bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Infectious Burden on Extent and Long-Term Prognosis of Atherosclerosis
Authors: Espinola-Klein Christine , Rupprecht Hans J. , Blankenberg Stefan , Bickel Christoph , Kopp Helmuth , Rippin Gerd , Victor Anja , Hafner Gerd , Schlumberger Wolfgang , Meyer Jürgen
Published: July 2002

Background
—

Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. In hypothesizing an association between infectious agents and the development of atherosclerosis, we would expect a correlation to the extent of atherosclerosis. Moreover, this effect could be multiplied by the number of pathogens to which an individual had been exposed.

Methods and Results
—

In 572 patients, IgG or IgA antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus,
Hemophilus influenzae
,
Chlamydia pneumoniae
,
Mycoplasma pneumoniae
, and
Helicobacter pylori
were measured. The extent of atherosclerosis was determined by coronary angiography, carotid duplex sonography, and evaluation of the ankle-arm index. Elevated IgA antibodies against
C pneumoniae
(
P
<0.04) and IgG antibodies against
H pylori
(
P
<0.02), cytomegalovirus (
P
<0.05), and herpes simplex virus 2 (
P
<0.01) were associated with advanced atherosclerosis (≥2 vascular regions), adjusted for age, sex, cardiovascular risk factors, and highly sensitive C-reactive protein. Infectious burden divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities was significantly associated with advanced atherosclerosis, with an odds ratio (95% CI) of 1.8 (1.2 to 2.6) for 4 to 5 (
P
<0.01) and 2.5 (1.2 to 5.1) for 6 to 8 seropositivities (
P
<0.02) (adjusted). After a mean follow-up of 3.2 years, cardiovascular mortality rate was 7.0% in patients with advanced atherosclerosis and seropositive for 0 to 3 pathogens compared with 20.0% in those seropositive for 6 to 8 pathogens.

Conclusions
—

Our results support the hypothesis that infectious agents are involved in the development of atherosclerosis. We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis.
Detection of Noncritical Coronary Stenosis at Rest Without Recourse to Exercise or Pharmacological Stress
Authors: Wei Kevin , Le Elizabeth , Jayaweera Ananda R. , Bin Jian-Ping , Goodman N. Craig , Kaul Sanjiv
Published: July 2002

Background
—

Currently, the detection of noncritical coronary stenoses requires some form of stress. We hypothesized that these stenoses can be detected at rest without recourse to stress by assessing adaptive changes that occur distally in the microcirculation.

Methods and Results
—

Phasic changes in myocardial video intensity (VI) were measured at rest with continuous high-mechanical-index (MI) contrast echocardiography in 15 open-chest dogs. Data were acquired at baseline and in the presence of different degrees of noncritical coronary stenosis. In 6 of these dogs, capillary blood volume was also measured at baseline using high-MI intermittent imaging with triggering performed separately at both end diastole and end systole. During continuous high-MI imaging, a significant increase in systolic VI was noted with coronary stenoses that resulted in progressive increases in the systolic/diastolic VI ratio with greater degrees of stenosis (
P
=0.003), with a mildly quadratic relation noted between the two: y=1.3 · 10
−6
· x
2
+0.01x+0.32,
P
<0.001,
r
=0.76, SEE=0.14. There was no difference in capillary blood volume between end diastole and end systole at baseline.

Conclusions
—

Capillary blood volume does not change between diastole and systole in vivo. Phasic changes in VI are noted at baseline during high-MI continuous imaging. The systolic component is negligible at baseline but increases with increasing levels of noncritical coronary stenosis because of adaptive changes in the microcirculation distal to the stenosis. Thus, the measurement of phasic changes in myocardial VI has the potential to detect coronary stenosis at rest without recourse to any form of stress.
Consequences of Atrial Tachycardia-Induced Remodeling Depend on the Preexisting Atrial Substrate
Authors: Shinagawa Kaori , Li Danshi , Leung Tack Ki , Nattel Stanley
Published: July 2002

Background
—

All animal studies of atrial tachycardia (AT) remodeling to date have been performed in normal hearts, but clinical atrial fibrillation (AF) often occurs in the setting of heart disease. This study evaluated the effects of a pathological AF substrate on AT-induced remodeling.

