bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Utility of Doppler Echocardiography and Tissue Doppler Imaging in the Estimation of Left Ventricular Filling Pressures
Authors: Ommen S. R. , Nishimura R. A. , Appleton C. P. , Miller F. A. , Oh J. K. , Redfield M. M. , Tajik A. J.
Published: June 2012

Background
—Noninvasive assessment of diastolic filling by Doppler echocardiography provides important information about left ventricular (LV) status in selected subsets of patients. This study was designed to assess whether mitral annular velocities as assessed by tissue Doppler imaging are associated with invasive measures of diastolic LV performance and whether additional information is gained over traditional Doppler variables.

Methods and Results
—One hundred consecutive patients referred for cardiac catheterization underwent simultaneous Doppler interrogation. Invasive measurements of LV pressures were obtained with micromanometer-tipped catheters, and the mean LV diastolic pressure (M-LVDP) was used as a surrogate for mean left atrial pressure. Doppler signals from the mitral inflow, pulmonary venous inflow, and TDI of the mitral annulus were obtained. Isolated parameters of transmitral flow correlated with M-LVDP only when ejection fraction <50%. The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/E′) showed a better correlation with M-LVDP than did other Doppler variables for all levels of systolic function. E/E′ <8 accurately predicted normal M-LVDP, and E/E′ >15 identified increased M-LVDP. Wide variability was present in those with E/E′ of 8 to 15. A subset of those patients with E/E′ 8 to 15 could be further defined by use of other Doppler data.

Conclusions
—The combination of tissue Doppler imaging of the mitral annulus and mitral inflow velocity curves provides better estimates of LV filling pressures than other methods (pulmonary vein, preload reduction). However, accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data.
Differential Effects of Estrogen and Progesterone on AT
1
Receptor Gene Expression in Vascular Smooth Muscle Cells
Authors: Nickenig Georg , Strehlow Kerstin , Wassmann Sven , Bäumer Anselm T. , Albory Katja , Sauer Heinrich , Böhm Michael
Published: June 2012

Background
—The beneficial vasoprotective effects of a postmenopausal estrogen replacement therapy may be prevented by a concomitant administration of progestins. To investigate the differential effects of estrogens and progesterone, we examined their influence on AT
1
receptor gene expression in vascular smooth muscle cells (VSMCs).

Methods and Results
—17β-Estradiol caused downregulation of AT
1
receptor mRNA expression to 46±14%, whereas progesterone led to a significant upregulation to 201±29%, as assessed by Northern analysis. Western blots revealed that estrogen induced a downregulation and progesterone an upregulation of the AT
1
receptor protein. Estrogen-induced decrease of AT
1
receptor expression was mediated through activation of estrogen receptors. Nuclear run-on assays revealed that 17β-estradiol did not alter AT
1
receptor mRNA transcription rate, whereas progesterone caused an enhanced AT
1
receptor mRNA transcription rate. 17β-Estradiol decreased the AT
1
receptor mRNA half-life from 5 to 2 hours, whereas progesterone induced a stabilization of AT
1
receptor mRNA to a half-life of 10 hours. Preincubation of VSMCs with PD98059, SB203580, herbimycin, wortmannin, or
N
ω
-nitro-
l
-arginine suggested that 17β-estradiol caused AT
1
receptor downregulation through nitric oxide–dependent pathways. Progesterone caused AT
1
receptor overexpression via PI
3
-kinase activation. Angiotensin II–induced release of reactive oxygen species was inhibited by estrogens. Progesterone itself enhanced the production of reactive oxygen species.

Conclusions
—Because AT
1
receptor regulation plays a pivotal role in the pathogenesis of hypertension and atherosclerosis, the differential effects of estrogen and progesterone on the expression of this gene may in part explain the potentially counteracting effects of these reproductive hormones on the incidence of postmenopausal cardiovascular diseases.
Spontaneously Occurring Arrhythmogenic Right Ventricular Cardiomyopathy in the Domestic Cat
Authors: Fox Philip R. , Maron Barry J. , Basso Cristina , Liu Si-Kwang , Thiene Gaetano
Published: June 2012

Background
—Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disease of incompletely resolved pathogenesis and is a largely unappreciated cause of sudden death in the young.

Methods and Results
—Clinical features of 12 domestic cats with ARVC (7 male; 1 to 20 years old, mean 7.3±5.2 years) were right-sided congestive heart failure (n=8), supraventricular tachyarrhythmias (n=5), ventricular tachycardia (n=3), polymorphic ventricular arrhythmias (n=6), and right bundle-branch block (n=5). ARVC was suspected in all 8 cats examined with echocardiography by marked enlargement of the right ventricle (RV) and right atrium and tricuspid regurgitation. Eight died of cardiovascular disease and 4 died of noncardiac conditions. At autopsy, hearts of ARVC cats were characterized grossly by moderate-to-severe RV cavity enlargement and wall thinning (n=12) and apical aneurysm formation (n=6). Histology demonstrated pronounced RV lesions in all 12 ARVC cats, including marked myocardial injury (myocyte death and atrophy) and repair (fibrous and/or fatty replacement). Injury and repair were also evident in the left ventricle (LV) in 10 cats, and 2 had involvement of both atria. Myocarditis was present in 10 of the 12 ARVC cats. Apoptosis was detected in 9 ARVC cats (mean apoptotic index, 28±23% RV, 21±19% LV, and 17±15% ventricular septum) but not in controls.

