bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Cardiac Function by Three-dimensional Echocardiography Compared With Conventional Noninvasive Methods
Authors: Gopal Aasha S. , Shen Zhanqing , Sapin Peter M. , Keller Andrew M. , Schnellbaecher Matthew J. , Leibowitz David W. , Akinboboye Olakunle O. , Rodney Roxanne A. , Blood David K. , King Donald L.
Published: June 2012

Background
Reliable, serial, noninvasive quantitative estimation of left ventricular ejection fraction is essential for selecting and timing therapeutic interventions in patients with heart disease. Equilibrium radionuclide angiography is widely used for this purpose but has well-recognized limitations. Advantages of echocardiography over equilibrium radionuclide angiography include assessment of wall motion, valvular pathology, and cardiac hemodynamics, in addition to portability, lack of radiation exposure, and substantially lower cost. However, conventional echocardiographic techniques are limited by geometric assumptions, image positioning errors, and use of subjective visual methods. To overcome these limitations, a three-dimensional echocardiographic method was developed. This study compares ejection fraction by three-dimensional echocardiography, quantitative two-dimensional echocardiography, and subjective two-dimensional echocardiographic visual estimation with that by equilibrium radionuclide angiography.

Methods and Results
Fifty-one unselected patients with suspected heart disease underwent left ventricular ejection fraction determination by equilibrium radionuclide angiography and three-dimensional echocardiography using an interactive line-of-intersection display and a new algorithm, ventricular surface reconstruction, for volume computation. In 44 patients, ejection fractions were also estimated visually by experienced observers from two-dimensional echocardiography and by quantitative two-dimensional echocardiography using an apical biplane summation-of-disks algorithm. An excellent correlation was obtained between three-dimensional echocardiography and equilibrium radionuclide angiography (
r
=.94 to .97, SEE=3.64% to 5.35%; limits of agreement, 10.3% to 13.3%) without significant underestimation or overestimation. SEE values and limits of agreement were twofold to threefold lower than corresponding values for all two-dimensional echocardiographic techniques. In addition, interobserver variability was significantly lower for the three-dimensional echocardiographic method (10.2%) than for the apical biplane summation-of-disks method (26.1%) and subjective visual estimation (33.3%).

Conclusions
Determination of ejection fraction by three-dimensional echocardiography yields results comparable to those obtained by equilibrium radionuclide angiography and is substantially superior to all two-dimensional echocardiographic methods. Therefore, three-dimensional echocardiography may be used for accurate serial quantification of left ventricular function as an alternative to equilibrium radionuclide angiography.
Transesophageal Echocardiographic Assessment of Mitral Valve Position and Pulmonary Venous Flow During Cardiopulmonary Resuscitation in Humans
Authors: Ma Matthew Huei-Ming , Hwang Juey-Jen , Lai Ling-Ping , Wang Shih-Ming , Huang Guan-Tarn , Shyu Kou-Gi , Ko Yu-Lin , Lin Jiunn-Lee , Chen Wen-Jone , Hsu Kwan-Lih , Chen Jin-Jer , Kuan Peiliang , Tseng Yung-Zu , Lien Wen-Pin
Published: June 2012

Background
The mechanisms of blood flow during closed-chest cardiopulmonary resuscitation (CPR) in humans have been debated since the technique was first described in 1960. Two competing models, the cardiac pump theory and the thoracic pump theory, have been proposed, and some investigators have used mitral valve position during the downstroke of chest compression to distinguish between them. Previous studies using either transthoracic or transesophageal echocardiography have yielded conflicting results, and there have been few, if any, hemodynamic or echocardiographic studies on pulmonary venous flow (PVF) during CPR.

Methods and Results
In this study, transesophageal two-dimensional and pulsed Doppler echocardiography were used to study mitral valve position and flow, together with PVF, in 20 adult patients undergoing manual CPR. In the 17 patients who could be analyzed, the mitral valve closed in 5 patients (group 1) during chest compression but stayed open or opened further in the remaining 12 patients (group 2). Peak forward mitral flow occurred during the release phase in group 1 but during the compression phase in group 2. During chest compression, PVF occurred in the forward direction (from the pulmonary vein to the left atrium) in 8 of the group 2 patients (group 2a) and in the backward direction (from the left atrium to the pulmonary vein) in all group 1 patients and the remaining 4 patients in group 2 (group 2b). The downtime (time from collapse to CPR) was significantly shorter (
P
<.05) for those in group 1 (7.0±4.4 minutes) than in groups 2a (19.8±7.7 minutes) and 2b (17.8±6.8 minutes).

Conclusions
Transesophageal echocardiography performed during manual CPR in humans disclosed three different patterns of mitral valve position and PVF during chest compression. The presence of an opened mitral valve with forward mitral flow and backward pulmonary venous flow during chest compression in a small number of subjects underscores this heterogeneity in blood flow and suggests the possible existence of a “left atrium pump” in addition to the currently known “left ventricle pump” and “chest pump” mechanisms.
Dietary Correction of Hypercholesterolemia in the Rabbit Normalizes Endothelial Superoxide Anion Production
Authors: Ohara Yuichi , Peterson Timothy E. , Sayegh Hassan S. , Subramanian Romesh R. , Wilcox Josiah N. , Harrison David G.
Published: June 2012

Background
We have shown that hypercholesterolemia increases vascular superoxide anion (O
2
−
) production, which could be responsible for augmented inactivation of endothelium-derived vascular relaxing factor. We sought to determine whether this increased vascular O
2
−
production is due to infiltration of macrophages into the intima and whether dietary treatment of hypercholesterolemia normalizes O
2
−
production.