Methods and Results
—

Fourteen control dogs, 12 AT-only dogs (400 bpm for 1 week), 14 congestive heart failure (CHF) dogs (CHF only, ventricular tachypacing, 220 to 240 bpm for 5 weeks), and 13 CHF+AT dogs (ventricular tachypacing-induced CHF, 1 week of AT superimposed on the last week of ventricular tachypacing) were studied for evaluation of AT effects in normal hearts (AT-only versus control dogs) and CHF hearts (CHF+AT versus CHF-only dogs). In normal hearts, AT strongly decreased the effective refractory period (ERP) and abolished ERP rate adaptation, whereas conduction velocity was unaltered. In CHF dogs, AT reduced ERP to a significantly lesser extent, did not alter ERP rate adaptation, and reduced conduction velocity. AT alone increased atrial vulnerability to extrastimuli and prolonged AF. In the presence of CHF, AT had no clear effect on atrial vulnerability but increased the prevalence of prolonged AF.

Conclusions
—

The electrophysiological effects of AT are different in hearts with a CHF-induced pathological substrate for AF than in normal hearts. These findings have potentially important implications for understanding how AF occurring in diseased hearts begets AF.
Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and β-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure
Authors: Gealekman Olga , Abassi Zaid , Rubinstein Irit , Winaver Joseph , Binah Ofer
Published: July 2002

Background
—

Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload–induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS in depressed cardiac contractile properties, intracellular Ca
2+
([Ca
2+
]
i
) transients, and β-adrenergic hyporesponsiveness.

Methods and Results
—

HF was induced by aortocaval fistula (ACF). Compensated and decompensated subgroups of HF were selected on the basis of daily sodium excretion. ACF induced cardiac hypertrophy in rats with compensated (36%) and decompensated (76%) HF. Whereas in HF rats, cardiac eNOS expression and activity were unchanged, iNOS expression and activity increased ≈2-fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated HF rats but not in controls. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in papillary muscle of HF rats, more pronouncedly in decompensated than in compensated rats. Isoproterenol-induced increases in the rates of [Ca
2+
]
i
activation and relaxation were also depressed in ACF rats. Selective iNOS blockade by
N
-(3-(aminomethyl)benzylacetamidine improved the attenuated β-adrenergic responsiveness in HF rats.

Conclusions
—

Our findings indicate that myocardial iNOS is activated in rats with volume-overload HF and suggest that increased iNOS activity contributes to depressed myocardial contractility and β-adrenergic hyporesponsiveness.
Fenestration Improves Clinical Outcome of the Fontan Procedure
Authors: Lemler Matthew S. , Scott William A. , Leonard Steven R. , Stromberg Daniel , Ramaciotti Claudio
Published: July 2002

Background
—

The Fontan procedure is the definitive operation for palliation of complex congenital heart disease with single-ventricle physiology. Fenestration of the Fontan circuit allows for shunting of deoxygenated blood to the systemic circulation. This procedure improved the clinical outcomes of patients who are at high risk for poor Fontan results. However, it is controversial whether fenestration is beneficial for standard-risk patients.

