bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Geometry and Function Preceding Neurally Mediated Syncope
Authors: Liu Jennifer E. , Hahn Rebecca T. , Stein Kenneth M. , Markowitz Steven M. , Okin Peter M. , Devereux Richard B. , Lerman Bruce B.
Published: June 2012

Background
—Neurally mediated syncope has been associated with increased left ventricular (LV) fractional shortening (FS) during tilt testing, which is consistent with the hypothesis that the stimulation of LV mechanoreceptors leads to reflex hypotension and/or bradycardia. However, FS does not represent true LV contractility because of its dependence on afterload and preload.

Methods and Results
—To elucidate the role of increased contractility in the mediation of neurally mediated syncope, we compared echocardiographic measures of LV performance corrected for end-systolic stress (ESS) in 21 patients (13 women and 8 men) with unexplained syncope who had either positive (n=10) or negative (n=11) responses to a tilt-table test. Two-dimensional echocardiographic LV imaging was performed at baseline and during the initial 5 minutes of upright tilt. In the supine position, both groups had similar LV end-diastolic volume indexes, stroke volumes, FS, circumferential ESS, and afterload-independent measures of LV performance (stress-corrected midwall and FS). However, after 5 minutes of upright tilt, patients who subsequently had a positive test had a lower stroke volume, lower stress-corrected midwall shortening, and endocardial FS. The tilt-positive group also had a greater fall in ESS and FS early during upright tilt.

Conclusions
—Reduced ESS, LV volume, and chamber function during initial upright tilt are associated with a subsequent positive tilt response in patients with unexplained syncope. These data suggest that if paradoxic activation of LV mechanoreceptors has a role in mediating neurally mediated syncope, it is not triggered by LV hypercontractility or increased systolic wall stress during the initial period of upright tilt.
Red Wine Polyphenols Inhibit Proliferation of Vascular Smooth Muscle Cells and Downregulate Expression of Cyclin A Gene
Authors: Iijima Katsuya , Yoshizumi Masao , Hashimoto Masayoshi , Kim Seungbum , Eto Masato , Ako Junya , Liang Yi-Qiang , Sudoh Noriko , Hosoda Kazuaki , Nakahara Koichi , Toba Kenji , Ouchi Yasuyoshi
Published: June 2012

Background
—Red wine polyphenols have been shown to contribute to the “French paradox” phenomenon, which consists of lower morbidity and mortality from coronary heart disease in the French population. Although vascular smooth muscle cell (VSMC) proliferation plays an important role in the progression of atherosclerotic lesions, the effects of red wine polyphenols on VSMC proliferation have not been elucidated.

Methods and Results
—We extracted the total polyphenolic fraction from red wine (RW-PF) by column chromatography. Treatment with RW-PF showed a potent inhibitory effect on the proliferation and DNA synthesis of cultured rat aortic smooth muscle cells (RASMCs). In contrast, the inhibitory effect of RW-PF on the proliferation of bovine carotid endothelial cells was observed only at much higher concentrations. To elucidate the molecular mechanisms of this antiproliferative effect of RW-PF on RASMCs, we investigated the effects of RW-PF on cell cycle regulation. RW-PF downregulated the expression of cyclin A mRNA and cyclin A promoter activity. In addition, RW-PF decreased the binding of nuclear proteins to the activating transcription factor (ATF) site in the cyclin A promoter and downregulated the mRNA levels of transcription factors, cAMP-responsive element–binding protein (CREB), and ATF-1.

Conclusions
—These results suggest that the downregulation of cyclin A gene expression may contribute to the antiproliferative effect of red wine polyphenols on RASMCs through the inhibition of transcription factor expression.
Insulin-Resistant Prediabetic Subjects Have More Atherogenic Risk Factors Than Insulin-Sensitive Prediabetic Subjects
Authors: Haffner Steven M. , Mykkänen Leena , Festa Andreas , Burke James P. , Stern Michael P.
Published: June 2012

Background
—Subjects who convert to type 2 diabetes mellitus have increased cardiovascular risk factors relative to nonconverters. However, it is not known whether these atherogenic changes in the prediabetic state are predominantly due to insulin resistance, decreased insulin secretion, or both.

Methods and Results
—We examined this issue in the 7-year follow-up of the San Antonio Heart Study, in which 195 of 1734 subjects converted to type 2 diabetes. At baseline, converters had significantly higher body mass index, waist circumference, triglyceride concentration, and blood pressure and lower HDL cholesterol than nonconverters. Atherogenic changes in converters were markedly attenuated (and no longer significant) after adjustment for the homeostasis model assessment of insulin resistance (HOMA IR, a surrogate for insulin resistance); in contrast, the differences in risk factors between converters and nonconverters increased after adjustment for the ratio of early insulin increment to early glucose increment (ΔI
30-0
/ΔG
30-0
) during an oral glucose tolerance test (a surrogate for insulin secretion). We also compared converters who had a predominant insulin resistance (high HOMA IR and high ΔI
30-0
/ΔG
30-0
) (n=56) and converters who had a predominant decrease in insulin secretion (low HOMA IR and low ΔI
30-0
/ΔG
30-0
) (n=31) with nonconverters (n=1539). Only the converters who were insulin resistant had higher blood pressure and triglyceride levels and lower HDL cholesterol levels than nonconverters.

