDL were not associated with increased levels of troponin I and C-reactive protein (
r
2
=0.089 and
r
2
=0.063, respectively).

Conclusions
—Elevated plasma levels of oxidized LDL are associated with CAD. Elevated plasma levels of MDA-modified LDL suggest plaque instability and may be useful for the identification of patients with acute coronary syndromes.
Coronary Stents
Authors: Pomerantsev Eugene V. , Kobayashi Yoshiki , Fitzgerald Peter J. , Grube Eberhard , Sanders William J. , Alderman Edwin L. , Oesterle Stephen N. , Yock Paul G. , Stertzer Simon H.
Published: June 2012

Background
—The validity of quantitative coronary angiography (QCA) after stent placement has been questioned because the optical density of a metallic stent, added to the density of a contrast-filled lumen, could affect border definition.

Methods and Results
—We deployed 3.0- and 4.0-mm Palmaz-Schatz, Wiktor, Multilink, NIR, and InStent stents in precision-cast phantoms. Central lumens of 2.0 mm were created. There was no difference between the “true” diameters of any stented lumen by both QCA and quantitative ultrasonic (QCU) measurement poststenting. QCA systematic error (SE) varied from 0.01 for the Wiktor stents to 0.14 mm for the Palmaz-Schatz stents; the random error (RE) was 0.03 to 0.14 mm. QCU SE varied from 0.05 to 0.11 mm, and RE ranged from 0.01 to 0.07 mm. At the next stage, 4.0-mm Wiktor and Palmaz-Schatz stents were deployed into the phantom lumens; 1.5-, 2.0-, 2.5- and 3.0-mm lumens were created inside the stents. QCA and QCU measurements of 1.5- to 2.5-mm residual lumens were overestimated by 0.1 to 0.3 mm. In the 3.0-mm residual lumen within the Wiktor stent, QCA underestimated the luminal size by −0.1 mm. There was no QCA inaccuracy for a 3.0-mm lumen within the Palmaz-Schatz stent. In patients, in 25 stented segments in both the Palmaz-Schatz and Wiktor groups, there was no difference between QCA and QCU diameters.

Conclusions
—QCU is sufficiently precise for the assessment of the coronary lumen after stenting. QCA can be used as an accurate method of poststent assessment, except when a very mild recurrence within a highly opaque stent is measured. In that instance, QCA may underestimate the luminal diameter.
Jarvik 2000 Heart
Authors: Westaby Stephen , Katsumata Takahiro , Houel Remi , Evans Rhys , Pigott David , Frazier O. H. , Jarvik Robert
Published: June 2012

Background
—Mechanical bridge to left ventricular recovery is an emerging strategy for the treatment of heart failure. We sought to validate the use of a new intracardiac axial flow impeller pump for this purpose.

Methods and Results
—The Jarvik 2000 Heart was implanted into 30 sheep to ascertain mechanical reliability, biocompatibility, and hemodynamic function. We attempted but failed to anticoagulate with warfarin. Elective explants with survival were performed in 3 animals to simulate bridge to recovery. Extensive autopsy studies were performed in all other animals. At speeds between 8000 and 12 000 rpm the device pumped up to 8 L/min, captured all mitral flow, and augmented cardiac output with elevation of mean arterial pressure. The pump was silent and hemolysis negligible. Nonpulsatile flow did not adversely affect neurological or renal function. Device removal proved straightforward and safe. A fractured inflow bearing occurred in 1 early model. There were no other pump failures, but power interruption occurred when the sheep chewed the cables or head-butted the percutaneous pedestal. At autopsy, there was no thromboembolism or primary thrombus formation in any device. Pump occlusion occurred in 2 sheep with bacterial endocarditis. One electively explanted pump, previously switched off for 5 months, had no thrombus in the device or vascular graft.

Conclusions
—The Jarvik 2000 Heart is a major advance in blood-pump technology and increases the scope of mechanical circulatory support. Reliability and ease of removal favor its use for bridge to myocyte recovery, as well as for bridge to transplantation or long-term support.
Oral Delivery of Anticoagulant Doses of Heparin
Authors: Baughman Robert A. , Kapoor Shiv C. , Agarwal Rajesh K. , Kisicki James , Catella-Lawson Francesca , FitzGerald Garret A.
Published: June 2012

Background
—Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium
N
-[8(-2-hydroxybenzoyl)amino]caprylate (SNAC), was evaluated with escalating oral heparin doses in a randomized, double-blind, controlled clinical study for safety, tolerability, and effects on indexes of anticoagulation.

