bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Myocardial Electrical Impedance Induced by Coronary Artery Occlusion in Pigs With and Without Preconditioning
Authors: Cinca Juan , Warren Mark , Carreño Ana , Tresànchez Màrius , Armadans Lluís , Gómez Pilar , Soler-Soler J.
Published: June 2012

Background
Myocardial ischemia increases tissue electrical resistivity leading to cell-to-cell uncoupling, and this effect is delayed by ischemic preconditioning in isolated myocardium. Alterations in myocardial resistivity elicited by ischemia in vivo may influence arrhythmogenesis and local ST-segment changes, but this is not well known.

Methods and Results
Myocardial impedance (resistivity [Ω · cm] and phase angle [°]), epicardial ST segment, and ventricular arrhythmias were analyzed during 4 hours of coronary artery occlusion in 11 anesthetized open-chest pigs; these were compared with 13 other pigs submitted to a similar coronary occlusion preceded by ischemic preconditioning. Myocardial resistivity rose slowly during the first 34±7 minutes of occlusion (237±41 to 359±59 Ω · cm), increased rapidly to 488±100 Ω · cm at 60 minutes, and reached a plateau value (718±266 Ω · cm, ANOVA;
P
<.01) at 150±69 minutes. By contrast, phase-angle changes began after 17 minutes of ischemia (−3.0±1.6° to −4.2±1.2° at 29±8 minutes) and evolved faster thereafter (−12.5±5.3° at 144±56 minutes). Marked changes in myocardial impedance were observed during the reversion of ST-segment elevation that occurred 1 to 4 hours after occlusion, but impedance changes were less apparent during the early ST-segment recovery seen at 15 to 35 minutes of ischemia. The second arrhythmia peak (30±5 minutes) coincided with the fast change in tissue impedance, and both were delayed (
P
<.05) by ischemic preconditioning.

Conclusions
A rapid impairment of myocardial impedance occurs after 30 minutes of coronary occlusion, and its onset is better defined by shift in phase angle than by rise in tissue resistivity. Phase 1b arrhythmias are associated with marked impedance changes, and both are delayed by preconditioning. Reversion of ST-segment elevation is partially associated with impairment of myocardial impedance, but other factors play a role as well.
Anatomy of the Normal Left Atrial Appendage
Authors: Veinot John P. , Harrity Phillip J. , Gentile Federico , Khandheria Bijoy K. , Bailey Kent R. , Eickholt Jeffrey T. , Seward James B. , Tajik A. Jamil , Edwards William D.
Published: June 2012

Background
Transesophageal echocardiography (TEE) is the diagnostic modality of choice for visualizing the left atrial appendage (LAA). This study defined the morphology of the LAA in normal autopsy specimen hearts and considered the implications of these findings for TEE studies.

Methods and Results
Five hundred normal autopsy hearts were reviewed (25 male and 25 female subjects from each decade for 10 decades). LAA length, width, orifice size, and number of lobes were recorded. Number of lobes was compared between sexes with the rank sum test and regressed against age. Mean length, width, and orifice size increased with age, up to age 20 years, in both sexes. Rates were significantly different between sexes for LAA size (
P
=.011) and width (
P
=.006). After age 20, statistically significant but clinically insignificant age-related changes were observed. Fifty-four percent of LAAs had two lobes (range, 1 to 4), with no age or sex differences. Lobes exist in different planes of the heart. Most pectinate muscles were ≥1 mm in width. Pectinate muscles <1 mm (2.6% of cases) were seen in only the first and last decades.

Conclusions
Age- and sex-related differences in LAA dimensions exist. These differences and the existence of multilobed appendages are important in the accurate TEE evaluation of LAA. Because lobes exist in different planes, imaging must be done in multiple planes to visualize the entire LAA.
Mitral Subvalvular Apparatus
Authors: Obadia Jean F. , Casali Cendrine , Chassignolle Jean F. , Janier Marc
Published: June 2012

Background
The aim of this study was to compare the function of the primary chordae attached to the free edge with that of the secondary chordae attached to the ventricular surface of the anterior mitral leaflet.

Methods and Results
An isolated working pig heart model was used. Three groups of 7 hearts were compared: Group A was the control group with intact leaflets. In group B, the primary chordae of the anterior leaflet were sectioned and the secondary chordae were left intact before assembly of the working heart model. In group C, the secondary chordae were sectioned and the primary chordae left intact. In group B, atrial and ventricular pressure evidenced dramatic mitral regurgitation. Video monitoring showed significant prolapse of the free edge of the anterior leaflet. Acute mitral regurgitation accounted for the decrease in aortic flow rate to 30 mL/min, significantly lower than in the control group (
P
=.006). In group C, sectioning of the secondary chordae left a competent mitral valve together with good coaptation of the anterior and posterior leaflets shown by video monitoring. However, aortic flow was lower than in the control group (
P
=.007), and ultrasonomicrometry evidenced impaired function (
P
=.009).