Methods and Results
A specific and sensitive assay for O
2
−
based on chemiluminescence of lucigenin was used; the amount of O
2
−
produced by vascular ring segments was quantified based on known quantities of O
2
−
produced by xanthine–xanthine oxidase standards. O
2
−
production of aortic segments from normal rabbits (n=9), cholesterol-fed rabbits (1% cholesterol diet for 1 month, n=7), and rabbits fed a 1% cholesterol diet for 1 month followed by a normal diet for 1 month (regression rabbits, n=5) was measured. At the end of these diets, serum cholesterol levels were 1.5±0.2, 26.0±3.9, and 1.8±0.5 mmol/L (58±6, 1000±150, and 71±19 mg/dL) in the normal, cholesterol-fed, and regression animals, respectively. Vessels from normal rabbits with endothelium produced 0.32±0.06 nmol O
2
−
/mg dry wt per minute, whereas those without endothelium produced approximately twice as much O
2
−
(0.66±0.12 nmol O
2
−
mg dry wt per minute. Vessels with endothelium from cholesterol-fed rabbits produced 4.5-fold more O
2
−
than vessels from normal animals. This increased production of O
2
−
was normalized by endothelial removal. This increased production of O
2
−
was not due to infiltration of macrophages in the intima, because there was no correlation between vascular O
2
−
production and macrophage infiltration assessed by immunohistochemistry with use of a specific antibody against rabbit macrophage. O
2
−
production by vessels from regression rabbits was similar to that observed in normal animals, and as in the normal rabbits, endothelial removal increased O
2
−
production. Aortic rings from these animals also were studied in organ chambers. Dietary lowering of cholesterol dramatically improved vasodilator responses to acetylcholine and
A23187
(
P
<.05 versus cholesterol-fed rabbits).

Conclusions
Dietary lowering of cholesterol not only improves endothelium-dependent vascular relaxation but also normalizes endothelial O
2
−
production. Decreases of O
2
−
production by dietary lowering of cholesterol not only may improve vasomotor control but also may improve other aspects of vascular integrity in atherosclerosis.
Long-term Cigarette Smoking Impairs Endothelium-Dependent Coronary Arterial Vasodilator Function
Authors: Zeiher Andreas M. , Schächinger Volker , Minners Jan
Published: June 2012

Background
Smoking is a primary risk factor for coronary and peripheral vascular disease. Because the endothelium is a principal target for the effects of risk factors early in the pathogenesis of atherosclerosis, we investigated whether long-term smoking is associated with impaired endothelial vasodilator function of epicardial conductance vessels regardless of the presence or absence of atherosclerotic lesions.

Methods and Results
Using quantitative coronary angiography, we measured epicardial artery diameter at baseline, after maximal increases in coronary blood flow that caused flow-mediated dilation (which is strictly endothelium dependent), and after intracoronary injection of nitroglycerin (an endothelium-independent dilator) in 96 patients. Endothelium-dependent, flow-mediated dilation was significantly (
P
<.0001) blunted in smokers (n=46) compared with nonsmokers (n=50). The ratio of flow-dependent dilation to nitroglycerin-induced dilation was significantly (
P
<.001) lower in smokers (0.34±0.32) compared with nonsmokers (0.59±0.23), indicating that the blunted dilator response to increased blood flow was out of proportion to the mildly impaired dilator response to nitroglycerin in smokers. In the presence of angiographically visible atherosclerosis, flow-dependent dilation was essentially absent (3.0±6.5%) in smokers. Multivariate analysis revealed that luminal irregularities by angiography (
P
<.0001) and smoking (
P
<.001) were the only variables to be independently associated with a reduced flow-dependent dilator response of epicardial arteries. Intracoronary ultrasound demonstrated that flow-dependent dilation progressively decreased with increasing atherosclerotic plaque load (
r
=−.82,
P
<.0001; n=24). However, over the entire range of wall thickening, segments from smokers exhibited a significantly (
P
<.01) impaired flow-dependent dilator response compared with those of nonsmokers.

Conclusions
Long-term cigarette smoking is associated with impaired endothelium-dependent coronary vasodilation regardless of the presence or absence of coronary atherosclerotic lesions.
Albumin Microbubble Echo-Contrast Material as an Enhancer for Ultrasound Accelerated Thrombolysis
Authors: Tachibana Katsuro , Tachibana Shunro
Published: June 2012

Background
Recent findings suggest that acoustic cavitation is responsible for acceleration of thrombolysis by ultrasound (US) energy. It is known that albumin microbubbles lower the threshold of acoustic cavitation production.