Methods and Results
—Increases in activated partial thromboplastin time (aPTT), anti-factors IIa and Xa, and tissue factor pathway inhibitor (TFPI) concentrations were detected when normal volunteers were dosed with 10.5 g SNAC/20 000 IU heparin by gavage in some subjects. For the entire group, 30 000 IU SNAC and heparin elevated TFPI from 74.9±7.6 to 254.2±12.3 mg/mL (
P
<0.001) 1 hour after dosing (
P
<0.001). Similar changes occurred in anti-factor IIa and anti-factor Xa. aPTT rose from 28±0.5 to 42.2±6.3 seconds 2 hours after dosing (
P
<0.01). No significant changes in vital signs, physical examination, ECGs, or clinical laboratory values were observed. Neither 30 000 IU heparin alone nor 10.5 g SNAC alone altered the hemostatic parameters. Emesis was associated with 10.5 g SNAC. A taste-masked preparation of SNAC 2.25 g was administered orally with heparin 30 000 to 150 000 IU. Both aPTT and anti-factor Xa increased with escalating doses of heparin. This preparation was well tolerated.

Conclusions
—Heparin, administered orally in combination with the delivery agent SNAC, produces significant elevations in 4 indexes of anticoagulant effect in healthy human volunteers. These results establish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of macromolecules.
Potential Benefit From Implantable Cardioverter-Defibrillator Therapy in Patients With and Without Heart Failure
Authors: Böcker Dirk , Bänsch Dietmar , Heinecke Achim , Weber Max , Brunn Jürgen , Hammel Dieter , Borggrefe Martin , Breithardt Günter , Block Michael
Published: June 2012

Background
—Whether patients with heart failure derive a benefit from therapy with implantable cardioverter-defibrillators (ICDs) has been questioned. The purpose of this study was to investigate whether New York Heart Association (NYHA) functional class had an impact on the potential benefit from ICD therapy as assessed from data stored in the memory of ICDs.

Methods and Results
—Between 1989 and 1996, 603 patients (77% men; 59% with coronary artery disease and 16% with dilated cardiomyopathy; age, 57±13 years; ejection fraction, 44±18%) were treated with an ICD with extended memory function (storage of electrograms and/or RR intervals from treated episodes) in combination with endocardial lead systems. The stages of heart failure (NYHA functional class I through III) at implantation were correlated with overall mortality and the recurrence of fast ventricular tachyarrhythmias (>240 bpm) during follow-up. The potential benefit of the device was estimated as the difference between overall mortality and the hypothetical death rate had the device not been implanted. The latter was based on the recurrence of fast and, without termination by the devices, presumably fatal ventricular tachyarrhythmias. In the overall group, a significant difference between hypothetical death rate and overall mortality was observed (13.9%, 23.5%, and 26.6% at 1, 3, and 5 years, respectively) that suggested a benefit from ICD implantation. In patients in NYHA class I, the estimated benefit, which increased over time, was 15.2%, 29.2%, and 35.6% after 1, 3, and 5 years, respectively. In patients in NYHA class II or III, the estimated benefit increased until the third year (21.8% and 21.9%, respectively) and then remained constant until the fifth year (22.9% and 23.8%, respectively). Even those patients in NYHA class III with a history of decompensated heart failure benefited from ICD implantation.

Conclusions
—Analysis of stored ECG data suggests that in patients with a history of ventricular tachycardia or ventricular fibrillation, ICD therapy may lead to a prolongation of life in NYHA classes I through III. The initial benefit is greatest in patients in NYHA class II and class III, but the estimated benefit might persist longest for patients in NYHA class I.
Chronic Amlodipine Treatment During the Development of Heart Failure
Authors: Spinale Francis G. , Mukherjee Rupak , Krombach R. Stephen , Clair Mark J. , Hendrick Jennifer W. , Houck Ward V. , Hebbar Latha , Kribbs Scott B. , Zellner James L. , Dodd Michael G.
Published: June 2012

Background
—This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined.