Conclusions
This study suggests that the primary and secondary chordae of the mitral subvalvular apparatus have different functions. The primary chordae of the anterior leaflet appeared to be more involved in mitral valve competence, whereas the secondary chordae appeared to be more involved in left ventricular geometry and function.
Functional Compartmentalization of ATP Is Involved in Angiotensin II–Mediated Closure of Cardiac ATP-Sensitive K
+
Channels
Authors: Tsuchiya Kunihiko , Horie Minoru , Watanuki Masato , Albrecht Carlos A. , Obayashi Kazuhiko , Fujiwara Hisayoshi , Sasayama Shigetake
Published: June 2012

Background
The effects of angiotensin II (Ang II) on ATP-sensitive K
+
channels (K
ATP
) were investigated in ventricular myocytes enzymatically isolated from adult guinea pig heart.

Methods and Results
In the whole-cell and cell-attached configurations (including open-cell-attached mode) of the patch-clamp technique, K
ATP
currents (
I
KATP
) were activated through metabolic poisoning by the use of inhibitors of both glycolytic and oxidative ATP productions at 37°C. In the whole-cell mode,
I
KATP
were reversibly suppressed by increasing extracellular glucose and Ang II (1 nmol/L). In the cell-attached mode, Ang II concentration-dependently inhibited single K
ATP
activities with an IC
50
value of 3.2±0.5 pmol/L (Hill coefficient=1.3±0.3). CV11974 (100 nmol/L), an angiotensin 1 (AT
1
) receptor-selective antagonist, blocked the inhibitory action of Ang II. Preincubation of myocytes with pertussis toxin (5 μg/mL for >120 min at 37°C) virtually prevented subsequent Ang II action. The inhibitory effect of Ang II was also abolished in the open-cell–attached mode (achieved by a prior perfusion of streptolysin-
O
, 0.08 U/mL). In this mode, through tiny membrane holes, the intracellular ATP concentration can be controlled by bathing extracellular solutions containing a known ATP concentration.

Conclusions
The inhibitory actions of Ang II on K
ATP
appear to be mediated by an increase in the subsarcolemmal ATP concentration that results from the inhibition of adenylate cyclase activities via AT
1
receptors/PTX-sensitive G proteins.
Predictive Power of the Relative Lymphocyte Concentration in Patients With Advanced Heart Failure
Authors: Ommen Steve R. , Hodge David O. , Rodeheffer Richard J. , McGregor Christopher G. A. , Thomson Stephen P. , Gibbons Raymond J.
Published: June 2012

Background
—The physiological stress suffered by patients with heart failure results in an increased production of cortisol and a shift in the leukocyte differential toward a decreased percentage of lymphocytes (%L). The purpose of this study was to determine the prognostic significance of a low %L in advanced heart failure.

Methods and Results
—Patients evaluated in our cardiac transplantation clinic between April 1988 and July 1995 were retrospectively reviewed (n=263). Fifty-two patients were excluded because they had recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. In the remaining 211 patients, we used Cox proportional hazards analysis to examine the association between survival and transplant-free survival with baseline variables. Univariate analysis showed a significant association between time to death and %L (
P
=.004), New York Heart Association (NYHA) class (
P
=.002), and maximal oxygen uptake (
P
=.05). Univariate analysis of the end point of survival free from transplantation yielded similar results. One- and 4-year survival rates for patients with a low %L (<20.3%) were 78% and 34% compared with 90% and 73% for those with a normal %L. Multivariate analysis showed NYHA class (
P
<.008) and %L (
P
<.01) were independent predictors of survival and survival free from cardiac transplantation.

Conclusions
The relative lymphocyte concentration is an inexpensive, readily available, simple prognostic marker in patients with symptomatic heart failure who do not have recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. It could be incorporated into clinical models to predict patient outcome and to aid in the selection of patients for cardiac transplantation.
Heart Failure and Echocardiographic Changes During Long-term Follow-up of Patients With Sick Sinus Syndrome Randomized to Single-Chamber Atrial or Ventricular Pacing
Authors: Nielsen Jens Cosedis , Andersen Henning Rud , Thomsen Poul Erik Bloch , Thuesen Leif , Mortensen Peter Thomas , Vesterlund Thomas , Pedersen Anders Kirstein
Published: June 2012

Background
—In patients with sick sinus syndrome, choice of pacing mode has been implicated in the development of congestive heart failure.

Methods and Results
—A total of 225 consecutive patients with sick sinus syndrome and intact atrioventricular conduction were randomized to either single-chamber atrial pacing (n=110) or single-chamber ventricular pacing (n=115). Clinical assessment included New York Heart Association classification, medication, and M-mode echocardiography before pacemaker implantation, after 3 months, and subsequently once every year. At long-term follow-up (mean, 5.5±2.4 years), NYHA class was higher in the ventricular group than in the atrial group (NYHA class I/II/III/IV: 65/44/4/0 versus 84/22/2/1 patients,
P
=.010). Increase in NYHA class during follow-up was observed in 35 of 113 patients in the ventricular group versus 10 of 109 in the atrial group (
P
<.0005). Increase in dose of diuretics from randomization to last follow-up was significantly higher in the ventricular group than in the atrial group (21±49 versus 8±42 mg furosemide/d,
P
=.033). The left ventricular fractional shortening decreased significantly in the ventricular group (from 0.36±0.12 to 0.31±0.08,
P
<.0005) but not in the atrial group (from 0.35±0.13 to 0.33±0.09,
P
=.087). The left atrial diameter increased significantly in both treatment groups (ventricular group: from 34±7 to 41±7 mm,
P
<.0005; atrial group: from 34±6 to 37±7 mm,
P
=.002), but the increase was significantly higher in the ventricular group than in the atrial group (
P
<.0005).