Conclusions
—Our data suggest that atherogenic changes in the prediabetic state are mainly seen in insulin-resistant subjects and that strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.
Effects of Continuous Positive Airway Pressure on Cardiovascular Outcomes in Heart Failure Patients With and Without Cheyne-Stokes Respiration
Authors: Sin Don D. , Logan Alexander G. , Fitzgerald Fabia S. , Liu Peter P. , Bradley T. Douglas
Published: June 2012

Background
—Continuous positive airway pressure (CPAP) improves cardiac function in patients with congestive heart failure (CHF) who also have Cheyne-Stokes respiration and central sleep apnea (CSR-CSA). However, the effects of CPAP in CHF patients without CSR-CSA have not been tested, and the long-term effects of this treatment on clinical cardiovascular outcomes are unknown.

Methods and Results
—We conducted a randomized, controlled trial in which 66 patients with CHF (29 with and 37 without CSR-CSA) were randomized to either a group that received CPAP nightly or to a control group. Change in left ventricular ejection fraction (LVEF) from baseline to 3 months and the combined mortality-cardiac transplantation rate over the median 2.2-year follow-up period were compared between the CPAP-treated and control groups. For the entire group of patients, CPAP had no significant effect on LVEF, but it was associated with a 60% relative risk reduction (95% confidence interval, 2% to 64%) in mortality–cardiac transplantation rate in patients who complied with CPAP therapy. Stratified analysis of patients with and without CSR-CSA revealed that those with CSR-CSA experienced both a significant improvement in LVEF at 3 months and a relative risk reduction of 81% (95% confidence interval, 26% to 95%) in the mortality–cardiac transplantation rate of those who used CPAP. CPAP had no significant effect on either of these outcomes in patients without CSR-CSA.

Conclusions
—CPAP improves cardiac function in CHF patients with CSR-CSA but not in those without it. Although not definitive, our findings also suggest that CPAP can reduce the combined mortality–cardiac transplantation rate in those CHF patients with CSR-CSA who comply with therapy.
Clinical and Therapeutic Profile of Patients Presenting With Acute Coronary Syndromes Who Do Not Have Significant Coronary Artery Disease
Authors: Roe Matthew T. , Harrington Robert A. , Prosper Danielle M. , Pieper Karen S. , Bhatt Deepak L. , Lincoff A. Michael , Simoons Maarten L. , Akkerhuis Martijn , Ohman E. Magnus , Kitt Michael M. , Vahanian Alec , Ruzyllo Witold , Karsch Karl , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
—A proportion of patients who present with suspected acute coronary syndrome (ACS) are found to have insignificant coronary artery disease (CAD) during coronary angiography, but these patients have not been well characterized.

Methods and Results
—Of the 5767 patients with non–ST-segment elevation ACS who were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and who underwent in-hospital angiography, 88% had significant CAD (any stenosis >50%), 6% had mild CAD (any stenosis >0% to ≤50%), and 6% had no CAD (no stenosis identified). The frequency of death or nonfatal myocardial infarction at 30 days was reduced with eptifibatide treatment in patients with significant CAD (18.3% versus 15.6% for placebo,
P
=0.006) but not in those with mild CAD (6.6% versus 5.4%,
P
=0.62) and with no CAD (3.0% versus 1.2%,
P
=0.28). We identified independent baseline predictors of insignificant CAD (mild or no CAD) and used them to develop a simple predictive nomogram of the probability of insignificant CAD for use at hospital presentation. This nomogram was validated in a separate population of patients with non–ST-segment elevation ACS.

Conclusions
—Patients with suspected ACS found to have insignificant CAD have a low risk of adverse outcomes, do not appear to benefit from treatment with eptifibatide, and can be predicted with a simple nomogram drawn from baseline characteristics. Because patients with significant CAD appear to have an enhanced benefit from eptifibatide treatment, the predictive nomogram developed can be used to determine indications for glycoprotein IIb/IIIa blockade.
Echocardiographic Characterization of Cardiomyopathy in Friedreich’s Ataxia With Tissue Doppler Echocardiographically Derived Myocardial Velocity Gradients
Authors: Dutka David P. , Donnelly J. Elisabeth , Palka Przemysław , Lange Aleksandra , Nunez Derek J. R. , Nihoyannopoulos Petros
Published: June 2012

Background
—Conventional and tissue Doppler echocardiographically derived myocardial velocity gradients (MVGs) were used to characterize the myocardium in patients with Friedreich’s ataxia (FRDA), and the relationship between MVGs and the mutation in the FRDA gene, a GAA triplet repeat expansion, was investigated.

Methods and Results
—We studied 29 patients with FRDA (10 men, mean age 31±9 years) who were homozygous for the GAA expansion in the FRDA gene and were without cardiac symptoms. A comparison was made with a group of 30 age-matched control subjects. In patients with FRDA, interventricular septal thickness (1.17±0.26 versus 0.85±0.13 cm,
P
<0.005), posterior left ventricular wall thickness (1.00±0.24 versus 0.88±0.15 cm,
P
<0.01), and left atrial diameter (3.3±0.5 versus 2.9±0.3 cm,
P
=0.01) were increased compared with control subjects. MVGs were reduced in FRDA during systole (3.1±1.2 versus 4.5±0.5 s
−1
,
P
<0.0001) and in early diastole (4.9±2.7 versus 8.8±1.8 s
−1
,
P
<0.0001) but increased in late diastole (2.0±1.3 versus 1.1±0.9 s
−1
,
P
<0.01). The strongest relationship was seen between age-corrected early diastolic MVGs and the GAA expansion in the smaller allele of the FRDA gene (
r
=−0.68,
P
<0.0001).