Conclusions
—In the common domestic cat, we identified a clinically relevant cardiomyopathy that closely mimics ARVC in humans. This unique feline model of human disease will be relevant to defining pathogenesis and investigating mechanisms responsible for disease progression in ARVC.
Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina
Authors: English Katherine M. , Steeds Richard P. , Jones T. Hugh , Diver Michael J. , Channer Kevin S.
Published: June 2012

Background
—Experimental studies suggest that androgens induce coronary vasodilatation. We performed this pilot project to examine the clinical effects of long-term low-dose androgens in men with angina.

Methods and Results
—Forty-six men with stable angina completed a 2-week, single-blind placebo run-in, followed by double-blind randomization to 5 mg testosterone daily by transdermal patch or matching placebo for 12 weeks, in addition to their current medication. Time to 1-mm ST-segment depression on treadmill exercise testing and hormone levels were measured and quality of life was assessed by SF-36 at baseline and after 4 and 12 weeks of treatment. Active treatment resulted in a 2-fold increase in androgen levels and an increase in time to 1-mm ST-segment depression from (mean±SEM) 309±27 seconds at baseline to 343±26 seconds after 4 weeks and to 361±22 seconds after 12 weeks. This change was statistically significant compared with that seen in the placebo group (from 266±25 seconds at baseline to 284±23 seconds after 4 weeks and to 292±24 seconds after 12 weeks;
P
=0.02 between the 2 groups by ANCOVA). The magnitude of the response was greater in those with lower baseline levels of bioavailable testosterone (
r
=−0.455,
P
<0.05). There were no significant changes in prostate specific antigen, hemoglobin, lipids, or coagulation profiles during the study. There were significant improvements in pain perception (
P
=0.026) and role limitation resulting from physical problems (
P
=0.024) in the testosterone-treated group.

Conclusions
—Low-dose supplemental testosterone treatment in men with chronic stable angina reduces exercise-induced myocardial ischemia.
Participation of Tyrosine Phosphorylation in Cytoskeletal Reorganization, α
IIb
β
3
Integrin Receptor Activation, and Aspirin-Insensitive Mechanisms of Thrombin-Stimulated Human Platelets
Authors: Santos M. Teresa , Moscardó Antonio , Vallés Juana , Martínez Marcial , Piñón Marta , Aznar Justo , Broekman M. Johan , Marcus Aaron J.
Published: June 2012

Background
—Fibrinogen binding to the active conformation of the α
IIb
β
3
integrin receptor (glycoprotein IIb/IIIa) and cytoskeletal reorganization are important events in platelet function. Tyrosine phosphorylation of platelet proteins plays an essential role in platelet signal transduction pathways. We studied the participation of tyrosine kinases on these aspects of platelet reactivity and their importance in cyclooxygenase (COX)-1–independent mechanisms in thrombin-stimulated human platelets.

Methods and Results
—Using washed platelets from normal donors and tyrphostin-A47 and aspirin as tyrosine kinase and COX-1 inhibitors, respectively, we found that tyrphostin-A47 downregulated (1) the thrombin-activated conformational change of α
IIb
β
3
, (2) actin polymerization and cytoskeletal reorganization, and (3) the quantity of tyrosine-phospho-rylated proteins associated with the reorganized cytoskeleton. The latter are important components of multimolecular signaling complexes. Concomitantly, platelet aggregation and secretion were significantly reduced. Aspirin did not affect receptor activation or tyrosine phosphorylation but did decrease the initial (30-second) burst of actin polymerization. Importantly, aspirin significantly amplified the inhibitory effect of tyrphostin-A47 on all aspects of platelet reactivity that we evaluated.

Conclusions
—Tyrosine protein phosphorylation is a regulatory control system of the inside-out mechanism of α
IIb
β
3
activation and cytoskeletal assembly in thrombin-stimulated human platelets. Inhibition of these aspects of platelet function with tyrphostin-A47 is amplified when platelets are treated with aspirin. Therefore, tyrosine phosphorylation is a major component of early signaling events and of COX-1–independent mechanisms of thrombin-induced platelet reactivity. The study results may indicate a novel target for therapeutic intervention.
Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats
Authors: Nagaya Noritoshi , Yokoyama Chieko , Kyotani Shingo , Shimonishi Manabu , Morishita Ryuichi , Uematsu Masaaki , Nishikimi Toshio , Nakanishi Norifumi , Ogihara Toshio , Yamagishi Masakazu , Miyatake Kunio , Kaneda Yasufumi , Tanabe Tadashi
Published: June 2012

Background
—Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.

Methods and Results
—The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan–liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene–transfected rats compared with controls [mean pulmonary arterial pressure, 31±1 versus 35±1 mm Hg (−12%); total pulmonary resistance, 0.087±0.01 versus 0.113±0.01 mm Hg · mL · min
−
1
· kg
−
1
(−23%), both
P
<0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF
1α
, a stable metabolite of prostacyclin, were significantly increased for ≥1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test,
P
<0.01).

Conclusions
—Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.
A New Role for P-Selectin in Shear-Induced Platelet Aggregation
Authors: Merten Michael , Chow Thomas , Hellums J. David , Thiagarajan Perumal
Published: June 2012

Background
—P-selectin, expressed on platelets on activation, mediates rolling of platelets on endothelial cells, but its role in shear-induced platelet aggregation is not known.