Conclusions
—During long-term follow-up, ventricular pacing is associated with a higher incidence of congestive heart failure and consumption of diuretics than atrial pacing. This is accompanied by a decrease in left ventricular fractional shortening and an increased dilatation of the left atrium in the ventricular paced patients.
Interaction of Coagulation Defects and Cardiovascular Risk Factors
Authors: Doggen Carine J. M. , Cats Volkert Manger , Bertina Rogier M. , Rosendaal Frits R.
Published: June 2012

Background
—A genetic variation located in the 3′-untranslated region of the prothrombin gene (prothrombin 20210 G→A) was recently described as a risk factor for venous thrombosis. We examined how the presence of this mutation affected the risk of myocardial infarction in a population-based case-control study. Furthermore, we studied the risk of myocardial infarction associated with the simultaneous presence of a coagulation defect (ie, the 20210 AG genotype of prothrombin or the factor V Leiden mutation) and major cardiovascular risk factors.

Methods and Results
—Among 560 men with a first myocardial infarction before the age of 70 years, 1.8% were heterozygous carriers of the 20210 variant of the prothrombin gene. The control group consisted of 646 men who were frequency matched by age. In the latter group, the frequency of the 20210 AG genotype was 1.2%. The risk of myocardial infarction in the presence of the
AG
genotype was increased by 50% (odds ratio, 1.5; 95% confidence interval [95% CI], 0.6 to 3.8). The risk of myocardial infarction for carriership of factor V Leiden mutation was increased by 40% (odds ratio, 1.4; 95% CI, 0.8 to 2.2). When a coagulation defect was present (ie, the 20210 AG prothrombin genotype or the factor V Leiden mutation), the risk of myocardial infarction for carriers versus noncarriers was 1.4 (95% CI, 0.9 to 2.2). This risk was substantially increased when one of the major cardiovascular risk factors of smoking, hypertension, diabetes mellitus, or obesity also was present, with odds ratios varying between 3 and 6. These risks exceeded those of the single effects of the cardiovascular risk factors (ie, in the absence of the coagulation defect).

Conclusions
—We conclude that in men the 20210 G→A variant of prothrombin is associated with an increased risk of myocardial infarction. The combined presence of major cardiovascular risk factors and carriership of a coagulation defect increases the risk considerably.
Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation
Authors: Rupprecht Hans J. , Darius Harald , Borkowski Ulrike , Voigtländer Thomas , Nowak Bernd , Genth Sabine , Meyer Jürgen
Published: June 2012

Background
—This study was performed to analyze the influence of either aspirin, ticlopidine, or their combination on platelet activation and aggregation parameters after stent implantation.

Methods and Results
—Sixty-one patients with successful implantation of a single Palmaz-Schatz stent in a native coronary artery were randomly assigned to either group A (aspirin 300 mg/d+ticlopidine 2×250 mg/d), group B (ticlopidine 2×250 mg/d), or group C (aspirin 300 mg/d). Platelet activation was evaluated on days 1, 7, and 14 by flow cytometry measurement of expression of CD62p (p-selectin) and the binding of fibrinogen to the platelet surface glycoprotein IIb/IIIa receptor. Platelet aggregation was induced by addition of ADP or collagen. Differences between treatment groups were compared by ANOVA. Between days 1 and 14, we observed a significant decrease in collagen-induced platelet aggregation in group A (62.2±2.5% versus 36.9±3.1%), whereas an increase was seen in group B (58.3±2.5% versus 67.7±3.2%) and no change was seen in group C (
P
<.0001). The ADP-induced aggregation declined significantly in group A (74.7±1.4% versus 55.3±2.6%), whereas a delayed reduction was seen in group B (72.0±3.0% versus 52.6±4.2%) and no change was seen in group C (
P
=.0017). The CD62p expression declined significantly in groups A (68.2±2.7% versus 41.3±2.7%) and B (64.8±2.9% versus 39.3±3.5%) but not in group C (
P
<.0001). Moreover, the fibrinogen binding decreased significantly in group A (61.0±4.3% versus 36.3±4.2%) and with delay in group B (58.3±2.2% versus 39.4±3.0%), whereas no alterations were seen in group C (
P
=.012).

Conclusions
—Our results demonstrate synergistic and accelerated platelet inhibitory effects of ticlopidine plus aspirin in patients after stent implantation compared with a monotherapy with either ticlopidine or aspirin alone.
Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide
Authors: Szokodi István , Kinnunen Pietari , Tavi Pasi , Weckström Matti , Tóth Miklós , Ruskoaho Heikki
Published: June 2012

Background
—Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro.

Methods and Results
—In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene–related peptide (CGRP) receptor antagonist, CGRP
8–37
, or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca
2+
release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic reticulum Ca
2+
ATPase and depletes intracellular Ca
2+
stores, attenuated the early increase in developed tension produced by ADM. In addition, inhibition of protein kinase C by staurosporine (10 nmol/L) and blockade of L-type Ca
2+
channels by diltiazem (1 μmol/L) significantly decreased the sustained phase of ADM-induced increase in developed tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and −50 mV transmembrane voltage, consistent with an increase in L-type Ca
2+
channel current during the plateau.