Methods and Results
—Sixteen pigs were studied under normal control conditions and after the development of chronic pacing–induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg · kg
−1
· d
−1
, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16±2 versus 31±2,
P
<0.05) and increased with concomitant amlodipine treatment (29±2,
P
<0.05). At rest, systemic and pulmonary vascular resistance (dyne · s
−1
· cm
−5
) increased with CHF compared with the normal control state (3102±251 versus 2156±66 and 1066±140 versus 253±24, respectively, both
P
<0.05) and were reduced with amlodipine treatment (2108±199 and 480±74, respectively,
P
<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4±0.9 versus 3.1±0.3,
P
<0.05) and was reduced with amlodipine treatment (6.6±1.1,
P
<0.5). With CHF, LV myocyte velocity of shortening (μm/s) was reduced compared with normal controls (39±1 versus 64±1,
P
<0.05) and was increased with chronic amlodipine treatment (52±1,
P
<0.05).

Conclusions
—Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.
Increased Expression of P-Selectin on Platelets Is a Risk Factor for Silent Cerebral Infarction in Patients With Atrial Fibrillation
Authors: Minamino Tetsuo , Kitakaze Masafumi , Sanada Shoji , Asanuama Hiroshi , Kurotobi Toshiya , Koretsune Yukihiro , Fukunami Masatake , Kuzuya Tsunehiko , Hoki Noritake , Hori Masatsugu
Published: June 2012

Background
—Platelet activation and decreased levels of nitrite and nitrate (NOx), stable end products of nitric oxide (NO), are reported in patients with atrial fibrillation (AF). We examined the time-course changes in plasma NOx levels and the expression of P-selectin on platelets after the onset of AF in a canine model and determined whether these parameters could be risk factors for silent cerebral infarction in patients with AF.

Methods and Results
—AF was induced by rapid atrial pacing in the canine model of AF. Plasma NOx levels were significantly decreased and the levels of P-selectin on platelets and of neutrophil/platelet conjugates were significantly increased after the onset of AF in this model. The in vitro experiments demonstrated that the inhibition of NO synthesis increased the expression of P-selectin on platelets. Plasma NOx levels (19.7±2.4 versus 27.5±2.8 μmol/L) were significantly lower in 25 patients with AF compared with age- (±2 years) and sex-matched control subjects. Conversely, the levels of P-selectin on platelets (7.6±0.8% versus 4.8±0.7%) and of neutrophil/platelet conjugates (14.8±0.9% versus 8.1±0.6%) were significantly higher in patients with AF. Multiple regression analysis revealed that increased P-selectin on platelets and advanced age were associated with the number of foci of silent cerebral infarction.

Conclusions
—An irregular heart rate that is characteristic of AF appeared to blunt NO synthesis. The increased expression of P-selectin on platelets associated with the reduced NO levels was a risk factor for silent cerebral infarction in patients with AF.
Improved Exercise Tolerance After Losartan and Enalapril in Heart Failure
Authors: Vescovo Giorgio , Dalla Libera Luciano , Serafini Francesco , Leprotti Cristiana , Facchin Luigi , Volterrani Maurizio , Ceconi Claudio , Ambrosio Giovanni Battista
Published: June 2012

Background
—In congestive heart failure, fatigue-resistant, oxidative, slow type I fibers are decreased in leg skeletal muscle, contributing to exercise capacity (EC) limitation. The mechanisms by which ACE inhibitors and AII antagonists improve EC is still unclear. We tested the hypothesis that improvement in EC is related to changes in skeletal muscle composition toward type I fibers.