Methods and Results
—Platelets were exposed to either a single pulse (30 seconds) or 3 pulses (10 seconds) of high shear stress (150 to 200 dynes/cm
2
) each followed by low shear stress (10 dynes/cm
2
) for 4.5 minutes or 90 seconds, respectively, at 37°C to resemble more closely in vivo conditions such as those in stenotic arteries. Under these conditions, platelet aggregation was significantly increased compared with low or high shear stress alone. Monoclonal anti–P-selectin antibodies inhibited shear-induced platelet aggregation, especially when induced by the combination of high and low shear stress, by ≈70% and had an additive effect on the inhibition by abciximab (anti–glycoprotein (GP) IIb/IIIa antibody). However, anti–P-selectin antibody inhibited shear-induced platelet aggregation only at 37°C, not at 22°C, whereas abciximab inhibited shear-induced platelet aggregation at both 22°C and 37°C. This differential effect of anti–P-selectin antibody is explained by the finding that shear-induced P-selectin expression on platelets was observed mainly at 37°C.

Conclusions
—These results indicate that pulsatile shear stress, which resembles flow conditions in stenotic arteries, induces significantly more platelet aggregation at 37°C than monophasic shear stress. Under these conditions, we show a novel role for P-selectin in platelet aggregation distinct from that of GP IIb/IIIa, which may be of importance in the initiation of thrombosis associated with atherosclerotic lesions.
Novel, Bedside, Tissue Factor–Dependent Clotting Assay Permits Improved Assessment of Combination Antithrombotic and Antiplatelet Therapy
Authors: Holmes Michael B. , Schneider David J. , Hayes Michael G. , Sobel Burton E. , Mann Kenneth G.
Published: June 2012

Background
—Because optimal use of combinations of antiplatelet and antithrombotic drugs requires improved methods for assessment of therapeutic efficacy, we developed an assay designed to increase sensitivity that is based on initiation of clotting by tissue factor in minimally altered whole blood.

Methods and Results
—Blood samples were obtained from healthy subjects, and the contact pathway of coagulation was inhibited with corn trypsin inhibitor (a specific factor XIIa inhibitor without effect on other coagulation factors). Clotting was initiated with relipidated tissue factor and detected with a Hemochron ACT instrument. Results were reproducible with samples from 25 healthy volunteers (mean time to clot, 125±17 seconds). Blood was also exposed to pharmacological concentrations of antithrombotic and antiplatelet agents in vitro. Heparin (0.25 anti-IIa/Xa U/mL) prolonged the time to clot by 2.4-fold (172 seconds,
P
<0.05); hirudin (1.0 anti-IIa U/mL), by 3-fold (250 seconds
P
<0.05); and enoxaparin (0.6 anti-Xa U/mL), by 2 -fold (123 seconds,
P
<0.05). Additive effects of antiplatelet agents were readily detectable with both heparin and hirudin. Thus, addition of 3 μg/mL abciximab to 1.0 anti-IIa/Xa U/mL heparin and to 1.0 anti-IIa U/mL hirudin further prolonged the times to clot by 140 and 67 seconds, respectively (
P
<0.05 for each). Addition of abciximab to enoxaparin did not further prolong the time to clot (increment, 13 seconds;
P
=NS).

Conclusions
—The assay developed should facilitate improved dose selection, titration, and monitoring of combination antithrombotic and antiplatelet treatment regimens.
Independent Association of High Blood Pressure and Aortic Atherosclerosis
Authors: Agmon Yoram , Khandheria Bijoy K. , Meissner Irene , Schwartz Gary L. , Petterson Tanya M. , O’Fallon W. Michael , Gentile Federico , Whisnant Jack P. , Wiebers David O. , Seward James B.
Published: June 2012

Background
—Atherosclerosis of the thoracic aorta is associated with stroke. The association between hypertension, a major risk factor for stroke, and aortic atherosclerosis has not been determined in the general population.

Methods and Results
—Transesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged ≥45 years participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. Blood pressure was assessed by multiple office measurements and 24-hour ambulatory blood pressure monitoring. The association between blood pressure variables and aortic atherosclerosis was evaluated by multiple logistic regression, adjusting for other associated variables. Among subjects with atherosclerosis, blood pressure variables associated with complex aortic atherosclerosis (protruding plaques ≥4 mm thick, mobile debris, or ulceration) were determined. Age and smoking history were independently associated with aortic atherosclerosis of any degree (
P
≤0.001) and with complex atherosclerosis (
P
=0.002), whereas sex, diabetes mellitus, and body mass index were not. Multiple systolic and pulse pressure variables (office and ambulatory), but none of the diastolic blood pressure variables, were associated with atherosclerosis and complex atherosclerosis, adjusting for age and smoking. Among subjects with atherosclerosis, the odds of complex atherosclerosis increased as ambulatory out-of-bed systolic blood pressure increased (odds ratio 1.43 per 10 mm Hg increase, 95% CI 1.10 to 1.87) and with hypertension treatment, adjusting for age and smoking history.