Conclusions
—Our results show that ADM enhances cardiac contractility via cAMP-independent mechanisms including Ca
2+
release from intracellular ryanodine- and thapsigargin-sensitive Ca
2+
stores, activation of protein kinase C, and Ca
2+
influx through L-type Ca
2+
channels.
Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors
Authors: Laufs Ulrich , La Fata Vito , Plutzky Jorge , Liao James K.
Published: June 2012

Background
—Oxidized low-density lipoprotein (ox-LDL) causes endothelial dysfunction in part by decreasing the availability of endothelial nitric oxide (NO). Although HMG CoA reductase inhibitors restore endothelial function by reducing serum cholesterol levels, it is not known whether they can also directly upregulate endothelial NO synthase (ecNOS) activity.

Methods and Results
—Human saphenous vein endothelial cells were treated with ox-LDL (50 μg/mL thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the presence of HMG CoA reductase inhibitors simvastatin and lovastatin. In a time-dependent manner, ox-LDL decreased ecNOS mRNA and protein levels (91±4% and 67±8% reduction after 72 hours, respectively). Both simvastatin (1 μmol/L) and lovastatin (10 μmol/L) upregulated ecNOS expression by 3.8-fold and 3.6-fold, respectively, and completely prevented its downregulation by ox-LDL. These effects of simvastatin on ecNOS expression correlated with changes in ecNOS activity. Although
l
-mevalonate alone did not affect ecNOS expression, cotreatment with
l
-mevalonate completely reversed ecNOS upregulation by simvastatin. Actinomycin D studies revealed that simvastatin stabilized ecNOS mRNA (τ
1/2
, 43 versus 35 hours). Nuclear run-on assays and transient transfection studies with a −1.6 kb ecNOS promoter construct showed that simvastatin did not affect ecNOS gene transcription.

Conclusions
—Inhibition of endothelial HMG CoA reductase upregulates ecNOS expression predominantly by posttranscriptional mechanisms. These findings suggest that HMG CoA reductase inhibitors may have beneficial effects in atherosclerosis beyond that attributed to the lowering of serum cholesterol by increasing ecNOS activity.
Reversal of Reflex-Induced Myocardial Ischemia by Median Nerve Stimulation
Authors: Li Peng , Pitsillides Koullis F. , Rendig Stephen V. , Pan Hui-Lin , Longhurst John C.
Published: June 2012

Background
—Acupuncture is reported to reduce myocardial ischemia, arrhythmias, and hypertension. To investigate the physiological mechanisms underlying these observations, a model of reflex-induced, reversible myocardial ischemia was developed to test the effects of median nerve stimulation as a surrogate for electroacupuncture.

Methods and Results
—Chloralose-anesthetized cats were instrumented to measure arterial blood pressure, left ventricular pressure, left ventricular dP/dt, heart rate, left anterior descending (LAD) coronary blood velocity, and regional wall motion. The LAD artery either was partially occluded or a small diagonal branch was ligated. Subsequently, transient reflex activation of the cardiovascular system was evoked by application of bradykinin (typically 1 μg/mL) to the gallbladder, which significantly increased myocardial oxygen demand (double product), left ventricular dP/dt, and coronary blood velocity and caused ischemia-induced regional dysfunction, evidenced by significant (
P
<.05) reduction in normalized wall thickening (10.7±4.2% versus −23.6±2.9%; control versus ischemia; n=7). However, when median nerves were stimulated with low frequency (5 Hz) to mimic electroacupuncture, bradykinin-induced change in normalized wall thickening was significantly improved (−23.6±2.9% versus 9.8±4.9%; ischemia versus median nerve stimulation,
P
<.05) and remained augmented ≥1 hour. Results were similar in partial and complete occlusion groups. Significant improvement in wall thickening was associated with unchanged increment of coronary blood velocity and significantly diminished increments of double product and diastolic blood pressure.

Conclusions
—These results suggest that stimulation of the median nerve to mimic electroacupuncture diminishes regional myocardial ischemia triggered by a sympathetically mediated increase in cardiac oxygen demand. The mechanism of this effect is related to reduction in cardiac oxygen demand, secondary to a diminished pressor response. These data provide the first documentation of the physiological mechanisms underlying the possible beneficial effect of electroacupuncture in the context of restricted coronary blood flow and augmented myocardial oxygen demand.
Predictors of Stroke Complicating Carotid Artery Stenting
Authors: Mathur Atul , Roubin Gary S. , Iyer Sriram S. , Piamsonboon Chumpol , Liu Ming W. , Gomez Camilo R. , Yadav Jay S. , Chastain Hollace D. , Fox Liesl M. , Dean Larry S. , Vitek Jiri J.
Published: June 2012

Background
—The evolving technique of carotid stenting is being evaluated as an alternative to endarterectomy. Identification of the factors that predispose a patient to neurological complications would facilitate further refinement of the technique and optimize patient selection.