Methods and Results
—Eight patients with congestive heart failure, NYHA classes I through IV, were treated for 6 months with enalapril (E) 20 mg/d, and another 8 with losartan (L) 50 mg/d. EC was assessed with maximal cardiopulmonary exercise testing at baseline and after treatment. Myosin heavy chain (MHC) composition of the gastrocnemius was studied after electrophoretic separation of slow MHC1, fast oxidative MHC2a, and fast glycolytic MHC2b isoforms from needle microbiopsies obtained at baseline and after 6 months. EC improved in both groups. Peak V̇
o
2
increased from 21.0±4.7 to 27.6±4.3 mL · kg
−1
· min
−1
(
P
=0.011) in the L group and from 17.5±5.0 to 25.0±5.5 mL · kg
−1
· min
−1
(
P
=0.014) in the E group. Similarly, ventilatory threshold changed from 15.0±4.0 to 19.9±4.9 mL (
P
=0.049) with L and from 12.0±1.9 to 15.4±3.5 mL (
P
=0.039) with E. MCH1 increased from 61.2±11.2% to 75.4±7.6% with L (
P
=0.012) and from 60.6±13.1% to 80.1±10.9% (
P
=0.006) with E. Similarly, MHC2a decreased from 21.20±9.5% to 12.9±4.4% (
P
=0.05) with L and from 19.9±7.8% to 11.8±7.9% (
P
=0.06) with E. MHC2b changed from 17.5±6.5% to 11.7±5.2% (
P
=0.07) with L and from 19.5±6.4% to 8.1±4.6% (
P
=0.0015) with E. There was a significant correlation between net changes in MHC1 and absolute changes in peak V̇
o
2
(
r
2
=0.29,
P
=0.029) and a trend to significance for MHC2a and 2b.

Conclusions
—Six months’ treatment with L and with E produces an improvement in EC of similar magnitude. These changes are accompanied by a reshift of MHCs of leg skeletal muscle toward the slow, more fatigue-resistant isoforms. Magnitude of MHC1 changes correlates with the net peak V̇
o
2
gain, which suggests that improved EC may be caused by favorable biochemical changes occurring in the skeletal muscle.
Pulmonary Vein Stenosis After Catheter Ablation of Atrial Fibrillation
Authors: Robbins Ivan M. , Colvin Edward V. , Doyle Thomas P. , Kemp W. Evans , Loyd James E. , McMahon William S. , Kay G. Neal
Published: June 2012

Background
—This report describes the complication of pulmonary vein stenosis with resultant severe pulmonary hypertension that developed in 2 patients after successful catheter ablation of chronic atrial fibrillation.

Methods and Results
—Three months after successful catheter ablation of atrial fibrillation, both patients developed progressive dyspnea and pulmonary hypertension. Both were found to have severe stenosis of all 4 pulmonary veins near the junction with the left atrium. Balloon dilation of the stenotic pulmonary veins was performed in these patients, with improvement in dyspnea and pulmonary hypertension.

Conclusions
—The complication of pulmonary vein stenosis is potentially life-threatening, and the application of radiofrequency current within the pulmonary veins with standard catheter technology should be avoided. This complication can be treated with balloon dilation, although the long-term course is unknown.
Enhanced Monocyte Tissue Factor Response After Experimental Balloon Angioplasty in Hypercholesterolemic Rabbit: Inhibition With Dietary
l
-Arginine
Authors: Corseaux Delphine , Le Tourneau Thierry , Six Isabelle , Ezekowitz Michael D. , Mc Fadden Eugene P. , Meurice Thibaud , Asseman Philippe , Bauters Christophe , Jude Brigitte
Published: June 2012

Background
—There is evidence that tissue factor (TF) is a major contributor to the thrombogenicity of a ruptured atherosclerotic plaque. Nitric oxide (NO) has antiatherogenic and antithrombotic properties. We investigated whether
l
-arginine (
l
-arg), the endogenous precursor of NO, might affect the ability of monocytes to produce TF.

Methods and Results
—We studied TF expression in 18 rabbits with atherosclerosis induced by bilateral iliac damage and 10 weeks of a 2% cholesterol diet. Six weeks after the initiation of the diet, an angioplasty was performed. After angioplasty, the surviving rabbits (n=15) were randomized to receive
l
-arg (2.25%) supplementation in drinking water (
l
-arg group, n=8) or no treatment (untreated group, n=7). TF expression was evaluated in mononuclear cells from arterial blood in the presence and absence of endotoxin stimulation. Monocyte TF expression, as assessed with an amidolytic assay, did not differ significantly before or after the induction of atherosclerotic lesions (87±15 versus 70±12 mU of TF/1000 monocytes,
P
=NS). Endotoxin-stimulated TF activity increased significantly 4 weeks after angioplasty (138±22 versus 70±12 mU of TF/1000 monocytes,
P
=0.02). This increase was blunted by
l
-arg (43±16 mU of TF/1000 monocytes,
P
=0.01).