Conclusions
—High blood pressure is independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, high blood pressure is associated with complex atherosclerosis.
Altered Stoichiometry of FKBP12.6 Versus Ryanodine Receptor as a Cause of Abnormal Ca
2+
Leak Through Ryanodine Receptor in Heart Failure
Authors: Yano Masafumi , Ono Kaoru , Ohkusa Tomoko , Suetsugu Masae , Kohno Masateru , Hisaoka Takayuki , Kobayashi Shigeki , Hisamatsu Yuji , Yamamoto Takeshi , Kohno Michihiro , Noguchi Naoya , Takasawa Shin , Okamoto Hiroshi , Matsuzaki Masunori
Published: June 2012

Background
—In the pathogenesis of cardiac dysfunction in heart failure, a decrease in the activity of the sarcoplasmic reticulum (SR) Ca
2+
-ATPase is believed to be a major determinant. Here, we report a novel mechanism of cardiac dysfunction revealed by assessing the functional interaction of FK506–binding protein (FKBP12.6) with the cardiac ryanodine receptor (RyR) in a canine model of pacing-induced heart failure.

Methods and Results
—SR vesicles were isolated from left ventricular muscles (normal and heart failure). The stoichiometry of FKBP12.6 per RyR was significantly decreased in failing SR, as assessed by the ratio of the B
max
values for [
3
H]dihydro-FK506 to those for [
3
H]ryanodine binding. In normal SR, the molar ratio was 3.6 (≈1 FKBP12.6 for each RyR monomer), whereas it was 1.6 in failing SR. In normal SR, FK506 caused a dose-dependent Ca
2+
leak that showed a close parallelism with the conformational change in RyR. In failing SR, a prominent Ca
2+
leak was observed even in the absence of FK506, and FK506 produced little or no further increase in Ca
2+
leak and only a slight conformational change in RyR. The level of protein expression of FKBP12.6 was indeed found to be significantly decreased in failing SR.

Conclusions
—An abnormal Ca
2+
leak through the RyR is present in heart failure, and this leak is presumably caused by a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. This abnormal Ca
2+
leak might possibly cause Ca
2+
overload and consequent diastolic dysfunction, as well as systolic dysfunction.
Contractile Adaptations Preserving Cardiac Output Predispose the Hypertrophied Canine Heart to Delayed Afterdepolarization–Dependent Ventricular Arrhythmias
Authors: de Groot S. H. Marieke , Schoenmakers Marieke , Molenschot Mirella M. C. , Leunissen Jet D. M. , Wellens Hein J. J. , Vos Marc A.
Published: June 2012

Background
—In dogs, chronic complete atrioventricular block (CAVB) results in structural (biventricular hypertrophy) and electrical (delayed repolarization) remodeling, which predisposes the heart to torsade de pointes arrhythmias. We assessed the contractile alterations in the CAVB dog and tested the hypothesis that these adaptations increase delayed afterdepolarization (DAD)–dependent triggered arrhythmias.

Methods and Results
—Steady-state and dynamic (fast pacing: 1 to 68 stimuli) left and right ventricular systolic and diastolic parameters were determined by positive and negative inotropic interventions at acute AVB and CAVB. Concomitantly, left and right ventricular endocardial monophasic action potentials were registered. In CAVB, all systolic contractile parameters were markedly increased, resulting in preserved cardiac output. The increase was most pronounced at low heart rates, altering the force-frequency response. At both acute AVB and CAVB, the degree of potentiation of cardiac function with pacing was dependent on the number of stimuli and showed a maximum at 8 to 13 stimuli. With CAVB, this potentiation curve was shifted upward, and it was only then that pacing resulted in DADs (in 8 of 10 dogs) and ectopic beats (EBs, in 6 of 10 dogs). The incidence of EBs in relation to the number of stimuli also had a maximum at 8 to 13 stimuli. Ouabain increased the incidence of DADs and EBs, whereas the negative inotropic interventions prevented them completely.

Conclusions
—The alterations responsible for improvement in systolic contractile function in CAVB dogs predispose the hypertrophied heart to DAD-dependent triggered arrhythmias during positive inotropic interventions.
Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells
Authors: Pasceri Vincenzo , Willerson James T. , Yeh Edward T. H.
Published: June 2012

Background
—The acute-phase reactant C-reactive protein (CRP) is an important risk factor for coronary heart disease. However, the possible effects of CRP on vascular cells are not known.

Methods and Results
—We tested the effects of CRP on expression of adhesion molecules in both human umbilical vein and coronary artery endothelial cells. Expression of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and E-selectin was assessed by flow cytometry. Incubation with recombinant human CRP (10 μg/mL) for 24 hours induced an ≈10-fold increase in expression of ICAM-1 and a significant expression of VCAM-1, whereas a 6-hour incubation induced significant E-selectin expression. Adhesion molecule induction was similar to that observed in endothelial cells activated with interleukin-1β. In coronary artery endothelial cells, induction of ICAM-1 and VCAM-1 was already present at 5 μg/mL and reached a maximum at 50 μg/mL, at which point a substantial increase in expression of E-selectin was also evident. The CRP effect was dependent on presence of human serum in the culture medium, because no effect was seen in cells cultured with serum-free medium. In contrast, interleukin-1β was able to induce adhesion molecule expression in the absence of human serum.