Methods and Results
—We analyzed the impact of various clinical, morphological, and procedural determinants on the development of procedural strokes in 231 patients who underwent elective (primary) stenting of 271 extracranial carotid arteries. The mean age of the patients was 68.7±10 years, 165 (71%) were males, and 139 (60%) had symptoms attributed to the lesion treated. This series represented a high-risk subset with 164 patients (71%) having significant coronary artery disease, 91 (39%) having bilateral disease, and 28 (12%) having contralateral carotid occlusion. Of the treated vessels, 59 (22%) had prior carotid endarterectomy, 66 (24%) had ulcerated plaques, and 87 (32%) had calcified lesions. Only 37 treated vessels (14%) would have been eligible for inclusion in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). There were 17 (6.2%) minor and 2 (0.7%) major strokes during and within 30 days of the procedure. NASCET-eligible patients had a low (2.7%) risk of procedural strokes after carotid stenting. The results of multivariate analysis revealed advanced age (
P
=.006) and presence of long or multiple stenoses (
P
=.006) as independent predictors of procedural strokes.

Conclusions
—During this procedural developmental phase of carotid stenting, neurological complications were highly dependent on patient selection. Advanced age and long or multiple stenoses were independent predictors of procedural stroke.
Comparison Between Noninvasive Indices of Baroreceptor Sensitivity and the Phenylephrine Method in Post–Myocardial Infarction Patients
Authors: Pitzalis Maria Vittoria , Mastropasqua Filippo , Passantino Andrea , Massari Francesco , Ligurgo Luana , Forleo Cinzia , Balducci Cataldo , Lombardi Federico , Rizzon Paolo
Published: June 2012

Background
—Depressed baroreflex sensitivity obtained by means of a phenylephrine test plays a prognostic role in patients with a previous myocardial infarction. Our purpose was to evaluate the correlation and agreement between the baroreflex sensitivity obtained with phenylephrine and that obtained by two noninvasive methods: the α-index and sequence analysis.

Methods and Results
—The α-index was measured by means of the spectral analysis of RR and systolic blood pressure variabilities in both the high- and low-frequency bands; sequences were identified from simultaneously recorded time series in which the RR and systolic blood pressure concurrently increased or decreased. Noninvasive baroreflex sensitivity tests were performed during both spontaneous and controlled respiration. Fifty-two consecutive patients with recent myocardial infarction underwent the analyses. Although the correlations between phenylephrine and either of the noninvasive methods were always significant, those found during controlled respiration had the highest
r
values (
r
=.70). However, the limits of agreement calculated by means of the Bland and Altman method were wide for both noninvasive methods.

Conclusions
—The results obtained by means of noninvasive baroreflex sensitivity assessments should not be used in clinical practice as an alternative to those obtained by the phenylephrine method.
Influence of Type of Surgery on the Occurrence of Parasympathetic Reinnervation After Cardiac Transplantation
Authors: Bernardi Luciano , Valenti Cinzia , Wdowczyck-Szulc Joanna , Frey Axel W. , Rinaldi Mauro , Spadacini Giammario , Passino Claudio , Martinelli Luigi , Viganò Mario , Finardi Giorgio
Published: June 2012

Background
—Cardiac autonomic reinnervation after human cardiac transplantation has been demonstrated frequently but to date only for sympathetic efferents. Standard surgical techniques leave many parasympathetic branches intact in the original atria and thus with less stimulus to reinnervate the donor atria.

Methods and Results
—We used changes in the RR-interval power spectrum induced by sinusoidal modulation of arterial baroreceptors by neck suction at different frequencies to detect both parasympathetic and sympathetic reinnervation in 79 subjects with “standard” and 10 “bicaval” heart transplants. In 24 subjects (17 standard and 7 bicaval), the protocol was repeated 6 and 11 months after transplantation. Neck suction at 0.20 Hz produced a component at 0.20 Hz in the RR-interval spectrum not due to respiration (fixed at 0.25 Hz), which suggested parasympathetic reinnervation, in 4 of 10 bicaval but in only 2 of 79 standard transplant subjects (whose recipient atria underwent >50% resection to remove scars of previous interventions),
P
<.001. In only 1 (bicaval) transplant subject was parasympathetic reinnervation present 6 months after transplantation (confirmed 3 months later); in 4 subjects, it was absent at 6 months but appeared after 11 months after transplantation. Atropine (0.04 mg/kg IV) abolished the response to fast (0.20 Hz) and reduced that to slow stimulation, confirming the presence of parasympathetic reinnervation (4 subjects).

Conclusions
—Parasympathetic reinnervation depends on the surgical technique: because bicaval surgery cuts all sympathetic and parasympathetic nerves, regeneration might be stimulated similarly in both branches. Standard surgery cuts only ≈50% of sympathetic fibers; most recipient parasympathetic axons remain intact, hence their regeneration might not be stimulated.
Cardiac Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-α
Authors: Bryant Debora , Becker Lisa , Richardson James , Shelton John , Franco Fatima , Peshock Ronald , Thompson Marita , Giroir Brett
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-α secretion is, at least in part, cardiac myocytes.

Methods and Results
—To determine the consequences of TNF-α production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-α coding sequence was driven by the murine α-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis.