Methods and Results
The present study was designed to determine whether the presence of albumin microbubbles used for echo-contrast material (Albunex) can further accelerate fibrinolysis by US. Artificial thrombus was produced by Chandler’s loop method with blood extracted from a healthy subject. Urokinase (UK, 1200 IU/mL) was added to the artificial thrombi placed in test tubes. Each thrombus was exposed to US (170 kHz) at a distance of 1.2 cm for a total of 60 seconds at an intensity of 0.5 W/cm
2
at intervals of 2 seconds on and 4 seconds off. Echo-contrast material (0.6×10
6
microspheres per mL) or 5% albumin (for control) was circulated near the thrombus at a rate of 1 mL/min during the US exposure. Fibrinolysis was later determined by percentage of weight loss of thrombus after 60 minutes of incubation (n=15). Fibrinolysis with UK alone was 26.6±4.8%. Fibrinolysis with UK+US treatment was 33.3±5.8%. Further increase of fibrinolysis to 51.3±7.7% occurred in the presence of Albunex (UK+US+Albunex). Statistical differences were obtained between all these groups (ANOVA).

Conclusions
The presence of the echo-contrast agent induced further acceleration of thrombolysis by US energy. It is suggested that this diagnostic echo-contrast material can be used as an alternative therapeutic US drug enhancer for thrombolysis.
Dynamic Electrophysiological Behavior of Human Atria During Paroxysmal Atrial Fibrillation
Authors: Capucci Alessandro , Biffi Mauro , Boriani Giuseppe , Ravelli Flavia , Nollo Giandomenico , Sabbatani Paolo , Orsi Carlo , Magnani Bruno
Published: June 2012

Background
The aims of our study were to investigate the meaning of local atrial activation and its behavior during paroxysmal atrial fibrillation and to study the effect of overdrive pacing on local atrial activity.

Methods and Results
Twenty-five patients with lone paroxysmal atrial fibrillation underwent electrophysiological study. Functional and effective atrial refractoriness was determined. Mean and fifth percentile values of 100 consecutive atrial fibrillation intervals (FF) were evaluated at three atrial sites either at arrhythmia onset or at self-termination (or at minute 5). A high-voltage burst pacing was performed after 6 minutes of stable atrial fibrillation in 10 patients. Mean FF intervals were evaluated 5 seconds before and after atrial pacing. Forty-nine atrial fibrillation episodes were induced: 39 self-terminating within 5 minutes and 10 long-lasting. A significant correlation was found between mean FF and atrial functional refractory period (
r
=.73,
P
<.001) and between fifth percentile FF and atrial effective refractory period (
r
=.57,
P
<.005). Atrial fibrillation self-termination was associated with significant mean FF prolongation, whereas long-lasting fibrillation behaved the opposite. In 10 patients, burst pacing resulted in significant shortening of the mean FF at the stimulation site; no changes were observed in the two distant recording sites.

Conclusions
The analysis of the FF intervals demonstrates a strict correlation with atrial functional refractoriness. The self-termination of atrial fibrillation is related to a prolongation of the functional refractoriness (mean FF), whereas a shortening of both functional and effective refractoriness (fifth percentile) is associated with atrial fibrillation persistence. The provoked shortening of the mean FF at the stimulation site is consistent with the presence of a gap of excitability during atrial fibrillation in the human atria.
Extracoronary Atherosclerotic Plaque at Multiple Sites and Total Coronary Calcification Deposit in Asymptomatic Men
Authors: Simon A. , Giral P. , Levenson J.
Published: June 2012

Background
Recent studies have suggested that knowledge of the extent of subclinical atherosclerosis may improve prognostic information in subjects at risk of cardiovascular disease. Therefore, we tested the value of extracoronary plaque detected with echography at multiple sites and that of total coronary calcification deposit evaluated with ultrafast computed tomography for predicting the risk of coronary events estimated on the basis of traditional risk factors.

Methods and Results
We analyzed in 618 asymptomatic at-risk men the extent of extracoronary atherosclerosis, as assessed with ultrasound imaging of carotid, aortic, and femoral sites and coded as number of disease sites (none, one, two, or three) on the basis of the presence of plaque at each site, and the amount of total coronary calcification deposit, as evaluated with ultrafast computed tomography and coded as grade 0, 1, 2, or 3 on the basis of the determination of a total coronary calcium score. Concomitantly, age, systolic pressure, total and HDL cholesterol levels, current smoking, presence of diabetes, and presence of ECG left ventricular hypertrophy (ECG-LVH) were evaluated with the goal of estimating coronary risk with the use of the Framingham Study risk algorithm. The prevalence rates of at least one extracoronary disease site and coronary calcification (any grade) were high (72% and 63%). There was a strong association between the number of extracoronary disease sites and the grade of coronary calcification (
P
<.001). As the number of extracoronary disease sites increased, age, systolic pressure, smoking frequency, and number of risk factors increased (
P
<.001). As the grade of coronary calcification increased, age and systolic pressure increased (
P
<.001), as did the number of risk factors (
P
<.01). The estimated coronary risk increased with the number of extracoronary disease sites and the grade of coronary calcification (
P
<.001). The odds ratio of coronary risk between three and no extracoronary disease site was 2.37 (95% confidence interval [CI], 1.08 to 5.21), whereas that between grade 3 and grade 0 of coronary calcification was 1.79 (95% CI, 0.94 to 3.40).