Methods and Results
—

This prospective, randomized trial evaluated the clinical utility of fenestration in patients with standard preoperative risk profiles for Fontan surgery. Forty-nine consecutive patients were assigned to undergo either a fenestrated (25 patients) or nonfenestrated (24 patients) Fontan procedure. The fenestrated and nonfenestrated groups were comparable with respect to age (
P
=0.944), body surface area (
P
=0.250), number of preoperative risk factors for poor outcome (
P
=0.681), cardiopulmonary bypass time (
P
=0.302), number of patients who required aortic cross-clamping (
P
=0.240), preoperative oxygen saturation (
P
=0.101), and number of patients with dominant left ventricular morphology (
P
=0.534). Patients in the fenestrated group had 55% less total chest tube drainage (
P
=0.036), 41% shorter total hospitalization (
P
=0.018), and 67% fewer additional procedures in the postoperative period (
P
=0.006) than those in the nonfenestrated group.

Conclusions
—

Baffle fenestration performed at the time of Fontan surgery improves short-term outcome in standard-risk patients by decreasing pleural drainage, hospital length of stay, and need for additional postoperative procedures.
Comparative Effects of Estrogen and Angiotensin-Converting Enzyme Inhibition on Plasminogen Activator Inhibitor-1 in Healthy Postmenopausal Women
Authors: Brown Nancy J. , Abbas Amira , Byrne Daniel , Schoenhard John A. , Vaughan Douglas E.
Published: July 2002

Background

—

This study compares the effect of estrogens and ACE inhibition on plasminogen activator inhibitor-1 (PAI-1) concentrations in healthy postmenopausal women, genotyped for a 4G/5G polymorphism in the
PAI-1
promoter, a polymorphism shown to influence PAI-1 concentrations.

Methods and Results

—

Morning estradiol, PAI-1, tissue plasminogen activator, plasma renin activity, angiotensin II, and aldosterone were measured in 19 postmenopausal women (5G/5G:4G/5G:4G4G=5:10:4, respectively) at baseline and during randomized, single-blind, crossover treatment with conjugated equine estrogens 0.625 mg per os per day, ramipril 10 mg per os per day, and combination estrogens and ramipril. Estradiol (
P
<0.005) and angiotensin II (
P
<0.01) were significantly higher during estrogens. Plasma renin activity was significantly increased during ACE inhibition (
P
<0.05). Both conjugated estrogens [PAI-1 antigen from 12.5 (7.6, 17.4) [mean (95% CI)] baseline to 6.6 (2.6, 10.7) ng/mL,
P
<0.01] and ACE inhibition [8.3 (4.9, 11.7) ng/mL,
P
<0.005] decreased PAI-1 without decreasing tissue plasminogen activator. The effect of combined therapy on PAI-1 [5.6 (2.3, 8.8) ng/mL] was significantly greater than that of ramipril alone (
P
<0.05). There was a significant effect of
PAI-1
4G/5G genotype on baseline PAI-1 concentrations (
P
=0.001) and a significant interactive effect of 4G/5G genotype and treatment, such that genotype influenced the change in PAI-1 during ramipril (
P
=0.011) or combined therapy (
P
=0.006) but not during estrogens (
P
=0.715).

Conclusions

—

ACE inhibition with ramipril and conjugated estrogens similarly decrease PAI-1 antigen concentrations in postmenopausal women. Larger studies that use clinical outcomes are needed to determine whether
PAI-1
4G/5G genotype should influence the choice of conjugated estrogens or ACE inhibition for the treatment of healthy postmenopausal women.
Clinical, Genetic, and Biophysical Characterization of
SCN5A
Mutations Associated With Atrioventricular Conduction Block
Authors: Wang Dao W. , Viswanathan Prakash C. , Balser Jeffrey R. , George Alfred L. , Benson D. Woodrow
Published: July 2002

Background

—

Three distinct cardiac arrhythmia disorders, the long-QT syndrome, Brugada syndrome, and conduction system disease, have been associated with heterozygous mutations in the cardiac voltage-gated sodium channel α-subunit gene (
SCN5A
). We present clinical, genetic, and biophysical features of 2 new
SCN5A
mutations that result in atrioventricular (AV) conduction block.

