bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of Mortality by Exercise Echocardiography
Authors: Marwick Thomas H. , Case Colin , Vasey Charles , Allen Susan , Short Leanne , Thomas James D.
Published: June 2012

Background
—In studies generally involving short follow-up, exercise echocardiography has been shown to predict composite end points. We sought to study the prediction of mortality with this test and to devise a strategy for combination with standard exercise testing.

Methods and Results
—Clinical, exercise testing, and echocardiographic data were collected in 5375 patients (aged 54±14 years, 3880 men) undergoing exercise echocardiography. The Duke treadmill score was derived from the results of treadmill exercise testing. Resting left ventricular (LV) function and the presence and severity of ischemia were interpreted by expert observers. Follow-up at 10.6 years (mean 5.5±1.9 years) was complete in 5211 patients (97%). The Duke score classified 59% of patients as low risk, 39% as intermediate risk, and 2% as high risk. Resting LV dysfunction was present in 1445 patients (27%), and the exercise echocardiogram was abnormal in 2525 patients (47%). Death occurred in 649 patients (12%). Over the first 6 years of follow-up, those with normal exercise echocardiograms had a mortality of 1% per year. Ischemia was an independent predictor of mortality. In sequential Cox models, the predictive power of clinical data was strengthened by adding the Duke score, resting LV function, and the results of exercise echocardiography. Exercise echocardiography was able to substratify patients with intermediate-risk Duke scores into groups with a yearly mortality of 2% to 7%.

Conclusions
—A normal exercise echocardiogram confers a low risk of death, and positive results are an independent predictor of death; ischemia is incremental to other data. This test may be particularly useful in patients with intermediate-risk Duke treadmill scores.
Detection of Coronary Artery Stenosis With Power Doppler Imaging
Authors: Villanueva Flordeliza S. , Gertz Edward W. , Csikari Melissa , Pulido Gregory , Fisher David , Sklenar Jiri
Published: June 2012

Background
—Power Doppler is a new imaging method for detecting microbubbles during myocardial contrast echocardiography (MCE) based on the registration of variance resulting from ultrasound-induced nonlinear bubble behavior. We tested the hypothesis that power Doppler imaging can be used to quantify coronary stenoses.

Methods and Results
—Three left anterior descending (LAD) coronary stenoses of varying severity were created in each of 9 open-chest dogs. MCE was performed by continuous intravenous infusion of a nitrogen-filled bilayer shell microbubble, PB127, during triggered power Doppler imaging at incremental pulsing intervals. MCE and radiolabeled microsphere measurements were made at baseline and during each stenosis, with and without adenosine stress. Videointensities in the LAD and left circumflex (LCx) beds were plotted against pulsing interval and fit to a previously described exponential function modeling microbubble destruction and replenishment, which was used to derive parameters of bubble velocity (β) and peak plateau videointensity (A). Contrast defects matching the location of radiolabeled microsphere hypoperfusion were clearly seen, without need for image processing. The product of β and A was linearly related to LAD/LCx flow (
r
=0.90,
P
<0.0001) and inversely related to stenosis gradient (
r
=−0.70,
P
<0.0001). Endocardial/epicardial flow ratios were visualized and quantifiable.

Conclusions
—As with B-mode harmonics, a model of microbubble destruction/replenishment can be applied to power Doppler data as a means to detect a broad range of stenoses. Image clarity and the lack of attenuation or requirement for background subtraction are additional advantages of this imaging approach. Power Doppler MCE imaging holds promise for the detection of coronary artery disease.
Anatomic-Electrophysiological Correlations Concerning the Pathways for Atrioventricular Conduction
Authors: Mazgalev Todor N. , Ho Siew Yen , Anderson Robert H.
Published: June 2012

Abstract
—The remarkable success of radiofrequency ablation in recent decades in curing atrioventricular nodal reentrant tachycardias has intensified efforts to provide a solid theoretical basis for understanding the mechanisms of atrioventricular transmission. These efforts, which were made by both anatomists and electrophysiologists, frequently resulted in seemingly controversial observations. Quantitatively and qualitatively, our understanding of the mysteries of propagation through the inhomogeneous and extremely complex atrioventricular conduction axis is much deeper than it was at the beginning of the past century. We must go back to the initial sources, nonetheless, in an attempt to provide a common ground for evaluating the morphological and electrophysiological principles of junctional arrhythmias. In this review, we provide an account of the initial descriptions, which still provide an appropriate foundation for interpreting recent electrophysiological findings.
High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers and Young Adults
Authors: Tuzcu E. Murat , Kapadia Samir R. , Tutar Eralp , Ziada Khaled M. , Hobbs Robert E. , McCarthy Patrick M. , Young James B. , Nissen Steven E.
Published: June 2012

Background
—Most of our knowledge about atherosclerosis at young ages is derived from necropsy studies, which have inherent limitations. Detailed, in vivo data on atherosclerosis in young individuals are limited. Intravascular ultrasonography provides a unique opportunity for in vivo characterization of early atherosclerosis in a clinically relevant context.