Conclusions
In an apparently healthy population, the extracoronary atherosclerotic burden as measured with multiple-site echography appears to be more powerful than the ultrafast computed tomography–detected coronary calcium burden in reflecting the multifactorial coronary risk profile. However, only men were included in the present study, and the present findings cannot be extrapolated to women.
Changes in Phasic Coronary Blood Flow Velocity Profile in Relation to Changes in Hemodynamic Parameters During Stress in Patients With Aortic Valve Stenosis
Authors: Petropoulakis Panaghiotis N. , Kyriakidis Michael K. , Tentolouris Costas A. , Kourouclis Costas V. , Toutouzas Pavlos K.
Published: June 2012

Background
Alterations in phasic coronary flow profile have been demonstrated at rest in patients with aortic valve stenosis (AVS) but have never been studied under conditions of hemodynamic stress.

Methods and Results
Thirty-four patients with significant pure AVS (21 with exertional symptoms [group 1], 13 asymptomatic [group 2]) and 9 control subjects (group 3), all with normal coronary arteries, were studied successively at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 μg · kg
−1
· min
−1
IV) by proximal left anterior descending (LAD) intracoronary Doppler flow velocimetry concomitant with hemodynamic measurements. Systolic retrograde coronary flow velocity (CFV) was recorded only in patients with AVS, and its resting peak value was positively correlated with peak aortic pressure gradient (APG) (
r
=.63,
P
<.001). In group 1, there was lower aortic valve area (0.58±0.10 versus 0.75±0.08 cm
2
,
P
<.001) and higher resting APG and peak systolic retrograde CFV than in group 2, and also higher resting peak diastolic and mean CFV than in groups 2 and 3. In the two AVS groups, there were no changes from rest in APG and retrograde CFV at peak pacing rate; however, these parameters increased concomitantly and significantly at peak dobutamine stress. The ratio of the resting systolic to diastolic CFV curve area was inversely correlated with mean APG (
r
=−.54,
P
<.001); it was significantly lower in group 1 than in groups 2 and 3 (0.19±0.07 versus 0.29±0.10 and 0.30±0.04, respectively, both
P
<.005) and increased at peak pacing (group 1, to 0.29±0.14; group 2, to 0.39±0.12; group 3, to 0.38±0.07; all
P
<.001). At peak dobutamine stress, it decreased in patients with AVS (group 1, to 0.05±0.05; group 2, to 0.08±0.03; both
P
<.001) but did not change in group 3 (0.25±0.05). From rest to peak dobutamine stress, in both AVS groups there was increased retrograde systolic (group 1, 441±483%; group 2, 681±356%; both
P
<.001), decreased total systolic (group 1, −66±25%,
P
<.001; group 2, −19±24%;
P
=NS), and increased diastolic (group 1, 33.4±31.7%; group 2, 197.7±105.1%; both
P
<.001; group 1 versus group 2,
P
<.001) CFV curve area. In contrast, group 3 showed comparable increases in both systolic (143.5±44.4%) and diastolic (197.1±75.2%) CFV area (both
P
<.001). The stress-induced increases in the mean CFV and blood flow exceeded or were comparable with the concomitant increases in the estimated myocardial metabolic demand in groups 2 and 3 but were significantly lower in group 1.

Conclusions
Stress-induced changes in LAD phasic CFV profile differ significantly between patients with and without AVS. In AVS, these changes are closely related to the concomitant stress-induced changes in hemodynamic parameters.
Circadian Variation in Human Ventricular Refractoriness
Authors: Kong Thomas Q. , Goldberger Jeffrey J. , Parker Michele , Wang Ted , Kadish Alan H.
Published: June 2012

Background
The incidence of sudden cardiac death is highest in the morning hours. Although a circadian variation in myocardial ischemia may be responsible in part for this observation, other factors also may be contributory. It is not known whether a circadian variation in ventricular refractoriness exists that may be related to the increased morning incidence of sudden cardiac death.

Methods and Results
Nine subjects with primary conduction system disease, no evidence of structural heart disease, and permanent pacemakers were studied. Autonomic nervous system function as assessed by tilt table and baroreflex sensitivity testing was normal in all subjects. Using noninvasive programmed stimulation, ventricular effective refractory periods were measured hourly for 24 hours. Potassium, epinephrine, and norepinephrine levels also were measured hourly. In a subset of five subjects, ventricular refractory periods were again measured hourly over 24 hours during β-blockade. A significant circadian variation in ventricular refractoriness was noted, with a mean difference between the shortest and longest refractory periods in individual subjects of 23 ms and 21 ms at drive cycle lengths of 600 ms and 400 ms, respectively. In eight subjects, the shortest refractory periods observed over 24 hours occurred within 2 hours of waking (random probability <10
−8
). Adjustment of refractory period data according to the hour of waking resulted in a better correlation between ventricular refractory periods and time. Although a significant circadian variation was observed in potassium and catecholamine levels, neither was an independent predictor of refractory periods after adjustment for the hour of waking. The adjusted time of day was the only significant (
P
<.0001) independent predictor of refractory periods. β-Blockade abolished the circadian variation in ventricular refractory periods.