Methods and Results

—

SCN5A
was used as a candidate gene in 2 children with AV block. Molecular genetic studies revealed G to A transition mutations that resulted in the substitution of serine for glycine (G298S) in the domain I S5-S6 loop and asparagine for aspartic acid (D1595N) within the S3 segment of domain IV. The functional consequences of G298S and D1595N were assessed by whole-cell patch clamp recording of recombinant mutant channels coexpressed with the β1 subunit in a cultured cell line (tsA201). Both mutations impair fast inactivation but do not exhibit sustained non-inactivating currents. The mutations also reduce sodium current density and enhance slower inactivation components. Action potential simulations predict that this combination of biophysical abnormalities will significantly slow myocardial conduction velocity.

Conclusions

—

A distinct pattern of biophysical abnormalities not previously observed for any other
SCN5A
mutant have been recognized in association with AV block. These data provide insight into the distinct clinical phenotypes resulting from mutation of a single ion channel.
TIMI Myocardial Perfusion Grade and ST Segment Resolution: Association With Infarct Size as Assessed by Single Photon Emission Computed Tomography Imaging
Authors: Angeja Brad G. , Gunda Madhavi , Murphy Sabina A. , Sobel Burton E. , Rundle Amy C. , Syed Mushabbar , Asfour Abdelrahim , Borzak Steven , Gourlay Steven G. , Barron Hal V. , Gibbons Raymond J. , Gibson C. Michael
Published: July 2002

Background

—

The TIMI myocardial perfusion grade (TMPG) and ST-segment resolution both reflect perfusion and are associated with mortality after thrombolysis for acute myocardial infarction. We hypothesized that these measures would also be associated with infarct size by single photon emission computed tomography (SPECT).

Methods and Results

—

In the LIMIT AMI trial (Limitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) of lytic monotherapy versus lytic plus rhuMAb CD18, early 90-minute TMPG (n=221) and ST segment resolution (n=242) were compared with subsequent SPECT Technetium-99 m Sestamibi, measuring the percentage of the left ventricle with no Sestamibi uptake. Infarct sizes were larger with TMPG 0 or 1 (a closed or stained myocardium) than with TMPG 2 or 3 (open myocardium, median 13% versus 7%,
P
=0.004). Infarcts were also larger in patients with no ST segment resolution (median 15%) or incomplete resolution (11%) than in those with complete resolution (6%, overall
P
=0.0001). The difference in infarct size by TMPG persisted when stratified by category of ST resolution.

Conclusions

—

There may be a pathophysiological link between early restoration of tissue-level perfusion and reduced subsequent infarct size that may partially explain why these early angiographic and electrocardiographic measures are associated with long-term survival.
Pivotal Role of a gp91
phox
-Containing NADPH Oxidase in Angiotensin II-Induced Cardiac Hypertrophy in Mice
Authors: Bendall Jennifer K. , Cave Alison C. , Heymes Christophe , Gall Nicholas , Shah Ajay M.
Published: July 2002

Background

—

Angiotensin II induces both cardiac and vascular smooth muscle (VSM) hypertrophy. Recent studies suggest a central role for a phagocyte-type NADPH oxidase in angiotensin II-induced VSM hypertrophy. The possible involvement of an NADPH oxidase in the development of cardiac hypertrophy has not been studied.

Methods and Results

—

Mice with targeted disruption of the NADPH oxidase subunit gp91
phox
(gp91
phox−/−
) and matched wild-type mice were subjected to subcutaneous angiotensin II infusion at a subpressor dose (0.3 mg/kg/day) for 2 weeks. Systolic blood pressure was unaltered by angiotensin II in either group. Angiotensin II significantly increased heart/body weight ratio, atrial natriuretic factor and β-myosin heavy chain mRNA expression, myocyte area, and cardiac collagen content in wild-type but not gp91
phox−/−
mice. Angiotensin II treatment increased myocardial NADPH oxidase activity in wild-type but not gp91
phox−/−
mice.