Methods and Results
—Intravascular ultrasound was performed in 262 heart transplant recipients 30.9±13.2 days after transplantation to investigate coronary arteries in young asymptomatic subjects. The donor population consisted of 146 men and 116 women (mean age of 33.4±13.2 years). Extensive imaging of all possible (including distal) coronary segments was performed. Sites with the greatest and least intimal thickness in each CASS segment were measured in multiple coronary arteries. Sites with intimal thickness ≥0.5 mm were defined as atherosclerotic. A total of 2014 sites within 1477 segments in 574 coronary arteries (2.2 arteries per person) were analyzed. An atherosclerotic lesion was present in 136 patients, or 51.9%. The prevalence of atherosclerosis varied from 17% in individuals <20 years old to 85% in subjects ≥50 years old. In subjects with atherosclerosis, intimal thickness and area stenosis averaged 1.08±0.48 mm and 32.7±15.9%, respectively. For all age groups, the average intimal thickness was greater in men than women, although the prevalence of atherosclerosis was similar (52% in men and 51.7% in women).

Conclusions
—This study demonstrates that coronary atherosclerosis begins at a young age and that lesions are present in 1 of 6 teenagers. These findings suggest the need for intensive efforts at coronary disease prevention in young adults.
Homocysteine Induces Expression and Secretion of Monocyte Chemoattractant Protein-1 and Interleukin-8 in Human Aortic Endothelial Cells
Authors: Poddar Ranjana , Sivasubramanian Natarajan , DiBello Patricia M. , Robinson Killian , Jacobsen Donald W.
Published: June 2012

Background
—Proinflammatory cytokines play key roles in atherogenesis and disease progression. Because hyperhomocysteinemia is an independent risk factor for cardiovascular disease, we hypothesized that homocysteine could be atherogenic by altering the expression of specific cytokines in vascular endothelial cells.

Methods and Results
—Northern blot and RNase protection assays showed that
dl
-homocysteine induced mRNA expression of the proinflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in cultured human aortic endothelial cells (HAECs). Homocysteine had no effect on expression of other cytokines, namely tumor necrosis factor-α, granulocyte-macrophage colony–stimulating factor, interleukin-1β, and transforming growth factor-β. MCP-1 mRNA expression increased 1 hour after homocysteine treatment, reached a maximum within 2 to 4 hours, and declined to basal levels over the next 24 hours. Induction of mRNA expression for both chemokines was observed with as little as 10 μmol/L
dl
-homocysteine, and maximal expression was achieved with 50 μmol/L
dl
-homocysteine. Homocysteine also triggered the release of MCP-1 and IL-8 protein from HAECs into the culture medium. The induction was specific for homocysteine, because equimolar concentrations of
l
-homocystine,
l
-cysteine, and
l
-methionine had no effect on mRNA levels and protein release. Furthermore,
l
-homocysteine induced chemokine expression, but
d
-homocysteine did not, thus demonstrating enantiomeric specificity. The culture medium from homocysteine-treated HAECs promoted chemotaxis in human peripheral blood monocytes and U937 cells. Anti–human recombinant MCP-1 antibody blocked the migration.

Conclusions
—Pathophysiological levels of
l
-homocysteine alter endothelial cell function by upregulating MCP-1 and IL-8 expression and secretion. This suggests that
l
-homocysteine may contribute to the initiation and progression of vascular disease by promoting leukocyte recruitment.
Cardiac-Specific LIM Protein FHL2 Modifies the Hypertrophic Response to β-Adrenergic Stimulation
Authors: Kong Yanfeng , Shelton John M. , Rothermel Beverly , Li Xiangqing , Richardson James A. , Bassel-Duby Rhonda , Williams R. Sanders
Published: June 2012

Background
—A deficiency of muscle LIM protein results in dilated cardiomyopathy, but the function of other LIM proteins in the heart has not been assessed previously. We have characterized the expression and function of FHL2, a heart-specific member of the LIM domain gene family.