Conclusions
—MVGs offer a means of further characterizing the myocardial abnormalities in patients with FRDA. Early diastolic MVGs appear to relate most closely to the genetic abnormality and the consequential reduction in frataxin protein.
Ribozyme Oligonucleotides Against Transforming Growth Factor-β Inhibited Neointimal Formation After Vascular Injury in Rat Model
Authors: Yamamoto Kei , Morishita Ryuichi , Tomita Naruya , Shimozato Takashi , Nakagami Hironori , Kikuchi Akira , Aoki Motokuni , Higaki Jitsuo , Kaneda Yasufumi , Ogihara Toshio
Published: June 2012

Background
—Because the mechanisms of atherosclerosis or restenosis after angioplasty have been postulated to involve an increase in transforming growth factor (TGF)-β, a selective decrease in TGF-β may have therapeutic value. Thus, we used the ribozyme strategy to actively cleave the targeted gene to selectively inhibit TGF-β expression.

Methods and Results
—We constructed ribozyme oligonucleotides (ONs) targeted to the sequence of the TGF-β gene that shows 100% homology among the human, rat, and mouse species. The specificity of ribozyme against TGF-β gene was confirmed by selective inhibition of TGF-β mRNA in cultured vascular smooth muscle cells as well as balloon-injured blood vessels in vivo. Importantly, the marked decrease in TGF-β resulted in significant inhibition of neointimal formation after vascular injury in a rat carotid artery model (
P
<0.01), whereas DNA-based control ONs and mismatched ribozyme ONs did not have any inhibitory effect on neointimal formation. Inhibition of neointimal formation was accompanied by (1) a reduction in collagen synthesis and mRNA expression of collagen I and III and (2) a significant decrease in DNA synthesis as assessed by proliferating cell nuclear antigen staining. Moreover, we modified ribozyme ONs containing phosphorothioate DNA and RNA targeted to the TGF-β gene. Of importance, modified ribozyme ONs showed a further reduction in TGF-β expression.

Conclusions
—Overall, this study provides the first evidence that selective blockade of TGF-β resulted in inhibition of neointimal formation, accompanied by a reduction in collagen synthesis and DNA synthesis in a rat model. We anticipate that modification of ribozyme ON pharmacokinetics will facilitate the potential clinical utility of the ribozyme strategy.
Determinants of the Degree of Functional Mitral Regurgitation in Patients With Systolic Left Ventricular Dysfunction
Authors: Yiu Siu F. , Enriquez-Sarano Maurice , Tribouilloy Christophe , Seward James B. , Tajik A. Jamil
Published: June 2012

Background
—Functional mitral regurgitation (FMR) occurs with a structurally normal valve as a complication of systolic left ventricular dysfunction (LVD). Determinants of degree of FMR are poorly defined; thus, mechanistic therapeutic approaches to FMR are hindered.

Methods and Results
—In a prospective study of 21 control subjects and 128 patients with LVD (defined as ejection fraction <50%, mean 31±9%) in sinus rhythm, we quantified simultaneously by echocardiography the effective regurgitant orifice (ERO) of FMR by using 2 methods: mitral deformation (valve and annulus) and left ventricular (LV) global (volumes, stress, function, and sphericity) and local (papillary muscle displacements and regional wall motion index) remodeling. A wide range of ERO (15±14 mm
2
, 0 to 87 mm
2
) was observed, unrelated to ejection fraction (
P
=0.32). The major determinant of ERO was mitral deformation, ie, systolic valvular tenting and annular contraction in univariate (
r
=0.74 and
r
=−0.61, respectively; both
P
<0.0001) and multivariate (both
P
<0.0001) analyses, independent of global LV remodeling. Systolic valvular tenting was strongly determined by local LV alterations, particularly apical (
r
=0.75) and posterior (
r
=0.70) displacement of papillary muscle, with confirmation in multivariate analysis (both
P
<0.0001), independent of LV volumes, function, and sphericity.

Conclusions
—The presence and degree of FMR complicating LVD are unrelated to the severity of LVD. Local LV remodeling (apical and posterior displacement of papillary muscles) leads to excess valvular tenting independent of global LV remodeling. In turn, excess tenting and loss of systolic annular contraction are associated with larger EROs. These determinants of FMR warrant consideration for specific approaches to the treatment of FMR complicating LVD.
Assessment of Coronary Stenosis Severity and Transmural Perfusion Gradient by Myocardial Contrast Echocardiography
Authors: Masugata Hisashi , Cotter Bruno , Peters Barry , Ohmori Koji , Mizushige Katsufumi , DeMaria Anthony N.
Published: June 2012

Background
—The present study (1) compared the ability of power Doppler imaging with that of gray-scale B-mode tissue imaging to opacify the myocardium and detect coronary stenosis by myocardial contrast echocardiography and (2) compared the response of video intensity (VI) to variable pulsing intervals for each modality.