Conclusions

—

A gp91
phox
-containing NADPH oxidase plays an important role in the development of angiotensin II-induced cardiac hypertrophy, independent of changes in blood pressure.
Stromelysin-1 (Matrix Metalloproteinase-3) and Tissue Inhibitor of Metalloproteinase-3 Are Overexpressed in the Wall of Abdominal Aortic Aneurysms
Authors: Carrell Tom W.G. , Burnand Kevin G. , Wells Graham M.A. , Clements John M. , Smith Alberto
Published: July 2002

Background
—

Atherosclerosis is implicated in the pathogenesis of abdominal aortic aneurysm (AAA) but more often causes aortic occlusive disease (AOD). The matrix metalloproteinases (MMPs) degrade extracellular matrix and may play a central role in the pathogenesis of AAA. The aim of this study was to examine differences in the patterns of MMP and MMP inhibitor expression between AAA and AOD.

Methods and Results
—

The expression of mRNA for 14 MMPs and 4 tissue inhibitors of metalloproteinases (TIMPs) was estimated in samples of aortic wall from 8 patients with AAA and 8 with AOD using the reverse-transcriptase polymerase chain reaction with a synthetic multicompetitor standard. AAA wall expressed significantly more stromelysin-1 (MMP-3) (mean log
10
ratio [copy enzyme cDNA/copy GAPDH cDNA], −1.9; range, −3.3 to −0.7) than the AOD wall (mean, 4; range, −5.7 to −2.4),
P
<0.005. TIMP-3 expression was significantly higher in AAA (mean, −1.7; range, −2.9 to −1.0) than AOD (mean, −3.6; range, −5.7 to −1.8),
P
<0.01. Expression of 8 other MMPs (1, 2, 7, 9, 11, 12, 14, and 17) was detected and was similar in AAA and AOD. Expression of the remaining 5 MMPs (−8, −10, −13, −15, and −16) was not detected in any of the samples.

Conclusions
—

Both AAA and AOD walls express similar levels of a wide range of MMPs, including cell membrane–bound MT-MMPs. Stromelysin-1 (MMP-3) and TIMP-3 were, however, over expressed in the AAA samples and may be involved aneurysm pathogenesis. Stromelysin-1 could provide a target for pharmacological inhibition.
Electroanatomic Substrate of Idiopathic Left Ventricular Tachycardia
Authors: Ouyang Feifan , Cappato Riccardo , Ernst Sabine , Goya Masahiko , Volkmer Marius , Hebe Joachim , Antz Matthias , Vogtmann Thomas , Schaumann Anselm , Fotuhi Parwis , Hoffmann-Riem Martin , Kuck Karl-Heinz
Published: July 2002

Background
—

An abnormal potential (retroPP) from the left posterior Purkinje network has been demonstrated during sinus rhythm (SR) in some patients with idiopathic left ventricular tachycardia (ILVT). We hypothesized that this potential can specifically be identified and be a critical substrate for ILVT.

Methods and Results
—

In 9 patients with ILVT and 6 control patients who underwent mapping of the left ventricle during SR using 3-dimensional electroanatomic mapping, an area with retroPP was found within the posterior Purkinje fiber network only in patients with ILVT. The earliest and latest retroPP was 185.4±57.4 and 465.2±37.3 ms after Purkinje potential; in the other patient with ILVT, an entire left ventricle mapping demonstrated a slow conduction area and passive retrograde activation along the posterior fascicle during ILVT. ILVT was noninducible in 3 patients after SR mapping. Diastolic potentials critical for ILVT during ILVT coincided with the earliest retroPP during SR in 7 patients. Mechanical termination of ILVT occurred in 5 patients. A single radiofrequency pulse was applied at the site with mechanical translation in 5 patients and the site with diastolic potential in 2 patients, and 3 radiofrequency pulses were delivered to the site with the earliest retroPP in the other 3 patients without inducible ILVT after SR mapping. No ILVT was inducible during control stimulation, and none recurred during follow-up of 9.1±5.1 months.