Methods and Results
—Expression of FHL2 mRNA and protein was examined by Northern blot, in situ hybridization, and Western blot analyses of fetal and adult mice. FHL2 transcripts are present at embryonic day (E) 7.5 within the cardiac crescent in a pattern that resembles that of Nkx2.5 mRNA. During later stages of cardiac development and in adult animals, FHL2 expression is localized to the myocardium and absent from endocardium, cardiac cushion, outflow tract, or coronary vasculature. The gene encoding FHL2 was disrupted by homologous recombination, and knockout mice devoid of FHL2 were found to undergo normal cardiovascular development. In the absence of FHL2, however, cardiac hypertrophy resulting from chronic infusion of isoproterenol is exaggerated (59% versus 20% increase in heart weight/body weight in FHL null versus wild-type mice;
P
<0.01).

Conclusions
—FHL2 is an early marker of cardiogenic cells and a cardiac-specific LIM protein in the adult. FHL2 is not required for normal cardiac development but modifies the hypertrophic response to β-adrenergic stimulation.
Select Flavonoids and Whole Juice From Purple Grapes Inhibit Platelet Function and Enhance Nitric Oxide Release
Authors: Freedman Jane E. , Parker Crawford , Li Liqing , Perlman Jacob A. , Frei Balz , Ivanov Vadim , Deak Leslie R. , Iafrati Mark D. , Folts John D.
Published: June 2012

Background
—Moderate red wine consumption is inversely associated with coronary ischemia, and both red wine and purple grape juice (PGJ) contain flavonoids with antioxidant and antiplatelet properties believed to be protective against cardiovascular events. Acute cardiac events are also associated with decreased platelet-derived nitric oxide (NO) release. In this study, the effects of PGJ and PGJ-derived flavonoids on platelet function and platelet NO production were determined.

Methods and Results
—Incubation of platelets with dilute PGJ led to inhibition of aggregation, enhanced release of platelet-derived NO, and decreased superoxide production. To confirm the in vivo relevance of these findings, 20 healthy subjects consumed 7 mL · kg
−1
· d
−1
of PGJ for 14 days. Platelet aggregation was inhibited after PGJ supplementation, platelet-derived NO production increased from 3.5±1.2 to 6.0±1.5 pmol/10
8
platelets, and superoxide release decreased from 29.5±5.0 to 19.2±3.1 arbitrary units (
P
<0.007 and
P
<0.05, respectively). α-Tocopherol levels increased significantly after PGJ consumption (from 15.6±0.7 to 17.6±0.9 μmol/L;
P
<0.009), and the plasma protein–independent antioxidant activity increased by 50.0% (
P
<0.05). Last, incubation of platelets with select flavonoid fractions isolated from PGJ consistently attenuated superoxide levels but had variable effects on whole-blood aggregation, platelet aggregation, and NO release.

Conclusions
—Both in vitro incubation and oral supplementation with PGJ decrease platelet aggregation, increase platelet-derived NO release, and decrease superoxide production. These findings may be a result of antioxidant-sparing and/or direct effects of select flavonoids found in PGJ. The suppression of platelet-mediated thrombosis represents a potential mechanism for the beneficial effects of purple grape products, independent of alcohol consumption, in cardiovascular disease.
Triggering Myocardial Infarction by Marijuana
Authors: Mittleman Murray A. , Lewis Rebecca A. , Maclure Malcolm , Sherwood Jane B. , Muller James E.
Published: June 2012

Background
—Marijuana use in the age group prone to coronary artery disease is higher than it was in the past. Smoking marijuana is known to have hemodynamic consequences, including a dose-dependent increase in heart rate, supine hypertension, and postural hypotension; however, whether it can trigger the onset of myocardial infarction is unknown.

Methods and Results
—In the Determinants of Myocardial Infarction Onset Study, we interviewed 3882 patients (1258 women) with acute myocardial infarction an average of 4 days after infarction onset. We used the case-crossover study design to compare the reported use of marijuana in the hour preceding symptoms of myocardial infarction onset to its expected frequency using self-matched control data. Of the 3882 patients, 124 (3.2%) reported smoking marijuana in the prior year, 37 within 24 hours and 9 within 1 hour of myocardial infarction symptoms. Compared with nonusers, marijuana users were more likely to be men (94% versus 67%,
P
<0.001), current cigarette smokers (68% versus 32%,
P
<0.001), and obese (43% versus 32%,
P
=0.008). They were less likely to have a history of angina (12% versus 25%,
P
<0.001) or hypertension (30% versus 44%,
P
=0.002). The risk of myocardial infarction onset was elevated 4.8 times over baseline (95% confidence interval, 2.4 to 9.5) in the 60 minutes after marijuana use. The elevated risk rapidly decreased thereafter.