Conclusions
—This study demonstrates that angioplasty-induced plaque rupture is associated with a marked increase in monocyte TF response that is blunted by the oral administration of
l
-arg. This suggests that the documented antithrombotic properties of NO may be related in part to an inhibitory effect on monocyte TF response.
Systemic Hypoxia Elevates Skeletal Muscle Interstitial Adenosine Levels in Humans
Authors: MacLean Dave A. , Sinoway Lawrence I. , Leuenberger Urs
Published: June 2012

Background
—Adenosine is a potent vasodilator that has been shown to increase in cardiac tissue in response to hypoxia. However, peripheral vasodilatation also occurs during hypoxia, and the vasoactive substance(s) responsible for skeletal muscle vasodilation have not yet been completely identified. Therefore, the purpose of this study was to measure and quantify skeletal muscle interstitial adenosine during acute systemic hypoxia.

Methods and Results
—Skeletal muscle interstitial adenosine concentrations were determined by the microdialysis technique, in which 4 semipermeable microdialysis probes were inserted into the vastus lateralis muscle of 6 healthy male subjects and perfused at a rate of 5 μL/min with Ringer’s solution. Sixty minutes after the insertion of the microdialysis probes, systemic hypoxia was induced for 30 minutes by having the subjects breathe a mixture of 10.5% O
2
in N
2
. Arterial oxygen saturation (fingertip oximeter) was lowered (
P
<0.05) from 96±0.7% to 74.9±1.4%, and forearm blood flow was increased 28%. During normoxia, the interstitial adenosine concentration was 0.44±0.08 μmol/L, and it was increased to 1.03±0.15 (
P
<0.05) and 0.85±0.09 (
P
<0.05) after 15 and 30 minutes of hypoxia, respectively.

Conclusions
—These data are consistent with the concept that during acute systemic hypoxia, interstitial adenosine plays a key role in stimulating peripheral vasodilation.
Bundle-Branch Block in a General Male Population
Authors: Eriksson Peter , Hansson Per-Olof , Eriksson Henry , Dellborg Mikael
Published: June 2012

Background
—Interest in bundle-branch block has focused primarily on its role as a predictor of mortality and coexisting cardiovascular diseases. Previous studies of prevalence, correlation to cardiovascular disease, and mortality have produced conflicting results.

Methods and Results
—We studied a random-sampled population of 855 men who were 50 years old in 1963 and followed them up for 30 years with repeated examinations. Men who developed bundle-branch block were studied with regard to cumulative incidence, relationship with cardiovascular disease/risk factors, and survival. The prevalence of bundle-branch block increases from 1% at age 50 years to 17% at age 80 years, resulting in a cumulative incidence of 18%. No significant relationship with ischemic heart disease or mortality was found. Men who would develop bundle-branch block had a bigger heart volume at age 50 years and developed diabetes mellitus and congestive heart disease during follow-up more often than control subjects.

Conclusions
—Bundle-branch block correlates strongly to age and is common in elderly men. Our results support the theory that bundle-branch block is a marker of a slowly progressing degenerative disease that also affects the myocardium.
Cellular Uptake Mechanisms of
99m
TcN-NOET in Cardiomyocytes From Newborn Rats
Authors: Riou Laurent , Ghezzi Catherine , Mouton Olivier , Mathieu Jean-Paul , Pasqualini Roberto , Comet Michel , Fagret Daniel
Published: June 2012

Background
—Bis[
N
-ethoxy,
N
-ethyl(dithiocarbamato)]nitrido Tc (V) (TcN-NOET) is a new technetium complex proposed as a tracer of myocardial perfusion. However, its cellular uptake mechanisms are unknown, although membrane localization on rat heart preparations and preferential binding to polymorphonuclear neutrophils (PMNs) have been reported. Because of the central role of calcium in PMN actions, a relationship was hypothesized between this ion flux and TcN-NOET cellular uptake.