Methods and Results
—Four grades of left anterior descending coronary artery (LAD) stenoses were created in 9 open-chest dogs. Stenoses reduced resting LAD flow by 25%, 50%, 75%, and 100% of baseline by flow probe. Myocardial contrast echocardiography was performed during varying ECG gated pulsing intervals (PIs) from 1:1 to 1:10. By gray-scale imaging, background-subtracted LAD bed VI was less than baseline VI at all PIs for the 100% reduced-flow state but not for any other flow state or interval. By power Doppler imaging, LAD bed VI was less than baseline VI at all intervals for 75% and 100% reduced-flow states but only 1:1 and 1:2 for 25% and 50% reduced-flow states, respectively. Correlation of VI and myocardial blood flow (determined by use of fluorescent microspheres) ratios from stenosed versus normal beds was stronger by power Doppler imaging. A transmural opacification gradient with stenosis was visualized and measured by power Doppler imaging, but it was insignificant by gray-scale imaging. The ratio of endocardial/epicardial flow determined by use of fluorescent microspheres was correlated with VI by power Doppler imaging at all PIs.

Conclusions
—Power Doppler imaging has advantages compared with gray-scale imaging in opacifying the myocardium and in detecting coronary stenosis and altered transmural distribution of myocardial perfusion from peak VI. Because VI differences from baseline at long PI vary for mild versus severe (75% and 100%, respectively) reduced-flow states, power Doppler imaging may provide a method to quantify coronary stenoses.
Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle
Authors: Voroshilovsky Olga , Qu Zhilin , Lee Moon-Hyoung , Ohara Toshihiko , Fishbein Gregory A. , Huang Hsun-Lun A. , Swerdlow Charles D. , Lin Shien-Fong , Garfinkel Alan , Weiss James N. , Karagueuzian Hrayr S. , Chen Peng-Sheng
Published: June 2012

Background
—The mechanisms by which 60-Hz alternating current (AC) can induce ventricular fibrillation (VF) are unknown.

Methods and Results
—We studied 7 isolated perfused swine right ventricles in vitro. The action potential duration restitution curve was determined. Optical mapping techniques were used to determine the patterns of activation on the epicardium during 5-second 60-Hz AC stimulation (10 to 999 μA). AC captured the right ventricles at 100±65 μA, which is significantly lower than the direct current pacing threshold (0.77±0.45 mA,
P
<0.05). AC induced ventricular tachycardia or VF at 477±266 μA, when the stimulated responses to AC had (1) short activation CLs (128±14 ms), (2) short diastolic intervals (16±9 ms), and (3) short diastolic intervals associated with a steep action potential duration restitution curve. Optical mapping studies showed that during rapid ventricular stimulation by AC, a wave front might encounter the refractory tail of an earlier wave front, resulting in the formation of a wave break and VF. Computer simulations reproduced these results.

Conclusions
—AC at strengths less than the regular pacing threshold can capture the ventricle at fast rates. Accidental AC leak to the ventricles could precipitate VF and sudden death if AC results in a fast ventricular rate coupled with a steep restitution curve and a nonuniform recovery of excitability of the myocardium.
Fetoscopic Direct Fetal Cardiac Access in Sheep
Authors: Kohl Thomas , Strümper Danja , Witteler Ralf , Merschhoff Gregor , Alexiene Rasa , Callenbeck Claudia , Asfour Boulos , Reckers Julia , Aryee Sebastian , Vahlhaus Christian , Vogt Johannes , Van Aken Hugo , Scheld Hans H.
Published: June 2012

Background
—Fetal cardiac interventions by direct ultrasound-guided approaches or open fetal cardiac surgery have been fraught with technical difficulties, as well as with significant maternal and fetal morbidity in humans. Therefore, the purpose of our study in sheep was to assess the feasibility and potential of fetoscopic direct fetal cardiac access.

Methods and Results
—In 15 anesthetized pregnant ewes (88 to 109 days of gestation; term, 145 days), 3 to 4 trocars were percutaneously placed in the uterus. Using videofetoscopic equipment, we assessed the feasibility of achieving direct fetal cardiac access. Minimally invasive direct fetal cardiac access by operative fetoscopy was achieved in 10 of the 15 fetal sheep. In 7 fetuses, the approach was successfully tested for fetal cardiac pacing (n=5) or antegrade fetal cardiac catheterization (n=2). Access was not achieved in 5 fetuses because of bleeding complications (n=2) or because the fetoscopic setup could not be established (n=3). All but 2 fetal sheep were alive at the end of the procedure. Acute fetal demise resulted from maternal hypotension or kinking of the fetal inferior caval vein by sternal suspension. Six ewes continued gestation; 3 of these went to term, with a normal fetal outcome. Two ewes died from septicemia 3 and 7 days after the procedure, and 1 ewe aborted 1 month after the procedure.

Conclusions
—Minimally invasive direct fetal cardiac access by operative fetoscopy is feasible in fetal sheep. The fetoscopic approach carries important potential for fetal cardiac pacing, antegrade fetal valvuloplasties, and resection of fetal intrapericardial teratomas in human fetuses.
Myocyte Response to β-Adrenergic Stimulation Is Preserved in the Noninfarcted Myocardium of Globally Dysfunctional Rat Hearts After Myocardial Infarction
Authors: Prahash Arun J. C. , Gupta Sudhir , Anand Inder S.
Published: June 2012

Background
—Cellular mechanisms underlying the diminished inotropic response of remodeled hearts after myocardial infarction (MI) remain unclear.