Conclusions
—CRP induces adhesion molecule expression in human endothelial cells in the presence of serum. These findings support the hypothesis that CRP may play a direct role in promoting the inflammatory component of atherosclerosis and present a potential target for the treatment of atherosclerosis.
Common Cholesteryl Ester Transfer Protein Mutations, Decreased HDL Cholesterol, and Possible Decreased Risk of Ischemic Heart Disease
Authors: Agerholm-Larsen Birgit , Tybjærg-Hansen Anne , Schnohr Peter , Steffensen Rolf , Nordestgaard Børge G.
Published: June 2012

Background
—Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from HDL in exchange for triglycerides in apolipoprotein B–containing lipoproteins.

Methods and Results
—We studied 2 common mutations in
CETP
, A373P and R451Q, in 8467 healthy women and men from the Danish general population and in 1636 Danish women and men with ischemic heart disease. The prevalence of 373P and 451Q was 0.10 and 0.07, respectively, for heterozygous carriers and 0.003 and 0.002, respectively, for homozygous carriers. All carriers of the 451Q allele also carried the 373P allele. HDL cholesterol in female noncarriers, heterozygotes, and homozygotes of 373P was 1.74±0.01 (mean±SE), 1.62±0.02, and 1.38±0.09 mmol/L, respectively (ANOVA,
P
<0.001). In men, equivalent values were 1.40±0.01, 1.26±0.02, and 1.19±0.09 mmol/L, respectively (ANOVA,
P
<0.001). HDL cholesterol decreased similarly as a function of 451Q genotypes and all 373P/451Q genotype combinations. Furthermore, apolipoprotein AI and the HDL cholesterol/apolipoprotein AI ratio was also lower in carriers of either of these mutations for both sexes. Finally, the
CETP
genotype was not associated with risk of ischemic heart disease unless we adjusted for HDL cholesterol: female heterozygous and homozygous carriers versus noncarriers had 36% lower risk of ischemic heart disease (95% CI 4% to 57%); in male carriers, we observed a similar trend.

Conclusions
—The A373P/R451Q polymorphism in
CETP
is associated with decreases in HDL cholesterol of 0.12 to 0.36 mmol/L in women and 0.14 to 0.21 mmol/L in men and possibly with a paradoxical 36% decrease in the risk of ischemic heart disease in women.
Change in Level of Physical Activity and Risk of All-Cause Mortality or Reinfarction
Authors: Steffen-Batey Lyn , Nichaman Milton Z. , Goff David C. , Frankowski Ralph F. , Hanis Craig L. , Ramsey David J. , Labarthe Darwin R.
Published: June 2012

Background
—The role of physical activity (PA) in reducing the risk of all-cause mortality or reinfarction after a first myocardial infarction (MI) remains unresolved, particularly for minority populations. The association between change in level of PA and risk of death or reinfarction was studied in 406 Mexican American and non-Hispanic white women and men who survived a first MI.

Methods and Results
—MI patients were interviewed at baseline and annually thereafter about PA, medical history, and risk factors of coronary heart disease. Change in level of PA after the index MI was categorized as (1) sedentary, no change (referent group), (2) decreased activity, (3) increased activity, and (4) active, no change. Over a 7-year period, the relative risk (95% CI) of death was as follows: 0.21 (0.10 to 0.44) for the active, no change group; 0.11 (0.03 to 0.46) for the increased activity group; and 0.49 (0.26 to 0.90) for the decreased activity group. The relative risk of reinfarction was as follows: 0.40 (0.24 to 0.66) for the active, no change group; 0.22 (0.09 to 0.50) for the increased activity group; and 0.93 (0.59 to 1.42) for the decreased activity group.

Conclusions
—These findings are consistent with a beneficial role of PA for Mexican American and non-Hispanic white women and men who survive a first MI and have practical implications for the management of MI survivors.
Angiotensin II Receptor Subtypes in the Skeletal Muscle Vasculature of Patients With Severe Congestive Heart Failure
Authors: Malendowicz Slawomir L. , Ennezat Pierre V. , Testa Marco , Murray Laura , Sonnenblick Edmund H. , Evans Todd , LeJemtel Thierry H.
Published: June 2012

Background
—Vascular remodeling occurs in the skeletal muscle of patients with severe congestive heart failure (CHF); this remodeling is mediated in part by increased activity of the renin-angiotensin system. Animal models suggest that in the vasculature, angiotensin II receptor type 2 (AT2-R) expression may be upregulated in pathological states associated with vascular remodeling. The therapeutic effects of an AT1-R antagonist may, therefore, be in part due to increased plasma angiotensin II levels, which stimulate AT2-R. However, whether AT2-R is expressed in the skeletal muscle vasculature of patients with severe CHF is unknown.

Methods and Results
—The steady-state transcript levels of the AT1-R and AT2-R genes were analyzed by reverse transcription–polymerase chain reaction in RNA samples prepared from the skeletal muscle of 12 patients with severe CHF (V̇O
2
<10 mL · kg
−1
· min
−1
) and 5 age-matched healthy subjects who underwent vastus lateralis biopsies. Human fetal skeletal muscle RNA served as a positive control for the expression of AT1-R and AT2-R gene transcripts. Transcripts from the AT1-R gene were detected readily in all samples. In contrast, transcripts from the AT2-R gene were only detected in fetal skeletal muscle samples and could not be detected in the skeletal muscle vasculature of healthy subjects or that of CHF patients, who were treated with either angiotensin-converting enzyme inhibitors or AT1-R antagonists.