Conclusions
A significant circadian variation in ventricular refractory periods exists. Maximal shortening between hourly refractory periods as well as the shortest refractory periods occur in the early morning hours when the incidence of sudden cardiac death is greatest. Fluctuations in β-adrenergic tone appear to be largely responsible for this phenomenon.
Efficacy and Safety of
d
-Sotalol, a Pure Class III Antiarrhythmic Compound, in Patients With Symptomatic Complex Ventricular Ectopy
Authors: Hohnloser Stefan H. , Meinertz Thomas , Stubbs Peter , Crijns Harry J.G.M. , Blanc Jean-Jacques , Rizzon Paolo , Cheuvart Brigitte
Published: June 2012

Background
There is increasing interest in pure class III antiarrhythmic compounds, ie, drugs in which the electrophysiological effect is confined to the propensity for producing an isolated lengthening of action potential duration.
d
-Sotalol represents the prototype of such pure class III agents. This double-blind, placebo-controlled, randomized dose-finding study evaluated the antiarrhythmic efficacy and safety of
d
-sotalol in patients with symptomatic chronic ventricular ectopy.

Methods and Results
A total of 233 patients presenting with ≥30 premature ventricular contractions (PVCs) per hour during drug-free Holter monitoring randomly received placebo or
d
-sotalol at dosages of 50, 100, or 200 mg BID. Drug efficacy was assessed by repeat Holter monitoring at the end of double-blind therapy. There was a dose-dependent increase in QT and QT
c
duration, indicating class III activity. A dose-related decrease in hourly PVC counts was observed, reaching statistical significance for patients receiving 200 mg
d
-sotalol BID (311 PVCs/h during baseline compared with 135 PVCs/h during active treatment,
P
<.05). Analysis of the primary efficacy criterion (ie, ≥75% reduction in total PVCs/h) revealed a significant treatment effect only for the highest
d
-sotalol dose, with 8 patients (14%) meeting this criterion. Eighteen patients reported side effects, which led to drug discontinuation in 5. One sudden death and one nonfatal cardiac arrest occurred in patients with dilative cardiomyopathy receiving 200 mg
d
-sotalol BID. No incidence of torsade de pointes was reported.

Conclusions
d
-Sotalol exerts dose-dependent class III activity in patients with symptomatic ventricular ectopy. Its PVC-suppressing activity is modest and becomes evident predominantly at dosages of 200 mg administered BID. The observation of drug-associated serious adverse arrhythmic events emphasizes the need for individualized careful dose titration, particularly in patients with advanced organic heart disease.
Low-Dose Radioactive Endovascular Stents Prevent Smooth Muscle Cell Proliferation and Neointimal Hyperplasia in Rabbits
Authors: Hehrlein Christoph , Gollan Christina , Dönges Klaus , Metz Jürgen , Riessen Reimer , Fehsenfeld Peter , von Hodenberg Eberhard , Kübler Wolfgang
Published: June 2012

Background
Restenosis induced by smooth muscle cell (SMC) migration and proliferation and neointimal thickening limits the clinical success of balloon angioplasty and stent implantation. In this study, the long-term effect of endovascular irradiation via low-dose radioactive stents on neointima formation was compared with conventional stent implantation in a rabbit model.

Methods and Results
Palmaz-Schatz stents were made radioactive in a cyclotron. The stents had a very low activity (maximum, 35 μCi), and thus, manipulation did not require extensive radiation protection. One, 4, 12, and 52 weeks after the implantation of nonradioactive stents and radioactive stents in rabbit iliac arteries, neointimal thickening was analyzed by quantitative histomorphometry. Immunostaining for endothelial cell von Willebrand factor, macrophages, SMC α-actin, collagen type I, and proliferating cell nuclear antigen (PCNA) was performed to determine radiation-induced changes in the arterial wall. SMC proliferation was quantified by computer-assisted cell counting of PCNA-immunoreactive cells. Neointima formation was markedly suppressed by the implantation of radioactive stents in a dose-dependent fashion at all observed time points. At peak proliferative activity of SMCs 1 week after nonradioactive stent implantation, 30±2% of SMCs in the neointima were proliferating, compared with 0.5±0.1% of SMCs after implantation of stents with an initial activity of 35 μCi (
P
<.001). The neointima covering radioactive stents was characterized by decreased smooth muscle cellularity and increased extracellular matrix formation. Further, we observed a delayed endothelialization depending on the radiation dose. No difference in vascular thrombosis was found after nonradioactive and radioactive stent implantation.

Conclusions
The results of this study clearly indicate that low-dose radioactive endovascular stents potently inhibit SMC proliferation and neointimal hyperplasia in rabbits.
Sudden Coronary Death
Authors: Farb Andrew , Tang Anita L. , Burke Allen P. , Sessums Laura , Liang Youhui , Virmani Renu
Published: June 2012

Background
The reported frequency of active coronary lesions (plaque rupture and coronary thrombosis) in sudden death due to coronary artery atherosclerosis (sudden coronary death) has varied from <20% to >80% of cases in previous series. In hearts lacking an active coronary lesion, sudden death has usually been attributed to a healed myocardial infarction. The purpose of the present study was to determine the frequency of active and inactive coronary lesions and myocardial infarction in individuals with sudden coronary death.