Conclusions
—Smoking marijuana is a rare trigger of acute myocardial infarction. Understanding the mechanism through which marijuana causes infarction may provide insight into the triggering of myocardial infarction by this and other, more common stressors.
Chlamydia pneumoniae
Infection Does Not Induce or Modify Atherosclerosis in Mice
Authors: Caligiuri Giuseppina , Rottenberg Martin , Nicoletti Antonino , Wigzell Hans , Hansson Göran K.
Published: June 2012

Background
—Seroepidemiological studies have linked
Chlamydia pneumoniae
(CP) to coronary heart disease, and recent experimental studies suggest that it may accelerate or even induce atherosclerosis. We therefore evaluated the effect of CP infection on atherosclerosis in atherosclerosis-prone apolipoprotein E–knockout (apoE-KO) and wild-type C57BL/6J mice.

Methods and Results
—Six- to 8-week-old female mice were infected intranasally with live CP and then fed a standard chow diet for 22 weeks. A subgroup of mice was reinfected 18 weeks after primary infection. Polymerase chain reaction analysis of lung tissue confirmed successful infection with CP, and ELISA assays demonstrated development of a humoral immune response. Despite this, no statistically significant differences in aortic atherosclerotic lesions were found between CP-infected and control apoE-KO mice. Furthermore, CP infection did not induce atherosclerosis in C57BL/6J mice.

Conclusions
—CP does not induce atherosclerosis in wild-type mice and does not accelerate atherosclerosis in chow-fed apoE-KO mice. Further studies will be necessary to clarify the explanation for the seroepidemiological association between CP and coronary heart disease in humans.
Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome
Authors: Yan Gan-Xin , Wu Ying , Liu Tengxian , Wang Jixin , Marinchak Roger A. , Kowey Peter R.
Published: June 2012

Background
—This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by
dl
-sotalol and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated.

Methods and Results
—Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations.
dl
-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 μmol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 μmol/L but shortened them at 30 μmol/L. Unlike
dl
-sotalol, azimilide (>3 μmol/L) increased epicardial APD markedly, causing a diminished TDR. Although both
dl
-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by
dl
-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 μmol/L) increased APD more than
dl
-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR.

Conclusions
—This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.
Speed of Intracranial Clot Lysis With Intravenous Tissue Plasminogen Activator Therapy
Authors: Alexandrov Andrei V. , Burgin W. Scott , Demchuk Andrew M. , El-Mitwalli Ashraf , Grotta James C.
Published: June 2012

Background
—Arterial recanalization precedes clinical improvement or may lead to hemorrhage or reperfusion injury. Speed of clot lysis was not previously measured in human stroke.

Methods and Results
—Transcranial Doppler (TCD) and the National Institutes of Health Stroke Scale (NIHSS) were used to monitor consecutive patients receiving intravenous tissue plasminogen activator (tPA), before tPA bolus and at 24 hours. Patients with complete or partial recanalization of the middle cerebral or basilar artery on TCD were studied. Recanalization was classified a priori as sudden (abrupt appearance of a normal or stenotic low-resistance signal), stepwise (flow improvement over 1 to 29 minutes), or slow (≥30 minutes). Recanalization was documented in 43 tPA-treated patients (age 68±17 years; NIHSS score 16.8±6, median 15 points). tPA bolus was given at a mean of 135±61 minutes after symptom onset. Recanalization began at a median of 17 minutes and was completed at 35 minutes after tPA bolus, with mean duration of recanalization of 23±16 minutes. Recanalization was sudden in 5, stepwise in 23, and slow in 15 patients. Faster recanalization predicted better short-term improvement (
P
=0.03). At 24 hours, 80%, 30%, and 13% of patients in these respective recanalization groups had NIHSS scores of 0 to 3. Symptomatic hemorrhage occurred in only 1 patient, who had stepwise recanalization 5.5 hours after stroke onset. Slow or partial recanalization with dampened flow signal was found in 53% of patients with total NIHSS scores >10 points at 24 hours (
P
=0.01). Complete recanalization (n=25) occurred faster (median 10 minutes) than partial recanalization (n=18; median 30 minutes;
P
=0.0001).

Conclusions
—Rapid arterial recanalization is associated with better short-term improvement, mostly likely because of faster and more complete clot breakup with low resistance of the distal circulatory bed. Slow (≥30 minutes) flow improvement and dampened flow signal are less favorable prognostic signs. These findings may be evaluated to assist with selection of patients for additional pharmacological or interventional treatment.
Fractional Flow Reserve to Determine the Appropriateness of Angioplasty in Moderate Coronary Stenosis
Authors: Bech G. Jan Willem , De Bruyne Bernard , Pijls Nico H.J. , de Muinck Ebo D. , Hoorntje Jan C.A. , Escaned Javier , Stella Pieter R. , Boersma Eric , Bartunek Jozef , Koolen Jacques J. , Wijns William
Published: June 2012

Background
—PTCA of a coronary stenosis without documented ischemia at noninvasive stress testing is often performed, but its benefit is unproven. Coronary pressure–derived fractional flow reserve (FFR) is an invasive index of stenosis severity that is a reliable substitute for noninvasive stress testing. A value of 0.75 identifies stenoses with hemodynamic significance.