Methods and Results
—The mechanisms of cellular uptake of TcN-NOET were investigated in newborn rat cardiomyocytes by study of the effect of calcium channel modulators on tracer binding. Nifedipine had no effect on tracer uptake at 1 minute. However, verapamil 0.1 μmol/L and diltiazem 0.5 μmol/L induced a 40% decrease in uptake. Conversely, Bay K 8644 0.25 μmol/L increased TcN-NOET uptake by 73%. Alterations in other membrane ion transports failed to modify tracer uptake, indicating the specificity of the relationship between TcN-NOET uptake and calcium channels. Kinetic studies indicated that cellular net accumulation of the tracer was slow (t
1/2
=28.5 minutes) and retention was prolonged (84% of initial activity retained after 120 minutes of washout). The energy dependence of TcN-NOET uptake was investigated after 60 minutes of metabolic inhibition by iodoacetic acid plus rotenone. The ATP decrease was not associated with reduction in tracer uptake at 1 minute (114.9±21.9% of control,
P
=NS).

Conclusions
—The decrease in uptake observed with verapamil and diltiazem, the increase with Bay K 8644, and the lack of effect with nifedipine suggest that TcN-NOET binds to L-type calcium channels in the open configuration, without entering cardiomyocytes. The kinetics of TcN-NOET accumulation and retention are slow, and the mechanism for cellular uptake is not energy-dependent. From a clinical point of view, the effect of concurrent treatment by calcium inhibitors on myocardial binding of TcN-NOET should be taken into account.
Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα
Authors: Mamontova Anna , Séguret-Macé Sandrine , Esposito Bruno , Chaniale Colette , Bouly Muriel , Delhaye-Bouchaud Nicole , Luc Gérald , Staels Bart , Duverger Nicolas , Mariani Jean , Tedgui Alain
Published: June 2012

Background
—Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown.

Methods and Results
—We show that the homozygous staggerer (
sg
/
sg
) mutant mouse, which carries a deletion within the nuclear receptor RORα gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition,
sg
/
sg
mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in
sg
/
sg
mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected.

Conclusions
—These results suggest that the RORα gene contributes to the plasma HDL level and susceptibility to atherosclerosis.
Extracellular K
+
Dependence of Inward Rectification Kinetics in Human Left Ventricular Cardiomyocytes
Authors: Bailly Patrick , Mouchonière Maud , Bénitah Jean-Pierre , Camilleri Lionel , Vassort Guy , Lorente Paco
Published: June 2012

Background
—In human ventricular cells, the inwardly rectifying K
+
current (
I
K1
) is very similar to that of other mammalian species, but detailed knowledge about the K
+
-dependent distribution of open and blocked states during rectification and about the K
+
-dependent modulation of inactivation on hyperpolarization is currently lacking.

Methods and Results
—We used the whole-cell patch-clamp technique to record
I
K1
in myocytes isolated from subendocardial layers of left ventricular septum from patients with nonfailing hearts with aortic stenosis and cardiac hypertrophy who were undergoing open-heart surgery. Outward currents were very small at voltages positive to the reversal potential but increased at high external [K
+
]. Chord conductance measurements and kinetic analyses allowed us to estimate the proportion of channels in the open state and of those showing either slow unblock or instantaneous unblock (the so-called slow or instantaneous “activation”) on hyperpolarization: the distribution in the individual states was dependent on external [K
+
]. The proportion of channels unblocking slowly was greater than that of channels unblocking instantaneously on hyperpolarization from the plateau voltage range. Hence, because of the previously reported link between the presence of highly protonated blocking molecules and slow unblock kinetics, it is suggested that high cellular concentrations of spermine may account for the low outward current density recorded in these cells. The current decrease observed on extended hyperpolarization was significantly relieved by an increase in external [K
+
].

Conclusions
—The pattern of
I
K1
current alterations observed in the present model of human ventricular hypertrophy might favor enhanced excitability and underlie ventricular arrhythmias, possibly via increased intracellular polyamine levels.
Offspring of Normal and Diabetic Rats Fed Saturated Fat in Pregnancy Demonstrate Vascular Dysfunction
Authors: Koukkou E. , Ghosh P. , Lowy C. , Poston L.
Published: June 2012

Background
—
Disturbances of the in utero environment may “program” for disease in later life. In this study, we determined whether dietary fat supplementation and/or diabetes in pregnancy can adversely affect vascular function in the offspring.