Methods and Results
The hearts of persons who died as a result of sudden coronary death underwent perfusion-fixation and postmortem angiography. An active coronary lesion was defined as a disrupted plaque, luminal fibrin/platelet thrombus, or both. We defined an inactive lesion as having a cross-sectional luminal stenosis of ≥75% with neither plaque disruption nor luminal thrombus. Ninety hearts were examined (from 72 men and 18 women; mean age at the time of death, 51±10 years). Acute myocardial infarction was present in 19 (21% [acute myocardial infarction only in 9, both acute and healed myocardial infarction in 10]), healed myocardial infarction only in 37 (41%), and no myocardial infarction in 34 (38%). Active coronary lesions were identified in 51 (57%): acute thrombi plus disrupted plaques in 27, acute thrombi only in 21, and disrupted plaques only in 3. In hearts with acute myocardial infarction, active coronary lesions were significantly more prevalent than in hearts with only healed myocardial infarction or hearts lacking an acute or a healed myocardial infarction (89%, 46%, and 50%, respectively;
P
<.005). Hearts without acute or healed myocardial infarction and without active lesions were similar to hearts with active lesions with respect to heart weight and severity of epicardial coronary disease.

Conclusions
Acute changes in coronary plaque morphology (thrombus, plaque disruption, or both) were found in 57% of cases of sudden coronary death. In hearts with myocardial scars and no acute infarction, active coronary lesions were identified in 46% of cases. Neither myocardial infarction (acute or healed) nor an active coronary lesion was present in 19% of hearts.
Unstable Angina
Authors: Silva Jose A. , Escobar Alvaro , Collins Tyrone J. , Ramee Stephen R. , White Christopher J.
Published: June 2012

Background
Patients with diabetes mellitus have a higher prevalence of atherosclerotic heart disease and a higher incidence of myocardial infarction than the general population. Diabetic patients also have several hematologic, rheologic, and metabolic abnormalities not present in their nondiabetic counterparts that may predispose them to atherosclerotic plaque rupture and intraluminal thrombosis and consequently may lead to the formation of morphologically complex plaques and the development of acute coronary syndromes.

Methods and Results
Percutaneous coronary angioscopy was performed in 55 consecutive patients with unstable angina. We observed plaque color, texture, and the incidence of intracoronary thrombus associated with the culprit lesions of these patients. The population consisted of 17 (31%) diabetic and 38 (69%) nondiabetic patients. The presence of coronary risk factors was not significantly different between the two populations. Ulcerated plaque was found in 16 of 17 (94%) diabetic patients versus 23 of 38 (60%) nondiabetic patients (
P
=.01). Intracoronary thrombi were seen in 16 of 17 (94%) diabetic patients versus 21 of 38 (55%) nondiabetic patients (
P
=.004).

Conclusions
The results of the angioscopic examination show that diabetic patients with unstable angina have a higher incidence of plaque ulceration and intracoronary thrombus formation than nondiabetic patients. This increased frequency of complex lesion morphology is consistent with the disproportionately higher risk for development of acute coronary syndromes in these patients.
Polymorphisms in the Lipoprotein Lipase Gene and Their Associations With Plasma Lipid Concentrations in 40-Year-Old Danish Men
Authors: Gerdes Christian , Gerdes Lars Ulrik , Hansen Peter Steen , Faergeman Ole
Published: June 2012

Background
In some previous studies,
Hin
dIII and
Pvu
II restriction fragment length polymorphisms (RFLPs) in the lipoprotein lipase (
LPL)
gene were associated with coronary heart disease and plasma concentrations of HDL cholesterol and triglycerides. However, the populations studied were relatively small and heterogeneous in regard to age, sex, and ethnic background.

Methods and Results
Associations of a
Hin
dIII (intron 8) and a
Pvu
II (intron 6) RFLP in the
LPL
gene with plasma concentrations of cholesterol, HDL cholesterol, non-HDL cholesterol, and triglycerides were studied in 457 randomly selected 40-year-old Danish men. The
Hin
dIII and the
Pvu
II sites were in strong linkage disequilibrium. The frequencies of the
H
+ and
P
+ alleles (+ denotes presence of cutting site) were 0.717 and 0.464, respectively. In multivariate analysis, there was a clear gene dosage effect of the
H
+ allele on HDL. The lowest HDL cholesterol concentration was in the
H
+
H
+ group, the highest concentration was in the
H
−
H
− group, and the
H
+
H
− group had intermediate HDL concentrations (
P
=.03). There was a similar, but not statistically significant gene dosage effect on triglyceride concentrations, with the highest value seen in the
H
+
H
+ group. There were no other associations between LPL RFLPs and lipoprotein components. In males reporting family history of premature ischemic heart disease, the
H
+
H
+ genotype was overrepresented (odds ratio, 2.75; 95% confidence interval, 1.37 to 5.53).

Conclusions
The results suggest that genetic variation in or near the
LPL
gene plays a role in interindividual differences in HDL cholesterol concentration and in risk of atherosclerosis and ischemic heart disease in men.
Some Coronary Risk Factors Related to the Insulin Resistance Syndrome and Treatment With Gemfibrozil
Authors: Tenkanen Leena , Mänttäri Matti , Manninen Vesa
Published: June 2012

Background
Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome—low HDL cholesterol and high triglyceride (TG) levels—responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data.