Conclusions
—This is the first report detailing the effects of tissue-specific production of TNF-α by cardiac myocytes in vivo. These findings indicate that production of TNF-α by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.
Lipoprotein Changes and Reduction in the Incidence of Major Coronary Heart Disease Events in the Scandinavian Simvastatin Survival Study (4S)
Authors: Pedersen Terje R. , Olsson Anders G. , Færgeman Ole , Kjekshus John , Wedel Hans , Berg Kåre , Wilhelmsen Lars , Haghfelt Torben , Thorgeirsson Gudmundur , Pyörälä Kalevi , Miettinen Tatu , Christophersen Bjørn , Tobert Jonathan A. , Musliner Thomas A. , Cook Thomas J.
Published: June 2012

Background
—The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides ≤2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction,
P
<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed.

Methods and Results
—The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%;
P
<.00001).

Conclusions
—These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.
Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo
Authors: Gries André , Bode Christoph , Peter Karlheinz , Herr Axel , Böhrer Hubert , Motsch Johann , Martin Eike
Published: June 2012

Background
—Recent data suggest that inhaled NO can inhibit platelet aggregation. This study investigates whether inhaled NO affects the expression level and avidity of platelet membrane receptors that mediate platelet adhesion and aggregation.

Methods and Results
—In 30 healthy volunteers, platelet-rich plasma was incubated with an air/5% CO
2
mixture containing 0, 100, 450, and 884 ppm inhaled NO. ADP- and collagen-induced platelet aggregation, the membrane expression of P-selectin, and the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor were determined before (t
0
) and during the 240 minutes of incubation. In addition, eight patients suffering from severe adult respiratory distress syndrome (ARDS) were investigated before and 120 minutes after the beginning of administration of 10 ppm inhaled NO. In vitro, NO led to a dose-dependent inhibition of both ADP-induced (3±3% at 884 ppm versus 70±6% at 0 ppm after 240 minutes;
P
<.001) and collagen-induced (13±5% versus 62±5%;
P
<.01) platelet aggregation. Furthermore, P-selectin expression (36±7% of t
0
value;
P
<.01) and fibrinogen binding (33±11%;
P
<.01) were inhibited. In patients with ARDS, after two who did not respond to NO inhalation with an improvement in oxygenation had been excluded, an increase in plasma cGMP, prolongation of in vitro bleeding time, and inhibition of platelet aggregation and P-selectin expression were observed, and fibrinogen binding was also inhibited (19±7% versus 30±8%;
P
<.05).

Conclusions
—NO-dependent inhibition of platelet aggregation may be caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa receptor.
Noninvasive Assessment of Significant Left Anterior Descending Coronary Artery Stenosis by Coronary Flow Velocity Reserve With Transthoracic Color Doppler Echocardiography
Authors: Hozumi Takeshi , Yoshida Kiyoshi , Ogata Yumiko , Akasaka Takashi , Asami Yoshio , Takagi Tsutomu , Morioka Shigefumi
Published: June 2012

Background
—Coronary flow reserve has been considered an important diagnostic index of the functional significance of coronary artery stenosis. With Doppler technique, it has been assessed as the ratio of hyperemic to basal coronary flow velocity (coronary flow velocity reserve [CFVR]) by invasive or semiinvasive methods with a Doppler catheter, a Doppler guide wire, and a transesophageal Doppler echocardiographic probe. Recent technological advancement in transthoracic Doppler echocardiography (TTDE) provides measurement of coronary flow velocity in the distal portion of the left anterior descending coronary artery (LAD) and may be useful in the noninvasive CFVR measurement. The purpose of this study was to evaluate the value of CFVR determined by TTDE for the assessment of significant LAD stenosis.

Methods and Results
—We studied 36 patients who underwent coronary angiography for the assessment of coronary artery disease. The study population consisted of 12 patients with significant LAD stenosis (group A) and 24 patients without significant LAD stenosis (group B). With TTDE, coronary flow velocities in the distal LAD were recorded at rest and during hyperemia induced by intravenous infusion of adenosine (0.14 mg · kg
−1
· min
−1
) under the guidance of color Doppler flow mapping. Adequate spectral Doppler recordings of coronary flow in the distal LAD for the assessment of CFVR were obtained in 34 of 36 study patients (94%). The peak and mean diastolic coronary flow velocities at baseline did not differ between groups A and B (23.6±10.3 versus 22.9±6.6 cm/s and 16.4±8.6 versus 14.5±4.0 cm/s, respectively). However, the peak and mean coronary flow velocities during hyperemia in group A were significantly smaller than those in group B (35.6±16.3 versus 54.2±16.3 cm/s and 24.7±13.1 versus 37.9±13.0 cm/s, respectively;
P
<.01). There were significant differences in CFVR obtained from peak and mean diastolic velocity between groups A and B (1.5±0.2 versus 2.4±0.4 and 1.5±0.2 versus 2.6±0.4, respectively;
P
<.001). A CFVR from peak diastolic velocity <2.0 had a sensitivity of 92% and a specificity of 82% for the presence of significant LAD stenosis. A CFVR from mean diastolic velocity <2.0 had a sensitivity of 92% and a specificity of 86% for the presence of significant LAD stenosis.

Conclusions
—CFVR determined by TTDE is useful in the noninvasive assessment of significant stenotic lesion in the LAD.
Arrhythmogenic Right Ventricular Cardiomyopathy and Fatty Replacement of the Right Ventricular Myocardium
Authors: Burke Allen P. , Farb Andrew , Tashko Gerti , Virmani Renu
Published: June 2012

Background
—The relationship between arrhythmogenic right ventricular cardiomyopathy (ARVC) and pure fat replacement of the right ventricle is unclear.