Methods and Results
—Female Sprague-Dawley rats were fed a breeding diet or a diet high in saturated fat (30% wt/wt) for 10 days before mating, throughout pregnancy, and postpartum. Endothelium-dependent relaxation to acetylcholine was blunted in isolated femoral arteries of 15-day-old weanling pups from dams fed the 30%-fat diet. Endothelial dysfunction and enhanced constrictor responses to norepinephrine were also observed in an additional study of 60-day-old offspring of dams fed 20% saturated fat. Rats with streptozotocin-induced diabetes were also fed saturated fat during pregnancy. Femoral arteries from their 15-day-old offspring showed impairment of endothelium-dependent dilation and enhanced constrictor responses to norepinephrine and the thromboxane mimetic
U46619
compared with young offspring of high-fat-fed normal dams. The 30%-fat diet was also deleterious to vascular function in the maternal diabetic animals when assessed in mesenteric arteries 16 days postpartum.

Conclusions
—A high-fat diet in pregnancy led to vascular dysfunction in rat weanlings and young adult offspring. Vascular function further deteriorated in weanlings if the maternal rat was diabetic.
Early Lumen Loss After Treatment of In-Stent Restenosis
Authors: Shiran Avinoam , Mintz Gary S. , Waksman Ron , Mehran Roxana , Abizaid Andrea , Kent Kenneth M. , Pichard Augusto D. , Satler Lowell F. , Popma Jeffrey J. , Leon Martin B.
Published: June 2012

Background
—Mechanisms of recurrence after treatment of in-stent restenosis are unknown.

Methods and Results
—We prospectively performed quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) in 37 lesions with Palmaz-Schatz stents enrolled in a study of intracoronary radiation for in-stent restenosis. Primary treatment was at the discretion of the operator: PTCA (n=8) or ablation+adjunct PTCA (n=29). Lesions were studied before intervention, immediately after primary intervention, and 42±8 minutes later. QCA measurements included minimal luminal diameter and diameter stenosis. Planar IVUS measurements included arterial, stent, lumen, and in-stent tissue areas. Stent, lumen, and in-stent tissue volumes were calculated by use of Simpson’s rule. Compared with immediately after intervention, the delayed (42±8 minutes) minimal lumen area decreased by 20% (5.8±1.9 to 4.5±1.3 mm
2
,
P
<0.0001) and the lumen volume by 12% (58±41 to 52±37 mm
3
,
P
=0.0001). Ten lesions (27%) had a ≥2.0-mm
2
decrease in minimum lumen area. Lumen loss (1) resulted from increased tissue with the stent, (2) correlated with lesion length and preintervention in-stent tissue, and (3) was not seen angiographically.

Conclusions
—There is significant tissue reintrusion shortly after catheter-based treatment of in-stent restenosis. This was greater in longer lesions and those with a larger in-stent tissue burden, was not reflected in the QCA measurements, and may contribute to recurrence.
Androgen Receptors Mediate Hypertrophy in Cardiac Myocytes
Authors: Marsh James D. , Lehmann Michael H. , Ritchie Rebecca H. , Gwathmey Judith K. , Green Glenn E. , Schiebinger Rick J.
Published: June 2012

Background
—The role of androgens in producing cardiac hypertrophy by direct action on cardiac myocytes is uncertain. Accordingly, we tested the hypothesis that cardiac myocytes in adult men and women express an androgen receptor gene and that myocytes respond to androgens by a hypertrophic response.

Methods and Results
—We used reverse transcription–polymerase chain reaction methods to demonstrate androgen receptor transcripts in multiple tissues and [
3
H]phenylalanine incorporation and atrial natriuretic peptide secretion as markers of hypertrophy in cultured rat myocytes. Messenger RNA encoding androgen receptors was detected in myocytes of male and female adult rats, neonatal rat myocytes, rat heart, dog heart, and infant and adult human heart. Both testosterone and dihydrotestosterone produced a robust receptor-specific hypertrophic response in myocytes, determined by indices of protein synthesis and atrial natriuretic peptide secretion.

Conclusions
—Androgen receptors are present in cardiac myocytes from multiple species, including normal men and women, in a context that permits androgens to modulate the cardiac phenotype and produce hypertrophy by direct, receptor-specific mechanisms. There are clinical implications for therapeutic or illicit use of androgens in humans.