Methods and Results
—In 325 patients for whom PTCA was planned and who did not have documented ischemia, FFR of the stenosis was measured. If FFR was >0.75, patients were randomly assigned to deferral (deferral group; n=91) or performance (performance group; n=90) of PTCA. If FFR was <0.75, PTCA was performed as planned (reference group; n=144). Clinical follow-up was obtained at 1, 3, 6, 12, and 24 months. Event-free survival was similar between the deferral and performance groups (92% versus 89% at 12 months and 89% versus 83% at 24 months) but was significantly lower in the reference group (80% at 12 months and 78% at 24 months). In addition, the percentage of patients free from angina was similar between the deferral and performance groups (49% versus 50% at 12 months and 70% versus 51% at 24 months) but was significantly higher in the reference group (67% at 12 and 80% at 24 months).

Conclusions
—In patients with a coronary stenosis without evidence of ischemia, coronary pressure–derived FFR identifies those who will benefit from PTCA.
Functional Blockade of Platelet-Derived Growth Factor Receptor-β but Not of Receptor-α Prevents Vascular Smooth Muscle Cell Accumulation in Fibrous Cap Lesions in Apolipoprotein E–Deficient Mice
Authors: Sano Hideto , Sudo Tetsuo , Yokode Masayuki , Murayama Toshinori , Kataoka Hiroshi , Takakura Nobuyuki , Nishikawa Satomi , Nishikawa Shin-Ichi , Kita Toru
Published: June 2012

Background
—The vascular smooth muscle cell (VSMC) is the central cell component involved in the fibroproliferative response in atherogenesis. As the lesion advances, VSMCs migrate from the media into the subendothelial space, thereby forming fibrous plaque lesions. Platelet-derived growth factor (PDGF) has been known to be a potent chemoattractant and mitogen for SMCs, but the pathophysiological role of the 2 PDGF receptors, receptor-α (PDGFR-α) and receptor-β (PDGFR-β) in atherogenesis is poorly understood. To clarify this problem, we prepared antagonistic rat monoclonal antibodies, APA5 and APB5, against murine PDGFR-α and PDGFR-β, respectively.

Methods and Results
—Apolipoprotein E–deficient mice were fed a high-fat diet containing 0.3% cholesterol from 6 weeks of age and subjected to injection with 1 mg/d IP of either antibody from 12 to 18 weeks every other day. In the mice injected with APB5, the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67% and 80%, respectively, compared with the control mice injected with irrelevant rat IgG. In contrast, the mice that received APA5 showed only minimal reduction of lesion size, and a large number of VSMCs were observed in the intima. In the intima of advanced lesions, APB5 immunolabeled VSMCs, whereas APA5 could detect VSMCs mainly in the media.

Conclusions
—These results indicate that PDGFR-β plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through PDGFR-β could affect atherogenesis in mice.
Ablation of Serotonin 5-HT
2B
Receptors in Mice Leads to Abnormal Cardiac Structure and Function
Authors: Nebigil Canan G. , Hickel Pierre , Messaddeq Nadia , Vonesch Jean-Luc , Douchet Marie P. , Monassier Laurent , György Katalin , Matz Rachel , Andriantsitohaina Ramaroson , Manivet Philippe , Launay Jean-Marie , Maroteaux Luc
Published: June 2012

Background
—Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Because little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT
1A
, 5-HT
1B
, or 5-HT
2C
) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT
2B
receptor–mutant mice to assess the putative role of serotonin in heart structure and function.

Methods and Results
—We have generated G
q
-coupled 5-HT
2B
receptor–null mice by homologous recombination. Surviving 5-HT
2B
receptor–mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT
2B
receptor–mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Z-stripe enlargement and N-cadherin downregulation. Echocardiography and ECG both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT
2B
receptor–mutant mice.

Conclusions
—Mutation of 5-HT
2B
receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT
2B
receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT
2B
receptor, regulates cardiac structure and function.
Genetic and Environmental Contributions to Platelet Aggregation
Authors: O’Donnell Christopher J. , Larson Martin G. , Feng DaLi , Sutherland Patrice A. , Lindpaintner Klaus , Myers Richard H. , D’Agostino Ralph A. , Levy Daniel , Tofler Geoffrey H.
Published: June 2012

Background
—Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized.