Methods and Results
—Myocardial thickness, epicardial fat thickness, percent fibrosis, and intramyocardial fat infiltration were measured in 16 sections each from 25 hearts with typical (fibrofatty) ARVC, 7 hearts with fat replacement of the right ventricle without fibrosis (FaRV), and 18 control hearts from patients who died of noncardiac causes. Patients with fibrofatty ARVC were younger than those with FaRV (31±14 versus 44±13 years,
P
=.02), more likely to have a history of arrhythmias or a family history of premature sudden death (56% versus 0%,
P
=.01), more likely male (80% versus 29%,
P
=.02), and less likely to have coexisting conditions that might have predisposed to sudden death (12% versus 86%,
P
<.001). Fibrofatty ARVC was characterized by right ventricular myocardial thinning, fat infiltration of the anterobasal and posterolateral apical right ventricle, subepicardial left ventricular fibrofatty replacements (64%), myocyte atrophy (96%), and lymphocytic myocarditis (80%). FaRV showed normal or increased myocardial thickness, a diffuse increase in intramyocardial and epicardial fat, little inflammation, and an absence of myocardial atrophy. Intramyocardial fat was frequently seen in normal hearts, especially in the anteroapical region, but was less extensive than in fibrofatty ARVC and FaRV.

Conclusions
—ARVC is a familial arrhythmogenic disease characterized by fibrofatty replacement of myocytes with scattered foci of inflammation. Fat infiltration per se is probably a different process that should not be considered synonymous with ARVC.
Pharmacodynamic Profile of Short-term Abciximab Treatment Demonstrates Prolonged Platelet Inhibition With Gradual Recovery From GP IIb/IIIa Receptor Blockade
Authors: Mascelli Mary A. , Lance Ellen T. , Damaraju Lakshmi , Wagner Carrie L. , Weisman Harlan F. , Jordan Robert E.
Published: June 2012

Background
—The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is approved for use in high-risk percutaneous coronary interventions. The purpose of the present study was to establish the pharmacodynamic profile and platelet-bound life span of abciximab.

Methods and Results
—The pharmacodynamics of abciximab (inhibition of ex vivo platelet aggregation and GP IIb/IIIa receptor blockade) were measured in 41 individuals who were randomized to receive a 0.25-mg/kg bolus and a 12-hour infusion of either 10 μg/min (EPIC regimen) or 0.125 μg · kg
−1
· min
−1
(EPILOG regimen) of the antiplatelet agent. At extended times, the amount and distribution of platelet-bound abciximab were monitored by flow cytometry. The EPIC and EPILOG infusion regimens exhibited equivalent blockade of both GP IIb/IIIa receptors and platelet aggregation throughout the duration of abciximab treatment. Flow cytometry revealed a single, highly fluorescent platelet population during treatment, consistent with complete saturation and homogeneous distribution of abciximab on circulating platelets. For 15 days after treatment, the fluorescence histograms remained unimodal with gradually diminishing fluorescence intensity, indicating decreasing levels of platelet-bound abciximab. At 8 and 15 days, which exceeds the normal circulating life span of platelets, median relative fluorescence intensity corresponded to 29 100 (29% GP IIb/IIIa receptor blockade) and 13 300 (13% GP IIb/IIIa receptor blockade) abciximab molecules bound per platelet, respectively.

Conclusions
—These results are consistent with continuous reequilibration of abciximab among circulating platelets and may explain the gradual recovery of platelet function and long-term prevention of ischemic complications by abciximab after coronary intervention.
Cellular Uncoupling During Ischemia in Hypertrophied and Failing Rabbit Ventricular Myocardium
Authors: Dekker Lukas R. C. , Rademaker Han , Vermeulen Jessica T. , Opthof Tobias , Coronel Ruben , Spaan Jos A. E. , Janse Michiel J.
Published: June 2012

Background
—Patients with heart failure show a very high incidence of arrhythmias and sudden death that is often preceded by ischemia; however, data on electrophysiological changes during ischemia in failing myocardium are sparse. We studied electrical uncoupling during ischemia in normal and failing myocardium.

Methods and Results
—Tissue resistance, intracellular Ca
2+
concentration (Indo-1 fluorescence ratio), and mechanical activity were simultaneously determined in arterially perfused right ventricular papillary muscles from 11 normal and 15 failing rabbits. Heart failure was induced by combined volume and pressure overload. Before sustained ischemia, muscles were subjected to control perfusion (non-PC) or ischemic preconditioning (PC). The onset of uncoupling during ischemia was equal in non-PC normal (13.6±0.9 minutes of ischemia) and non-PC failing hearts (13.3±0.7 minutes of ischemia). PC postponed uncoupling in normal hearts by 10 minutes. In failing hearts, however, PC caused a large variability in the onset of uncoupling during ischemia (mean, 12.2.±2.1; range, 5 to 22 minutes of ischemia). The duration of uncoupling process was prolonged in failing hearts (12.9±0.9 minutes) compared with normal hearts (7.8±0.4 minutes). The degree of heart failure and relative heart weight of the failing hearts significantly correlated with the earlier uncoupling after PC and the duration of uncoupling. In every experiment, the start of Ca
2+
rise and contracture preceded uncoupling during ischemia.