Methods and Results
—Left ventricular (LV) remodeling and function were assessed by 2D echocardiography and isolated perfused heart studies in 6-week post-MI and sham-operated rats. LV myocytes from sham and noninfarcted MI hearts were used for morphometric and functional studies. β-Adrenergic receptor (β-AR) agonist isoproterenol (ISO)-induced contractile response was measured in isolated hearts. The effects of ISO and forskolin on contractile function and calcium transients of isolated myocytes were recorded. ISO-induced cAMP generation was compared in sham and MI myocytes. β-AR density was measured by radioligand binding. MI hearts were remodeled (LV diameter 8.5±0.3 versus 5.7±0.3 mm,
P
<0.001) and showed global (% fractional shortening 19.1±2.5 versus 55.3±2.2,
P
<0.01) and regional contractile dysfunction of noninfarcted myocardium (% systolic posterior wall thickening 37±4 versus 62±10,
P
<0.01). Isolated heart function (LV developed pressure 58±2 versus 72±3 mm Hg,
P
=0.004) and ISO concentration response were reduced in MI hearts. Myocytes from the noninfarcted LV were structurally remodeled (32% longer and 18% wider), but their contractile response and intracellular calcium kinetics to ISO and forskolin were not diminished. β-AR receptor density (B
max
24±1.5 versus 22.4±1.6 fmol/mg protein) and β-AR agonist–stimulated cAMP were similar in both groups.

Conclusions
—Isolated myocytes from the remodeled and dysfunctional myocardium are structurally modified but contract normally under basal conditions and in response to β-AR stimulation. β-AR density is preserved in remodeled myocytes. Nonmyocyte factors may be more important in the genesis of contractile dysfunction in the remodeled rat heart up to 6 weeks after MI.
Heart Failure Affects Mitochondrial but Not Myofibrillar Intrinsic Properties of Skeletal Muscle
Authors: De Sousa E. , Veksler V. , Bigard X. , Mateo P. , Ventura-Clapier R.
Published: June 2012

Background
—Congestive heart failure (CHF) induces abnormalities in skeletal muscle that are thought to in part explain exercise intolerance. The aim of the present study was to determine whether these changes actually result in contractile or metabolic functional alterations and whether they are muscle type specific.

Methods and Results
—With a rat model of CHF (induced by aortic banding), we studied mitochondrial function, mechanical properties, and creatine kinase (CK) compartmentation in situ in permeabilized fibers from soleus (SOL), an oxidative slow-twitch muscle, and white gastrocnemius (GAS), a glycolytic fast-twitch muscle. Animals were studied 7 months after surgery, and CHF was documented on the basis of anatomic data. Alterations in skeletal muscle phenotype were documented with an increased proportion of fast-type fiber and fast myosin heavy chain, decreased capillary-to-fiber ratio, and decreased citrate synthase activity. Despite a slow-to-fast phenotype transition in SOL, no change was observed in contractile capacity or calcium sensitivity. However, muscles from CHF rats exhibited a dramatic decrease in oxidative capacities (oxygen consumption per gram of fiber dry weight) of 35% for SOL and 45% for GAS (
P
<0.001). Moreover, the regulation of respiration with ADP and mitochondrial CK and adenylate kinase was impaired in CHF SOL. Mitochondrial CK activity and content (Western blots) were dramatically decreased in both muscles.

Conclusions
—CHF results in alterations in both mitochondrial function and phosphotransfer systems but unchanged myofibrillar function in skeletal muscles, which suggests a myopathy of metabolic origin in CHF.
Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B
2
Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway
Authors: Brown Nancy J. , Gainer James V. , Murphey Laine J. , Vaughan Douglas E.
Published: June 2012

Background
—Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B
2
receptor–dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown.

Methods and Results
—We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 μg/min), and nitroprusside (0.8, 1.6, and 3.2 μg/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B
2
receptor antagonist HOE 140 (100 μg/kg IV), (2) the NO synthase inhibitor
l
-
N
G
-monomethyl-
l
-arginine (L-NMMA, 4 μmol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B
2
receptor antagonism attenuated vasodilator (
P
=0.004) and tPA (
P
=0.043) responses to bradykinin, without attenuating the vasodilator response to nitroprusside (
P
=0.36). L-NMMA decreased basal forearm blood flow (from 2.35±0.31 to 1.73±0.22 mL/min per 100 mL,
P
=0.01) and blunted the vasodilator response to acetylcholine (
P
=0.013) and bradykinin (
P
=0.07,
P
=0.038 for forearm vascular resistance) but not that to nitroprusside (
P
=0.47). However, there was no effect of L-NMMA on basal (
P
=0.7) or bradykinin-stimulated tPA release (
P
=0.45). Indomethacin decreased urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F
1α
(
P
=0.04). The vasodilator response to endothelium-dependent (
P
=0.019 for bradykinin) and endothelium-independent (
P
=0.019) vasodilators was enhanced during indomethacin administration. In contrast, there was no effect of indomethacin alone (
P
=0.99) or indomethacin plus L-NMMA (
P
=0.36) on bradykinin-stimulated tPA release.