Methods and Results
—We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (
P
=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were −0.01, 0.05, and −0.02, respectively (all
P
>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein
IIIa Pl

A2

polymorphism and the fibrinogen
Hind III
β-148 polymorphism contributed <1% to the overall variance.

Conclusions
—In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.
Aspirin, Warfarin, or the Combination for Secondary Prevention of Coronary Events in Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Surgery
Authors: Huynh Thao , Théroux Pierre , Bogaty Peter , Nasmith James , Solymoss Susan
Published: June 2012

Background
—Patients with a non–ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy. This trial investigated the potential benefit of secondary prevention with warfarin.

Methods and Results
—In a double-blind randomized trial, 135 patients with unstable angina or non–ST-segment elevation myocardial infarction, with prior CABG, and who were poor candidates for a revascularization procedure received therapy with aspirin and placebo+warfarin, warfarin and placebo+aspirin, or aspirin and warfarin for 12 months. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5. The primary end point (death or myocardial infarction or unstable angina requiring hospitalization 1 year after randomization) occurred in 14.6% of the patients in the warfarin-alone group, in 11.5% of patients in the aspirin-alone group, and in 11.3% of patients randomized to the combination therapy (
P
=0.76). Subgroup analyses by risk features provided no indications that warfarin alone or in combination with aspirin could be of benefit over aspirin alone. Bleeding was more frequent in the 2 groups of patients administered warfarin.

Conclusions
—Moderate-intensity oral anticoagulation alone or combined with low-dose aspirin does not appear to be superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non–ST-elevation acute coronary syndromes and previous CABG.
Angiotensin-Converting Enzyme Inhibition Attenuates Hypofibrinolysis and Reduces Cardiac Perivascular Fibrosis in Genetically Obese Diabetic Mice
Authors: Zaman A. K. M. Tarikuz , Fujii Satoshi , Sawa Hirotumi , Goto Daisuke , Ishimori Naoki , Watano Keiko , Kaneko Takeaki , Furumoto Tomoo , Sugawara Taeko , Sakuma Ichiro , Kitabatake Akira , Sobel Burton E.
Published: June 2012

Background
—Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.

Methods and Results
—To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription–polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.

Conclusions
—Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.
Pravastatin and the Development of Diabetes Mellitus
Authors: Freeman Dilys J. , Norrie John , Sattar Naveed , Neely R. Dermot G. , Cobbe Stuart M. , Ford Ian , Isles Christopher , Lorimer A. Ross , Macfarlane Peter W. , McKillop James H. , Packard Christopher J. , Shepherd James , Gaw Allan
Published: June 2012

Background
—We examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study.

Methods and Results
—Our definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of ≥7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of ≥7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort.

Conclusions
—We concluded that the assignment to pravastatin therapy resulted in a 30% reduction (
P
=0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.
Intravenous Immunoglobulin in Acute Rheumatic Fever
Authors: Voss L. M. , Wilson N. J. , Neutze J. M. , Whitlock R. M. L. , Ameratunga R. V. , Cairns L. M. , Lennon D. R.
Published: June 2012

Background
—Acute rheumatic fever (ARF) remains the leading cause of acquired heart disease in children worldwide. No therapeutic agent has been shown to alter the clinical outcome of the acute illness. Immunological mechanisms appear to be involved in the pathogenesis of ARF. Intravenous immunoglobulin (IVIG), a proven immunomodulator, may benefit cardiac conditions of an autoimmune nature. We investigated whether IVIG modified the natural history of ARF by reducing the extent and severity of carditis.

Methods and Results
—This prospective, double-blind, randomized, placebo-controlled trial evaluated IVIG in patients with a first episode of rheumatic fever, stratifying patients by the presence and severity of carditis before randomization. Patients were randomly allocated to receive 1 g/kg IVIG on days 1 and 2 and 0.4 g/kg on days 14 and 28, or they received a placebo infusion. Clinical, laboratory, and echocardiographic evaluation was performed at 0, 2, 4, 6, 26, and 52 weeks. Fifty-nine patients were treated, of whom 39 had carditis (including 4 subclinical) and/or migratory polyarthritis (n=39). There was no difference between groups in the rate of normalization of the erythrocyte sedimentation rate or acute-phase proteins at the 6-week follow-up. On echocardiography, 59% in the IVIG group and 69% in the placebo group had carditis at baseline. There was no significant difference in the cardiac outcome, including the proportion of valves involved, or in the severity of valvar regurgitation at 1 year. At 1 year, 41% of the IVIG and 50% of the placebo group had carditis.