Conclusions
—The duration of the process of ischemia-induced electrical uncoupling in failing hearts is prolonged compared with that in normal hearts. Ischemic PC has detrimental effects in severely failing papillary muscles because it advances the moment of irreversible ischemic damage.
Polymorphism of the NADH/NADPH Oxidase
p22 phox
Gene in Patients With Coronary Artery Disease
Authors: Inoue Nobutaka , Kawashima Seinosuke , Kanazawa Kenji , Yamada Shinichiro , Akita Hozuka , Yokoyama Mitsuhiro
Published: June 2012

Background
—Oxidative stress in the vasculature has been implicated in the pathogenesis of coronary artery disease (CAD). NADH/NADPH oxidase is a key enzyme of superoxide production in the vasculature.
p22 phox
, an essential component of NADH/NADPH oxidase, has four types of polymorphism. The C242T polymorphism changes histidine-72 to tyrosine, located in the potential heme-binding sites, whereas A640G polymorphism is located in the 3′ untranslated region.

Methods and Results
—We investigated whether these polymorphisms were associated with risk of CAD by use of restriction fragment length polymorphism (RFLP). The prevalence of the TC+TT genotype of the C242T polymorphism was significantly more frequent in control subjects (n=201) than in the patients with CAD (n=201). The odds ratio of the TC+TT versus CC genotype of the C242T polymorphism between control subjects and case patients was 0.49 (95% CI, 0.28 to 0.87) (
P
=.015). The prevalence of the genotypes of the A640G polymorphism was not different between groups. The association of C242T polymorphism of the
p22 phox
gene with CAD was statistically significant and independent of other risk factors.

Conclusions
—The mutation of the potential heme-binding site of the
p22 phox
gene may reduce susceptibility to CAD. Our observations suggest that the C242T polymorphism of the
p22 phox
gene is a novel genetic marker that has a protective effect on coronary risk.
Passive Smoking Induces Atherogenic Changes in Low-Density Lipoprotein
Authors: Valkonen Miia , Kuusi Timo
Published: June 2012

Background
—According to the American Heart Association, passive smoking is an important risk factor for coronary heart disease (CHD), but the mechanisms underlying this association are not fully understood. We studied the acute effect of passive smoking on the factors that influence the development of CHD: the antioxidant defense of human serum, the extent of lipid peroxidation, and the accumulation of LDL cholesterol in cultured human macrophages, the precursors of foam cells in atherosclerotic lesions.

Methods and Results
—Blood samples were collected during 2 ordinary working days from healthy, nonsmoking subjects (n=10) before and after (up to 5.5 hours) spending half an hour in a smoke-free area (day 1) or in a room for smokers (day 2). Passive smoking caused an acute decrease (1.5 hours after exposure) in serum ascorbic acid (
P
<.001) and in serum antioxidant defense (
P
<.001), a decreased capacity of LDL to resist oxidation (
P
<.01), and the appearance of increased amounts of lipid peroxidation end products in serum (
P
<.01). Finally, LDL isolated from subjects after passive smoking was taken up by cultured macrophages at an increased rate (
P
<.05).

Conclusions
—Exposure of nonsmoking subjects to secondhand smoke breaks down the serum antioxidant defense, leading to accelerated lipid peroxidation, LDL modification, and accumulation of LDL cholesterol in human macrophages. These data provide the pathophysiological background for the recent epidemiological evidence about the increased CHD risk among passive smokers.
Endovascular β-Radiation to Reduce Restenosis After Coronary Balloon Angioplasty
Authors: King Spencer B. , Williams David O. , Chougule Prakash , Klein J. Larry , Waksman Ron , Hilstead Richard , Macdonald Joan , Anderberg Kris , Crocker Ian R.
Published: June 2012

Background
—In the porcine overstretch injury model of restenosis, endovascular β-radiation reduces neointima formation. To determine whether this therapy could be applied to patients with coronary artery disease, a special device was developed to allow delivery of 12 encapsulated
90
Sr/Y sources, measuring a total of 30 mm, to various sites within the coronary arterial tree. This study was designed to evaluate the feasibility of the delivery of 12, 14, or 16 Gy at 2 mm after balloon angioplasty of stenoses of native coronary vessels.

Methods and Results
—Delivery of β-radiation was attempted in 23 patients after successful balloon angioplasty. Source delivery was successful in 21 of the 23 patients (91%). There was no in-hospital or 30-day morbidity or mortality. Follow-up quantitative coronary arteriography in 20 patients demonstrated a late loss of 0.05 mm, a late loss index of 4%, and a restenosis rate of 15%. The use of the β-emitter
90
Sr/Y significantly reduced treatment time and operator exposure compared with previous trials with the γ-emitter
192
Ir.

Conclusions
—In this study, the administration of endovascular β-radiation after angioplasty was safe and feasible and substantially altered the postangioplasty late lumen loss, resulting in a lower-than-expected rate of restenosis. On the basis of these encouraging results, a multicenter, randomized trial with operators and patients blinded to treatment assignment is planned.