Conclusions
—The AT2-R gene is not expressed in the skeletal muscle of patients with CHF. In the absence of detectable AT2-R gene transcripts, the AT2-R pathway is unlikely to contribute to the effects of AT1-R antagonists on the skeletal muscle vasculature in patients with severe CHF.
Association Between White Blood Cell Count, Epicardial Blood Flow, Myocardial Perfusion, and Clinical Outcomes in the Setting of Acute Myocardial Infarction
Authors: Barron Hal V. , Cannon Christopher P. , Murphy Sabina A. , Braunwald Eugene , Gibson C. Michael
Published: June 2012

Background
—Elevation of the white blood cell (WBC) count during acute myocardial infarction (AMI) is associated with adverse outcomes. We examined the relationship between the WBC count and angiographic findings to gain insight into this relationship.

Results and Methods
—We evaluated data from 975 patients in the Thrombolysis In Myocardial Infarction (TIMI) 10A and 10B trials. Patients with a closed artery at 60 and 90 minutes had higher a WBC count than patients with an open artery (
P
=0.02). Likewise, the presence of angiographically apparent thrombus was associated with a higher WBC count (11.5±5.2×10
9
/L, n=290, versus 10.7±3.5×10
9
/L, n=648;
P
=0.008). In addition, a higher WBC count was associated with poorer TIMI myocardial perfusion grades (4-way
P
=0.04). Mortality rates were higher in patients with a higher WBC count (0% for WBC count 0 to 5×10
9
/L, 4.9% for WBC count 5 to 10×10
9
/L, 3.8% for WBC count 10 to 15×10
9
/L, 10.4% for WBC count >15×10
9
/L;
P
=0.03). The development of new congestive heart failure or shock was also associated with a higher WBC count (0% for WBC count 0 to 5×10
9
/L, 5.2% for WBC count 5 to 10×10
9
/L, 6.1% for WBC count 10 to 15×10
9
/L, 17.1% for WBC count >15×10
9
/L;
P
<0.001), an observation that remained significant in a multivariable model that adjusted for potential confounding variables (odds ratio 1.21,
P
=0.002).

Conclusions
—Elevation in WBC count was associated with reduced epicardial blood flow and myocardial perfusion, thromboresistance (arteries open later and have a greater thrombus burden), and a higher incidence of new congestive heart failure and death. These observations provide a potential explanation for the higher mortality rate observed among AMI patients with elevated WBC counts and helps explain the growing body of literature that links inflammation and cardiovascular disease.
Detection of
Chlamydia pneumoniae
DNA in CD3+ Lymphocytes From Healthy Blood Donors and Patients With Coronary Artery Disease
Authors: Kaul Ravi , Uphoff Janet , Wiedeman Jean , Yadlapalli Sanjay , Wenman Wanda M.
Published: June 2012

Background
—
Chlamydia pneumoniae
is an intracellular bacterium responsible for respiratory tract infections. Recent studies have implicated this organism in the pathogenesis of atherosclerosis.

Methods and Results
—To address how the organism is transported from lungs to cardiac vessels, we characterized the cell population within peripheral blood mononuclear cells (PBMCs) that harbor
C pneumoniae
DNA. Adherent and nonadherent PBMCs from 28 patients with coronary artery disease (CAD) and 19 healthy blood donors were evaluated for the presence of
C pneumoniae
DNA by touchdown nested polymerase chain reaction (nPCR). Of the 28 patients, 10 (36%) had detectable PCR product in their nonadherent and 3 (10%) in their adherent PBMC population.
C pneumoniae
–specific PCR results were positive for 5 of 19 (26%) healthy blood donors. PCR positivity was detected only in the nonadherent cell population among this group of individuals. Fractionation of nonadherent PBMCs identified
C pneumoniae
–specific PCR signal among the CD3+ T-cell population exclusively. Of the 18 PCR-positive subjects (13 patients and 5 healthy control subjects), 67% (8 patients and 4 healthy blood donors) tested positive for
C pneumoniae
–specific IgG serology. Interestingly, 2 patients became PCR negative on a repeated blood draw 5 months after initial detection of
C pneumoniae
DNA despite retaining
C pneumoniae
–specific antibodies.

Conclusions
—Our results demonstrate marginally significant prevalence of
C pneumoniae
DNA in patients with CAD compared with healthy subjects (
P
=0.082). In contrast, the prevalence of IgG seropositivity among the 2 groups did not reach statistical significance (
P
=0.306). We also provide unequivocal evidence for the presence of
C pneumoniae
DNA predominantly among the circulating CD3+ T-cell population.
Efficacy and Safety of Oral Dofetilide in Converting to and Maintaining Sinus Rhythm in Patients With Chronic Atrial Fibrillation or Atrial Flutter
Authors: Singh Steven , Zoble Robert G. , Yellen Laurence , Brodsky Michael A. , Feld Gregory K. , Berk Martin , Billing Clare B.
Published: June 2012

Background
—This double-blind, multicenter, placebo-controlled study determined the efficacy and safety of dofetilide in converting atrial fibrillation (AF) or atrial flutter (AFl) to sinus rhythm (SR) and maintaining SR for 1 year.