Conclusions
—IVIG did not alter the natural history of ARF, with no detectable difference in the clinical, laboratory, or echocardiographic parameters of the disease process during the subsequent 12 months.
Sino-MONICA Project
Authors: Wu Zhaosu , Yao Chonghua , Zhao Dong , Wu Guixian , Wang Wei , Liu Jing , Zeng Zhechun , Wu Yingkai
Published: June 2012

Background
—The Sino-MONICA project is a 7-year study monitoring trends and determinants of cardiovascular disease (CVD) in geographically defined populations in different parts of China.

Methods and Results
—The study is a community-based prospective disease surveillance that uses the methodology and criteria of the World Health Organization’s Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) project, with slight modifications for local use. After a pilot study of 2 years (1985 through 1986), data collection started formally on January 1, 1987, and ended on December 31, 1993. The main results were as follows. By international standards, both the incidence and mortality rate of coronary heart disease in Chinese populations were low. The highest incidence was 108.7 of 100 000 (1987 to 1989), and the lowest was 3.3 of 100 000 for men 35 to 64 years of age, a 33-fold difference. Both the incidence and mortality rate of cerebrovascular disease were high. The highest incidence was 553.3 of 100 000 (1987 to 1989), and the lowest was 33.0 of 100 000 for men 35 to 64 years of age, a 17-fold difference. There were significant geographic variations in both CVD incidence and mortality rate, with higher rates in the north and lower rates in the south. During 1987 to 1993, increasing trends were found in CVD rates in some populations, whereas decreasing trends were found in others. The trends were not significant statistically in most cases.

Conclusions
—Monitoring CVD with international standardized methods in China is feasible and urgently needed in view of the rapid socioeconomic development and transition of disease patterns taking place in China. The results are of significance in combating CVD both at home and abroad.
Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia
Authors: Laitinen Päivi J. , Brown Kevin M. , Piippo Kirsi , Swan Heikki , Devaney Joe M. , Brahmbhatt Bhoomi , Donarum Elizabeth A. , Marino Michael , Tiso Natascia , Viitasalo Matti , Toivonen Lauri , Stephan Dietrich A. , Kontula Kimmo
Published: June 2012

Background
—Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of ≈30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]).

Methods and Results
—In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders.

Conclusions
—Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
Interleukin-3 Stimulates Migration and Proliferation of Vascular Smooth Muscle Cells
Authors: Brizzi Maria Felice , Formato Luisa , Dentelli Patrizia , Rosso Arturo , Pavan Marzia , Garbarino Giovanni , Pegoraro Marco , Camussi Giovanni , Pegoraro Luigi
Published: June 2012

Background
—Cytokines released by activated T lymphocytes are key regulators of chronic inflammatory response, including atherosclerosis. The aim of this study was to investigate the presence of interleukin-3 (IL-3) in lymphocytes infiltrating the atherosclerotic plaque and the effect of this cytokine on primary vascular smooth muscle cells (SMCs).

Methods and Results
—Twenty atherosclerotic carotid arterial specimens and 5 early atherosclerotic lesions from the internal carotid were manually minced to fragments, and T lymphocytes infiltrating the atherosclerotic plaque were isolated on solid-phase anti-CD3 polystyrene plates. Southern blot analysis demonstrated that in all samples, lymphocytes expressed IL-3 and IL-2 receptor α-chain transcripts, indicating that in this context, the activated T lymphocytes may release IL-3. We further analyzed the expression of the IL-3 receptor and the biological effects exerted by the ligand on vascular SMCs. β-IL-3–transducing subunit was detected both on cultured SMCs and on endothelial cells and SMCs within atheroma. The analysis of the IL-3–induced biological effects demonstrated that it was able to trigger both mitogenic and motogenic signals. Moreover, we demonstrated that the addition of PD98059, a known inhibitor of the MAP–extracellular signaling-regulated/MAP kinase pathway, completely inhibited IL-3–mediated MAP kinase activation and IL-3–induced migration and proliferation. Finally, IL-3 was found to stimulate vascular endothelial growth factor (VEGF) gene transcription.

Conclusions
—IL-3, expressed by activated T lymphocytes infiltrating early and advanced atherosclerotic plaques, may sustain the atherosclerotic process either directly, by activating SMC migration and proliferation, or indirectly, via VEGF production.
Effects of Early Angiotensin-Converting Enzyme Inhibition on Cardiac Gene Expression After Acute Myocardial Infarction
Authors: Jin Hongkui , Yang Renhui , Awad Tarif A. , Wang Fay , Li Wei , Williams Simon-Peter , Ogasawara Annie , Shimada Brian , Williams P. Mickey , de Feo Gianfranco , Paoni Nicholas F.
Published: June 2012

Background
—ACE inhibition after myocardial infarction (MI) has been shown to have beneficial effects on cardiac anatomy and function. The purpose of this study was to examine the effects of ACE inhibition on cardiac gene expression after MI.