Methods and Results
We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass index (BMI) >26 kg/m
2
, the net difference in cardiac end points between gemfibrozil and placebo groups was 21 (25 of 1119 versus 46 of 1081), and in those with BMI ≤26 kg/m
2
, it was 7 (31 of 927 versus 38 of 954). The risk reduction with gemfibrozil was 78% (
P
=.002) among those with BMI >26 kg/m
2
and dyslipidemia (TG ≥2.3 mmol/L and HDL cholesterol <1.08 mmol/L). Among those with BMI >26 kg/m
2
and three or four of the following factors present—smoking, sedentary lifestyle, blood pressure ≥140/90 mm Hg, or blood glucose >4.4 mmol/L—the risk reduction was 68% (
P
=.03).

Conclusions
Gemfibrozil reduced the coronary risk mainly in overweight subjects with additional risk factors known to contribute to the insulin-resistance syndrome or predispose to it.
Effects of Increasing Maintenance Dose of Digoxin on Left Ventricular Function and Neurohormones in Patients With Chronic Heart Failure Treated With Diuretics and Angiotensin-Converting Enzyme Inhibitors
Authors: Gheorghiade Mihai , B. Hall Veronica , Jacobsen Gordon , Alam Mohsin , Rosman Howard , Goldstein Sidney
Published: June 2012

Background
Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied.

Methods and Results
We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20±0.07 to 0.39±0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67±0.22 to 1.22±0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7±9.6% to 27.1±11.8% (
P
=.007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4±10.4% to 23.7±8.9%) in the placebo group but not in patients who continued to receive digoxin (
P
=.002).

Conclusions
The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.
Identification and Molecular Analysis of Two ApoB Gene Mutations Causing Low Plasma Cholesterol Levels
Authors: Welty Francine K. , Ordovas Jose , Schaefer Ernst J. , Wilson Peter W.F. , Young Stephen G.
Published: June 2012

Background
Familial hypobetalipoproteinemia (FHB) is an autosomal codominant disorder characterized by abnormally low plasma levels of apoB and LDL cholesterol. Heterozygotes for FHB almost always have plasma LDL cholesterol levels <70 mg/dL and are asymptomatic. Because the low cholesterol levels may protect FHB heterozygotes from coronary heart disease, the mechanisms for FHB are of considerable interest.

Methods and Results
The plasma lipoproteins of 29 subjects with LDL cholesterol levels <70 mg/dL were examined by SDS-PAGE. One subject who had virtually undetectable levels of LDL cholesterol had a truncated apoB, apoB-44.4, in his lipoproteins; a second subject with an LDL cholesterol level of 44 mg/dL had apoB-55 in his lipoproteins. The apoB-44.4 (2014 amino acids in length) resulted from a frameshift caused by an 11-bp insertion in exon 26 of the apoB gene; the apoB-55 (2494 amino acids) was caused by a nonsense mutation in exon 26 of the apoB gene. The apoB-55 mutation occurred at a CpG dinucleotide pair, a mutational hot spot, and was identical to a mutation described previously in a subject with hypobetalipoproteinemia. Our subject with apoB-55, however, had a different haplotype than the subject described previously, suggesting that the two apoB-55 mutations may have arisen independently. Of note, the apoB-55 proband’s father, who had very low cholesterol levels and who probably carried the apoB-55 mutation, had significant coronary and aortic atherosclerosis at autopsy.

Conclusions
In a study of adults with low LDL cholesterol levels, we discovered two subjects with truncated apoB proteins and identified the responsible mutations. ApoB gene mutations causing truncated apoB are not particularly rare in subjects with low cholesterol levels. The role of these mutations in preventing atherosclerosis deserves further study.
cAMP Response Element Binding Protein Is Expressed and Phosphorylated in the Human Heart
Authors: Müller Frank Ulrich , Bokník Peter , Horst Andreas , Knapp Jörg , Linck Bettina , Schmitz Wilhelm , Vahlensieck Ute , Böhm Michael , Deng Mario C. , Scheld Hans H.
Published: June 2012

Background
In end-stage failing human hearts and in rat hearts after prolonged in vivo β-adrenergic treatment, several proteins involved in the cAMP-dependent signal transduction are altered on the protein, mRNA, or transcriptional level, eg, β-adrenoceptors, G-proteins, or proteins of Ca
2+
homeostasis. In many tissues, cAMP-dependent transcriptional regulation occurs through the cAMP response element binding protein (CREB) and related transcription factors binding as dimers to cAMP response elements (CREs) in the promoter regions of regulated genes.

Methods and Results
To investigate a possible role of CREB in the human heart, nuclear protein of explanted failing and nonfailing human hearts was used to test for CRE specific binding properties in gel mobility shift assays. CRE specific binding was found in competition studies, and CREB and its phosphorylated form were immunologically identified in supershift experiments. The alternatively spliced CREB isoforms CREB327 and CREB341 were found to be expressed on the mRNA level by the reverse transcriptase–polymerase chain reaction.

Conclusions
We conclude that in the failing and nonfailing human heart, CREB is expressed on the protein and mRNA levels and that CREB is phosphorylated and able to bind to CREs, indicating a functional role of CREB in the human heart.
Rapid Angiographic Progression of Coronary Artery Disease in Patients With Angina Pectoris
Authors: Kaski Juan Carlos , Chester Michael R. , Chen Lijia , Katritsis Demosthenes
Published: June 2012

Background
Rapid disease progression commonly underlies acute coronary events, and “complex” stenosis morphology may play a role in this phenomenon.