Methods and Results
—Patients with AF or AFl (n=325) were randomized to 125, 250, or 500 μg dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (Cl
Cr
). Pharmacological cardioversion rates for 125, 250, and 500 μg dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 μg versus placebo;
P
=0.015 and
P
<0.001, respectively). Seventy percent of pharmacological cardioversions with dofetilide were achieved in 24 hours and 91% in 36 hours. For the 250 patients who successfully cardioverted pharmacologically or electrically, the probability of remaining in SR at 1 year was 0.40, 0.37, 0.58 for 125, 250, and 500 μg dofetilide, respectively, and 0.25 for placebo (500 μg versus placebo,
P
=0.001). Two cases of torsade de pointes occurred, 1 on day 2 and the other on day 3 (0.8% of all patients given active drug); 1 sudden cardiac death, classified as proarrhythmic, occurred on day 8 (0.4% of all patients given active drug).

Conclusions
—Dofetilide, a new class III antiarrhythmic agent, is moderately effective in cardioverting AF or AFl to SR and significantly effective in maintaining SR for 1 year. In-hospital initiation and dosage adjustment based on QTc and Cl
Cr
are necessary to minimize a small but nonnegligible proarrhythmic risk.
Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation
Authors: Wilhelm Markus J. , Pratschke Johann , Beato Francisca , Taal Maarten , Kusaka Mamoru , Hancock Wayne W. , Tilney Nicholas L.
Published: June 2012

Background
—Donor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation.

Methods and Results
—Functioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean±SD, 9.3±0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6±0.7 days,
P
=0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls.

Conclusions
—Donor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.
Demographic, Belief, and Situational Factors Influencing the Decision to Utilize Emergency Medical Services Among Chest Pain Patients
Authors: Brown Adam L. , Mann N. Clay , Daya Mohamud , Goldberg Robert , Meischke Hendrika , Taylor Judy , Smith Kevin , Osganian Stavroula , Cooper Lawton
Published: June 2012

Background
—Empirical evidence suggests that people value emergency medical services (EMS) but that they may not use the service when experiencing chest pain. This study evaluates this phenomenon and the factors associated with the failure to use EMS during a potential cardiac event.

Methods and Results
—Baseline data were gathered from a randomized, controlled community trial (REACT) that was conducted in 20 US communities. A random-digit-dial survey documented bystander intentions to use EMS for cardiac symptoms in each community. An emergency department surveillance system documented the mode of transport among chest pain patients in each community and collected ancillary data, including situational factors surrounding the chest pain event. Logistic regression identified factors associated with failure to use EMS. A total of 962 community members responded to the phone survey, and data were collected on 875 chest pain emergency department arrivals. The mean proportion of community members intending to use EMS during a witnessed cardiac event was 89%; the mean proportion of patients observed using the service was 23%, with significant geographic differences (range, 10% to 48% use). After controlling for covariates, non-EMS users were more likely to try antacids/aspirin and call a doctor and were less likely to subscribe to (or participate in) an EMS prepayment plan.

Conclusions
—The results of this study indicate that indecision, self-treatment, physician contact, and financial concerns may undermine a chest pain patient’s intention to use EMS.
Renal Function, Neurohormonal Activation, and Survival in Patients With Chronic Heart Failure
Authors: Hillege Hans L. , Girbes Armand R. J. , de Kam Pieter J. , Boomsma Frans , de Zeeuw Dick , Charlesworth Andrew , Hampton John R. , van Veldhuisen Dirk J.
Published: June 2012

Background
—Because renal function is affected by chronic heart failure (CHF) and it relates to both cardiovascular and hemodynamic properties, it should have additional prognostic value. We studied whether renal function is a predictor for mortality in advanced CHF, and we assessed its relative contribution compared with other established risk factors. In addition, we studied the relation between renal function and neurohormonal activation.

Methods and Results
—The study population consisted of 1906 patients with CHF who were enrolled in a recent survival trial (Second Prospective Randomized study of Ibopamine on Mortality and Efficacy). In a subgroup of 372 patients, plasma neurohormones were determined. The baseline glomerular filtration rate (GFR
c
) was calculated using the Cockroft Gault equation. GFR
c
was the most powerful predictor of mortality; it was followed by New York Heart Association functional class and the use of angiotensin-converting enzyme inhibitors. Patients in the lowest quartile of GFR
c
values (<44 mL/min) had almost 3 times the risk of mortality (relative risk, 2.85;
P
<0.001) of patients in the highest quartile (>76 mL/min). Impaired left ventricular ejection fraction (LVEF) was only modestly predictive (
P
=0.053). GFR
c
was inversely related with N-terminal atrial natriuretic peptide (ANP;
r
=−0.53) and, to a lesser extent, with ANP itself (
r
=−0.35; both
P
<0.001).

Conclusions
—Impaired renal function (GFR
c
) is a stronger predictor of mortality than impaired cardiac function (LVEF and New York Heart Association class) in advanced CHF, and it is associated with increased levels of N-terminal ANP. Moreover, impaired renal function was not related to LVEF, which suggests that factors other than reduced cardiac output are causally involved.
Ultrasound Imaging–Guided Noninvasive Ultrasound Thrombolysis
Authors: Rosenschein Uri , Furman Vladimir , Kerner Efim , Fabian Itzchak , Bernheim Joelle , Eshel Yoram
Published: June 2012

Background
—Catheter-based therapeutic ultrasound thrombolysis was recently shown to be effective and safe. The purpose of this work was to study the safety and efficacy of external high-intensity focused ultrasound thrombolysis guided by ultrasound imaging in experimental settings.