Methods and Results
—Rats were randomized to receive captopril or no treatment 1 day after MI. Eight weeks later, cardiac function and hemodynamics were measured by use of indwelling catheters and perivascular flow probes. Myocardial gene expression was assessed with DNA microarrays and real-time reverse transcription–polymerase chain reaction. The ratios of heart and left ventricular weights to body weight were significantly increased by MI and normalized by captopril. Cardiac index and stroke volume index were lower in the untreated MI group than in sham controls but were normal in the MI+captopril group. Thirty-seven genes were found to be differentially expressed between the untreated MI group and sham controls; 31 were induced and 6 repressed. Captopril partially or completely inhibited changes in 10 of the genes. The 37 genes clustered into 11 functional groups, and 6 had ≥1 genes whose expression was modified by ACE inhibition.

Conclusions
—ACE inhibition after MI inhibits cardiac hypertrophy, preserves cardiac function, and attenuates changes in myocardial gene expression. Gene expression profiling reveals, however, that some elements of the pathophysiology may be unaffected by the treatment and be targets for new therapies.
Cardioselective Infection With Coxsackievirus B3 Requires Intact Type I Interferon Signaling
Authors: Wessely Rainer , Klingel Karin , Knowlton Kirk U. , Kandolf Reinhard
Published: June 2012

Background
—Interferons (IFNs) play an important role in antiviral defense and have therapeutic potential in coxsackievirus heart disease. However, little is known about the relative contributions of type I and type II IFN signaling in coxsackievirus B3 (CVB3) infection or their role in the cardioselective nature of CVB3 infection.

Methods and Results
—Wild-type mice and mice deficient for either the type I or the type II IFN receptor (IFNR) were infected with CVB3. Infection of the type I IFNR–deficient mice with >10
3
plaque-forming units (pfu) of CVB3 resulted in 100% mortality within 2 to 4 days after infection. Death was rare in wild-type and type II IFNR–deficient mice after inoculation with as much as 10
8
pfu of CVB3. Surprisingly, the early mortality in the type I IFNR–deficient mice was not accompanied by higher virus titers in the heart. Unexpectedly, a dramatic increase of viral RNA in the liver was found to correlate with early mortality in type I IFNR–deficient mice.

Conclusions
—Type I but not type II IFN signaling is essential for the prevention of early death due to CVB3 infection. Interestingly, neither type I or type II IFN signaling has a dramatic effect on early viral replication in the heart. However, lethal viral replication in the liver is controlled by type I IFNs. These results demonstrate that the IFN system is capable of modulating both viral pathogenicity and tissue tropism.
Angiotensin II Blockade Reverses Myocardial Fibrosis in a Transgenic Mouse Model of Human Hypertrophic Cardiomyopathy
Authors: Lim Do-Sun , Lutucuta Silvia , Bachireddy Pavan , Youker Keith , Evans Alida , Entman Mark , Roberts Robert , Marian Ali J.
Published: June 2012

Background
—Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. We propose that hypertrophy and fibrosis are secondary to the activation of trophic and mitotic factors and, thus, potentially reversible. We determined whether the blockade of angiotensin II, a known cardiotrophic factor, could reverse or attenuate interstitial fibrosis in a transgenic mouse model of human HCM.

Methods and Results
—We randomized 24 adult cardiac troponin T (cTnT-Q
92
) mice, which exhibit myocyte disarray and interstitial fibrosis, to treatment with losartan or placebo and included 12 nontransgenic mice as controls. The mean dose of losartan and the mean duration of therapy were 14.2±5.3 mg · kg
–1
· d
–1
and 42±9.6 days, respectively. Mean age, number of males and females, and heart/body weight ratio were similar in the groups. Collagen volume fraction and extent of myocyte disarray were increased in the cTnT-Q
92
mice (placebo group) compared with nontransgenic mice (9.9±6.8% versus 4.5±2.2%,
P
=0.01, and 27.6±10.6% versus 3.9±2.3%,
P
<0.001, respectively). Treatment with losartan reduced collagen volume fraction by 49% to 4.9±2.9%. The expression of collagen 1α (I) and transforming growth factor-β1, a mediator of angiotensin II profibrotic effect, were also reduced by 50%. Losartan had no effect on myocyte disarray.

Conclusions
—Treatment with losartan reversed interstitial fibrosis and the expression of collagen 1α (I) and transforming growth factor-β1 in the hearts of cTnT-Q
92
mice. These findings suggest that losartan has the potential to reverse or attenuate interstitial fibrosis, a major predictor of sudden cardiac death, in human patients with HCM.