Conclusions
—These data indicate that bradykinin stimulates tPA release from human endothelium through a B
2
receptor–dependent, NO synthase–independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor.
Insulin Resistance and Hyperinsulinemia
Authors: Galvan Alfredo Quiñones , Galetta Fabio , Natali Andrea , Muscelli Elza , Sironi Anna Maria , Cini Giuseppe , Camastra Stefania , Ferrannini Ele
Published: June 2012

Background
—Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive.

Methods and Results
—We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg · m
−
2
), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI ≥27 kg · m
−
2
, n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50±8 and 55±10 g · m
−
2.7
, respectively) than in 13 nonobese, normotensive subjects (40±8 g · m
−
2.7
,
P
=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (
P
=0.003) and BMI (
P
=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg · m
−
2
=+11%), the two factors being additive.

Conclusions
—When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.
Angiogenesis Is Induced in a Rabbit Model of Hindlimb Ischemia by Naked DNA Encoding an HIF-1α/VP16 Hybrid Transcription Factor
Authors: Vincent Karen A. , Shyu Kou-Gi , Luo Yuxia , Magner Meredith , Tio Rene A. , Jiang Canwen , Goldberg Mark A. , Akita Geoffrey Y. , Gregory Richard J. , Isner Jeffrey M.
Published: June 2012

Background
—Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that regulates expression of genes involved in O
2
homeostasis, including vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis. We sought to exploit this native adaptive response to hypoxia as a treatment for chronic ischemia.

Methods and Results
—A hybrid protein consisting of DNA-binding and dimerization domains from the HIF-1α subunit and the transactivation domain from herpes simplex virus VP16 protein was constructed to create a strong, constitutive transcriptional activator. After transfection into HeLa, C6, and Hep3B cells, this chimeric transcription factor was shown to activate expression of the endogenous VEGF gene, as well as several other HIF-1 target genes in vitro. The bioactivity of HIF-1α/VP16 hybrid gene transfer in vivo was examined in a rabbit model of hindlimb ischemia. Administration of HIF-1α/VP16 was associated with significant improvements in calf blood pressure ratio, angiographic score, resting and maximal regional blood flow, and capillary density (all
P
<0.01).

Conclusions
—The HIF-1α/VP16 hybrid transcription factor is able to promote significant improvement in perfusion of an ischemic limb. These results confirm the feasibility of a novel approach for therapeutic angiogenesis in which neovascularization may be achieved indirectly by use of a transcriptional regulatory strategy.
Oxidized LDL Increases the Sensitivity of the Contractile Apparatus in Isolated Resistance Arteries for Ca
2+
via a Rho- and Rho Kinase–Dependent Mechanism
Authors: Bolz Steffen-Sebastian , Galle Jan , Derwand Roland , de Wit Cor , Pohl Ulrich
Published: June 2012

Background
—Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor–mediated dilations. We studied, in hamster skeletal muscle resistance arteries (213±8 μm; n=51), whether an altered vascular smooth muscle (VSM) response, particularly sensitization of the VSM contractile apparatus to Ca
2+
, is involved in this oxLDL effect.

Methods and Results
—VSM or endothelial [Ca
2+
]
i
and vascular diameter were measured in response to norepinephrine (0.3 μmol/L), sodium nitroprusside (10 μmol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 μmol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 μmol/L). OxLDL significantly increased resting VSM [Ca
2+
]
i
(11±3%), decreased diameter (8±2%), and enhanced norepinephrine-induced constrictions. Dilations to sodium nitroprusside and C-type natriuretic peptide were significantly reduced (by 10±2% and 35±6%), whereas dose-response curves for papaverine and ACh were shifted to the right, despite unchanged increases in endothelial Ca
2+
after ACh. OxLDL significantly shifted the Ca
2+
-diameter relation to the left, as assessed by stepwise increasing extracellular Ca
2+
(0 to 3 mmol/L) in depolarized skeletal muscle resistance arteries. This sensitization to Ca
2+
by oxLDL was abolished after inhibition of Rho (C3 transferase) or Rho kinase (Y27632).

Conclusions
—OxLDL reduces VSM responsiveness to vasodilators by increasing VSM Ca
2+
but preferentially by sensitizing VSM to Ca
2+
via a Rho- and Rho kinase–dependent pathway.
Hypertriglyceridemic Waist
Authors: Lemieux Isabelle , Pascot Agnès , Couillard Charles , Lamarche Benoı̂t , Tchernof André , Alméras Natalie , Bergeron Jean , Gaudet Daniel , Tremblay Gérald , Prud’homme Denis , Nadeau André , Després Jean-Pierre
Published: June 2012

Background
—The present study tested the hypothesis that simple variables, such as waist circumference and fasting plasma triglyceride (TG) concentrations, could be used as screening tools for the identification of men characterized by a metabolic triad of nontraditional risk factors (elevated insulin and apolipoprotein [apo] B and small, dense LDL particles).

Methods and Results
—Results of the metabolic study (study 1) conducted on 185 healthy men indicate that a large proportion (>80%) of men with waist circumference values ≥90 cm and with elevated TG levels (≥2.0 mmol/L) were characterized by the atherogenic metabolic triad. Validation of the model in an angiographic study (study 2) on a sample of 287 men with and without coronary artery disease (CAD) revealed that only men with both elevated waist and TG levels were at increased risk of CAD (odds ratio of 3.6,
P
<0.03) compared with men with low waist and TG levels.