Methods and Results
—A therapeutic transducer was constructed from an acoustic lens and integrated with an ultrasound imaging transducer. In vitro clots were inserted into bovine arterial segments and sonicated under real-time ultrasound imaging guidance in a water tank. With pulsed-wave (PW) ultrasound, the total sonication time correlated with thrombolysis efficiency (
r
2
=0.7666). A thrombolysis efficiency of 91% was achieved with optimal PW parameters (1:25 duty cycle, 200-μs pulse length) at an intensity (I
spta
) of >35±5 W/cm
2
. Ultrasound imaging during sonication showed the cavitation field as a spherical cloud of echo-dense material. Within <2 minutes, the vessel lumen evidenced neither residual clot nor damage to the arterial wall. On serial filtration, 93±1% of the lysed clot became subcapillary in size (<8 μm). In vitro safety studies, however, showed arterial damage when an I
spta
of 45 W/cm
2
was used for periods of ≥300 seconds.

Conclusions
—External high-intensity focused ultrasound thrombolysis using optimal PW parameters for periods of ≤300 seconds appears to be a safe and effective method to induce thrombolysis. The procedure can be guided by ultrasound imaging, thereby allowing the monitoring of therapy.
Potential Contribution of a Novel Antifibrotic Factor, Hepatocyte Growth Factor, to Prevention of Myocardial Fibrosis by Angiotensin II Blockade in Cardiomyopathic Hamsters
Authors: Taniyama Yoshiaki , Morishita Ryuichi , Nakagami Hironori , Moriguchi Atsushi , Sakonjo Hiroshi , Shokei-Kim  , Matsumoto Kunio , Nakamura Toshikazu , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Background
—Because hepatocyte growth factor (HGF) prevented and/or regressed fibrosis in liver and pulmonary injury models, HGF may play an important role in the pathogenesis of fibrotic cardiovascular disease. Because angiotensin (Ang) II significantly decreased local HGF production, we performed (1) in vitro experiments using fibroblasts and (2) administration of an ACE inhibitor (temocapril) and an Ang II type 1 receptor antagonist (CS-866) to cardiomyopathic hamsters.

Methods and Results
—In human fibroblasts, HGF significantly increased the production of matrix metalloprotease-1 (MMP-1) and urokinase plasminogen activator, whereas HGF also significantly attenuated the reduction of MMP-1 activity induced by Ang II. In contrast, HGF significantly decreased transforming growth factor (TGF)-β mRNA stimulated by Ang II, whereas HGF also decreased basal TGF-β protein level without affecting growth. Similarly, in rat cardiac fibroblasts, HGF inhibited the expression and production of TGF-β, whereas HGF upregulated its specific receptor, c-met. Conversely, in vivo experiments revealed that administration of temocapril and CS-866 to cardiomyopathic hamsters resulted in a significant decrease in fibrotic area and increase in cardiac HGF concentration and mRNA (
P
<0.01), whereas cardiac concentration and mRNA of HGF were significantly decreased in cardiomyopathic hamsters. In contrast, mRNA expression of collagen III was markedly decreased by treatment with temocapril and CS-866.

Conclusions
—Here, we demonstrated that Ang II blockade prevented myocardial fibrosis in the cardiomyopathic hamster, accompanied by a significant increase in cardiac HGF. Overall, increase in local HGF expression may participate in the prevention of myocardial injury by Ang II blockade through its antifibrotic action.
Reverse Remodeling of Cardiac Myocyte Hypertrophy in Hypertension and Failure by Targeting of the Renin-Angiotensin System
Authors: Tamura Tetsutaro , Said Suleman , Harris Jennifer , Lu Wenyan , Gerdes A. Martin
Published: June 2012

Background
—ACE inhibitors (ACEIs) and angiotensin II type 1 (AT
1
) receptor blockers are effective in reducing left ventricular mass in hypertension and heart failure. However, the ability of these drugs to reverse excessive myocyte lengthening and transverse growth in heart failure is unknown.

Methods and Results
—
l
-158,809 (an AT
1
blocker; AT
1
), enalapril (an ACEI), and hydralazine (a vasodilator) were administered to spontaneously hypertensive heart failure rats between 6 and 10 months of age (early treatment) and between 18 and 22 months of age (late treatment). After 4 months of treatment, hemodynamics and chamber dimensions were collected before left ventricular myocyte isolation and subsequent analysis of myocyte shape. Each drug reduced systolic blood pressures to normal values. In the early and late studies, the ACEI reduced myocyte volume. Myocyte length was also reduced in the late study. However, the AT
1
was most effective in reversing myocyte dimensions to near-normal values in both studies. Hydralazine was ineffective in reducing cell size but arrested progression of myocyte lengthening in the late study. Changes in myocyte shape reflected alterations in chamber dimensions and wall thickness.

Conclusions
—Reversal of myocyte hypertrophy was produced in hypertensive/heart failure rats with an AT
1
. The ACEI was effective but to a lesser extent. Results indicate that it is possible to significantly reverse myocyte remodeling pharmacologically even if therapy is initiated near the onset of failure. Further work is needed to determine whether similar results can be obtained in humans.