Methods and Results
We studied the role of complex stenosis morphology in rapid disease progression in 94 consecutive patients awaiting routine coronary angioplasty. Coronary arteriography was repeated at 8±3 months’ follow-up, immediately preceding angioplasty (68 patients) or after an acute coronary event (26 patients). Disease progression of 217 stenoses, of which 79 (36%) were “complex” and 138 (64%) were “smooth,” was assessed by computerized angiography. At presentation, 63 patients had stable angina pectoris and 31 had unstable angina that settled rapidly with medical therapy. At follow-up, 23 patients (24%) had progression of preexisting stenoses and 71 (76%) had no progression. Patients with progression were younger (55±12 years) than those without (58±9 years) but did not differ with regard to risk factors, previous myocardial infarction, or severity and extent of coronary disease. Twenty-three lesions (11%) progressed, 15 to total occlusion (11 complex and 4 smooth; 65%). Progression occurred in 17 of the 79 complex stenoses (22%) and in 6 of the 138 smooth lesions (4%) (
P
=.002). Mean stenosis diameter reduction was also significantly greater in complex than in smooth lesions (11.6% versus 3.9% change;
P
<.001). Acute coronary events occurred in 57% of patients with progression compared with 18% of those without progression (
P
<.001) and were more frequent in patients who presented with unstable angina (
P
=.002).

Conclusions
Rapid stenosis progression is not uncommon, and complex stenoses are at risk more than smooth lesions.
Impaired Myocardial Tissue Perfusion Early After Successful Thrombolysis
Authors: Maes Alex , Van de Werf Frans , Nuyts Johan , Bormans Guy , Desmet Walter , Mortelmans Luc
Published: June 2012

Background
Impaired tissue reperfusion after successful recanalization of an epicardial coronary artery has been documented both in animals and in patients with acute myocardial infarction. Whether this phenomenon can be demonstrated with positron emission tomography (PET) and whether it has an effect on late recovery of flow, metabolism, and function are unknown.

Methods and Results
Thirty patients with an acute myocardial infarction and TIMI flow grade 3 of the infarcted vessel at 90 minutes after thrombolytic therapy were studied. Within 24 hours after thrombolysis, at 5 days and at 3 months, myocardial blood flow was measured with
13
NH
3
.
18
FDG uptake was measured at 5 days. Radionuclide left ventricular angiograms were acquired at 5 days and at 3 months. In 11 patients (37%), regional myocardial flow was severely impaired (<50% of normally perfused myocardium) despite successful thrombolysis. No recovery of left ventricular function occurred in any of these patients at 3 months. In 12 patients (40%), intermediate flows (50% to 75% of normal) were found, with functional improvement after angioplasty only in regions with a PET mismatch. Seven patients (23%) had high flow values early after successful thrombolysis (>75% of normal) and showed preserved regional contractile function at 3 months.

Conclusions
This study is the first demonstration with PET of impaired myocardial tissue perfusion in patients with an acute myocardial infarction after successful thrombolysis. Functional recovery of the reperfused myocardium is observed only when adequate tissue flow is restored. PET may be helpful in selecting patients in whom additional revascularization can improve recovery of left ventricular function.
Mental Stress–Induced Ischemia in the Laboratory and Ambulatory Ischemia During Daily Life
Authors: Blumenthal James A. , Jiang Wei , Waugh Robert A. , Frid David J. , Morris James J. , Coleman R. Edward , Hanson Michael , Babyak Michael , Thyrum Elizabeth T. , Krantz David S. , O’Connor Christopher
Published: June 2012

Background
The purpose of this study was to determine the correspondence of mental stress–induced ischemia in the laboratory with ambulatory ischemia and to assess the relationship between hemodynamic responses to mental stress and the occurrence of ischemia. Although exercise testing is usually used to elicit myocardial ischemia, ischemia during daily life usually occurs at relatively low heart rates and in the absence of strenuous physical exercise. Mental stress has been shown to trigger ischemic events in the laboratory at lower heart rates but at blood pressures comparable to exercise. We therefore compared the extent to which mental stress and exercise testing identify patients who develop ischemia out of hospital.

Methods and Results
One hundred thirty-two patients with documented coronary disease and recent evidence of exercise-induced myocardial ischemia underwent 48-hour ambulatory monitoring and radionuclide ventriculography during exercise and mental stress testing. Patients who displayed mental stress–induced ischemia in the laboratory were more likely to exhibit ischemia during daily life (
P
<.021). Furthermore, patients who exhibited ischemia during ambulatory monitoring displayed larger diastolic blood pressure (
P
<.006), heart rate (
P
<.039), and rate-pressure product responses (
P
<.018) during mental stress.

Conclusions
Among patients with prior positive exercise stress tests, mental stress–induced ischemia, defined by new wall motion abnormalities, predicts daily ischemia independent of exercise-induced ischemia. Exaggerated hemodynamic responses during mental stress testing also identify individuals who are more likely to exhibit myocardial ischemia during daily life and mental stress.