Conclusions
—It is suggested that the simultaneous measurement and interpretation of waist circumference and fasting TG could be used as inexpensive screening tools to identify men characterized by the atherogenic metabolic triad (hyperinsulinemia, elevated apo B, small, dense LDL) and at high risk for CAD.
Reduction of Atrial Defibrillation Threshold With an Interatrial Septal Electrode
Authors: Zheng Xiangsheng , Benser Michael E. , Walcott Gregory P. , Girouard Steven D. , Rollins Dennis L. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
—The standard lead configuration for internal atrial defibrillation consists of a shock between electrodes in the right atrial appendage (RAA) and coronary sinus (CS). We tested the hypothesis that the atrial defibrillation threshold (ADFT) of this RAA→CS configuration would be lowered with use of an additional electrode at the atrial septum (SP).

Methods and Results
—Sustained atrial fibrillation was induced in 8 closed-chest sheep with burst pacing and continuous pericardial infusion of acetyl-β-methylcholine. Defibrillation electrodes were situated in the RAA, CS, pulmonary artery (PA), low right atrium (LRA), and across the SP. ADFTs of RAA→CS and 4 other lead configurations were determined in random order by use of a multiple-reversal protocol. Biphasic waveforms of 3/1-ms duration were used for all single and sequential shocks. The ADFT delivered energies for the single-shock configurations were 1.27±0.67 J for RAA→CS and 0.86±0.59 J for RAA+CS→SP; the ADFTs for the sequential-shock configurations were 0.39±0.18 J for RAA→SP/CS→SP, 1.16±0.72 J for CS→SP/RAA→SP, and 0.68±0.46 J for RAA→CS/LRA→PA. Except for CS→SP/RAA→SP versus RAA→CS and RAA→CS/LRA→PA versus RAA+CS→SP, the ADFT delivered energies of all of the configurations were significantly different from each other (
P
<0.05).

Conclusions
—The ADFT of the standard RAA→CS configuration is markedly reduced with an additional electrode at the atrial SP.
Electrophysiological Deterioration During Long-Duration Ventricular Fibrillation
Authors: Tovar Oscar H. , Jones Janice L.
Published: June 2012

Background
—Probability of survival from sudden cardiac arrest caused by ventricular fibrillation (VF) decreases rapidly with fibrillation duration. We hypothesized that cellular ischemia/fibrillation-induced electrophysiological deterioration underlies decreased survival.

Methods and Results
—We determined fibrillation monophasic action potential (MAP) morphology including action potential frequency content, duration, cycle length, developing diastolic intervals, and amplitude as a function of ischemic fibrillation duration in 10 isolated rabbit hearts. We also correlated ECG frequency (used clinically) and MAP amplitude and frequency. Fibrillation cycle length and diastole duration increased, whereas APD
100
shortened significantly with time (
P
<0.001). Between 1 and 3 minutes, diastole appeared primarily as the result of APD
100
shortening, with only small changes in cycle length. Between 2 and 5 minutes, diastole increased primarily as the result of increased cycle length. Diastole developed progressively from 5% of VF cycles at 5 seconds to ≈100% of VF cycles by 120 seconds (
P
<0.001). Diastole increased from 1% of cycle length at 5 seconds to 62% at 5 minutes. Its duration increased from 4.7 ms at 5 seconds to 90 ms at 5 minutes (
P
<0.001). Both MAP and ECG 1/frequency closely correlated with fibrillation cycle length.

Conclusions
—These results show a rapid and progressive electrophysiological deterioration during fibrillation, leading to electrical diastole between fibrillation action potentials. This rapid deterioration may explain the decreased probability of successful resuscitation after prolonged fibrillation. Therefore, a greater understanding of cellular deterioration during fibrillation may lead to improved resuscitation methods, including development of specific defibrillator waveforms for out-of-hospital cardiac arrest.
Emergency Polytetrafluoroethylene-Covered Stent Implantation to Treat Coronary Ruptures
Authors: Briguori Carlo , Nishida Takahiro , Anzuini Angelo , Di Mario Carlo , Grube Eberhard , Colombo Antonio
Published: June 2012

Background
—Coronary perforation is a life-threatening complication of percutaneous interventions. In the past few years, the implantation of covered stents has emerged as a strategy for treatment when the traditional conservative approach (ie, prolonged balloon inflation and reversal of anticoagulation) fails.

Methods and Results
—Since May 1997 (when polytetrafluoroethylene [PTFE]-covered stents were available at our institutions), 11 of the 12 consecutive patients who had coronary ruptures that were unsuccessfully sealed with prolonged balloon inflation and reversal of anticoagulation were treated with 12 PTFE-covered stents (PTFE group). The efficacy of the PTFE-covered stent was compared with that of noncovered stents, which were used to treat 17 perforations (non-PTFE group). One patient sustained a very distal perforation that was not suitable for covered stent sealing and underwent emergency surgery. All vessel ruptures treated with PTFE-covered stent implantation were successfully sealed. The time necessary to deploy the stent was 10±3 minutes (range, 4 to 15 minutes). All patients but one were discharged from the hospital and had an optimal early clinical outcome. One patient underwent emergency bypass surgery and died in the intensive care unit. The occurrence of cardiac tamponade and the necessity for emergency surgery was significantly lower in the PTFE group than in the non-PTFE group. At 14±4 months, the 10 discharged patients had not experienced any major adverse cardiac events.

Conclusions
—This preliminary study supports the utility of the PTFE-covered stent for the nonsurgical treatment of vessel ruptures.
Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays
Authors: Yang Jiacheng , Moravec Christine S. , Sussman Mark A. , DiPaola Nicholas R. , Fu Dechen , Hawthorn Lesley , Mitchell Christina A. , Young James B. , Francis Gary S. , McCarthy Patrick M. , Bond Meredith
Published: June 2012

Background
—Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure.

Methods and Results
—We used high-density oligonucleotide arrays to explore changes in expression of ≈7000 genes in 2 nonfailing and 2 failing human hearts with diagnoses of end-stage ischemic and dilated cardiomyopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsarcomeric myosin regulatory light chain-2 [MLC
2
], and β-actin); (2) genes responsible for degradation and disassembly of myocardial proteins (α
1
-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in metabolism (ATP synthase α-subunit, succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose reductase, and TIM17 preprotein translocase); (4) genes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (αB-crystallin and μ-crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we then compared expression of proteins encoded by the differentially expressed genes, αB-crystallin, SLIM1, gelsolin, α
1
-antichymotrypsin, and ubiquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein expression was also increased in cardiomyopathic hearts from tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET) mice.

Conclusions
—Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.
Abnormal Baroreflex Responses in Patients With Idiopathic Orthostatic Intolerance
Authors: Farquhar William B. , Taylor J. Andrew , Darling Stephen E. , Chase Karen P. , Freeman Roy
Published: June 2012

Background
—Patients diagnosed with idiopathic orthostatic intolerance report symptoms of lightheadedness, fatigue, and nausea accompanied by an exaggerated tachycardia when assuming the upright posture. Often, these symptoms are present in the absence of any decrease in arterial pressure. We hypothesized that patients with idiopathic orthostatic intolerance would have impaired cardiac vagal and integrated baroreflex function, lower blood volume, and increased venous compliance.

Methods and Results
—Sixteen patients and 14 healthy control subjects underwent the modified Oxford technique to assess cardiac vagal baroreflex sensitivity. Progressive lower-body negative pressure (to –50 mm Hg; LBNP) was used to examine the integrated baroreflex response to progressive hypovolemic stimuli. Blood volume and venous compliance were also assessed. Patients with idiopathic orthostatic intolerance had lower cardiac vagal baroreflex sensitivity (12±1 versus 25±4 ms/mm Hg;
P
≤0.01). The integrated baroreflex response to low levels of LBNP was characterized by shorter R-R intervals and more symptoms such as lightheadedness, despite similar levels of blood pressure. There was a trend toward lower blood volume in the patient group (56±2 versus 63±3 mL/kg;
P
=0.054).

Conclusions
—Patients with idiopathic orthostatic intolerance have lower cardiac vagal baroreflex sensitivity and marginally lower blood volume and respond with faster heart rates despite similar levels of arterial pressure during LBNP. These findings may contribute to the exaggerated postural tachycardia and symptoms observed in patients with this disorder.
Ischemia-Reperfusion Injury at the Microvascular Level
Authors: Galiuto Leonarda , DeMaria Anthony N. , del Balzo Ughetta , May-Newman Karen , Flaim Stephen F. , Wolf Paul L. , Kirchengast Michael , Iliceto Sabino
Published: June 2012

Background
—The purpose of this study was to verify whether endothelin A–antagonist administration at the time of coronary reperfusion preserves postischemic microvasculature and whether myocardial contrast echo (MCE) is able to detect pharmacologically induced changes in microvascular reflow.

Methods and Results
—Twenty dogs underwent 90 minutes of LAD occlusion (OCC) followed by 180 minutes of reperfusion (RP). Five minutes before LAD reopening, an intravenous bolus (5 mg/kg) of LU 135252 was given in 10 dogs and vehicle in the remaining 10. At baseline (BSL), OCC, and 90 and 180 minutes of RP, microvascular flow (BF) was assessed by microspheres, and MCE was performed with intravenous echo contrast. MCE videointensity and BF were expressed as risk area/control ratio. Myocardial thickness of the risk area was calculated by 2D echo. No differences in BF between the 2 groups were observed at BSL, OCC, and 90 minutes of RP. At 180 minutes of RP, BF was decreased in controls (70±7.4% of BSL;
P
<0.005 versus BSL) and preserved in LU 135252–treated animals (89±4% of BSL;
P
=NS versus BSL;
P
<0.05 versus controls). Videointensity at MCE closely followed the changes in BF observed in both groups throughout the protocol. Myocardial thickness at 180 minutes of RP increased to 138.6±9.9% of BSL in controls and remained at 108.9±7.4% of BSL in treated dogs (
P
<0.05).

Conclusions
—Endothelin A–antagonist treatment at the time of reperfusion significantly limited the progressive decrease in postischemic microvascular reflow and the increase in myocardial thickness. MCE allowed a reliable evaluation of pharmacologically induced changes in microvascular flow.