Conclusion
—

In patients with ILVT, abnormal retroPP within the posterior Purkinje fiber network is a common finding. The earliest retroPP critical for ILVT substrate can be used for guiding successful ablation.
Noninvasive Assessment of Coronary Microcirculatory Function in Postmenopausal Women and Effects of Short-Term and Long-Term Estrogen Administration
Authors: Campisi Roxana , Nathan Lauren , Pampaloni Miguel Hernandez , Schöder Heiko , Sayre James W. , Chaudhuri Gautam , Schelbert Heinrich R.
Published: July 2002

Background
—

Estrogen improves endothelial function in the coronary conduit vessels of animals; however, its effects on the coronary microcirculation have not been studied completely in humans.

Methods and Results
—

We measured myocardial blood flow (MBF) with a PET scan at rest, during cold pressor testing (CPT), and during dipyridamole hyperemia in 54 postmenopausal women without coronary artery disease. Of these, 23 were not and 31 women were taking long-term hormone replacement therapy (HRT) using estrogen either alone or with a progestogen. Each group was subdivided by coronary risk factors (RFs). Twelve young healthy women served as controls. In women not taking HRT, MBF measurements were repeated after 25 mg of conjugated equine estrogens IV. Neither short estrogen nor long-term HRT affected MBF at rest in women with and without RFs. Dipyridamole MBF was attenuated only in the women with RF who were not taking HRT. Short-term estrogen and long-term HRT did not reverse the abnormal response. MBF responses to CPT were abnormal in women not taking HRT, regardless of RFs (20±15% versus 32±21%) and remained unchanged after short-term estrogen administration. Long-term HRT normalized the response to CPT only in women without RF (53±22% versus 59±36% in the young women; NS). MBFs were similar for women on estrogen alone or estrogen plus a progestogen, regardless of presence or absence of RFs.

Conclusion
—

Menopause is associated with abnormal CPT (an indirect measure of endothelial function), which can be reversed by long-term HRT only when RFs are absent. Progestogens do not antagonize this effect. Long-term HRT may therefore be useful in the primary prevention of coronary artery disease in women without RFs.
Monocyte/Macrophage Regulation of Vascular Calcification In Vitro
Authors: Tintut Yin , Patel Jignesh , Territo Mary , Saini Trishal , Parhami Farhad , Demer Linda L.
Published: July 2002

Background

—

Calcification is a common complication of atherosclerosis and other chronic inflammatory processes that involves infiltration of monocytes and accumulation of macrophages.

Methods and Results

—

To determine whether these cells modulate vascular calcification in vitro, calcifying vascular cells (CVCs), a subpopulation of osteoblast-like cells derived from the artery wall, were cocultured with human peripheral blood monocytes for 5 days. Results showed that alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation, was significantly greater in cocultures than in cultures of CVCs or monocytes alone. Both ALP activity and matrix mineralization increased in proportion to the number of monocytes added. Activation of monocyte/macrophages (M/Ms) by oxidized LDL further increased ALP activity in cocultures. However, neither conditioned medium from oxidized-LDL–activated M/Ms or transwell coculture had this effect on CVCs, which suggests a need for cell-to-cell contact. In contrast, conditioned medium from lipopolysaccharide-activated M/Ms increased ALP activity of CVCs. ELISA showed that lipopolysaccharide-activated M/Ms secreted tumor necrosis factor-α, and neutralizing antibody to tumor necrosis factor-α attenuated the induction of ALP activity by the conditioned media.

Conclusions

—

These results suggest that M/Ms enhance in vitro vascular calcification via 2 independent mechanisms: cell-cell interaction and production of soluble factors such as tumor necrosis factor-α.
Gene Therapy Strategy for Long-Term Myocardial Protection Using Adeno-Associated Virus-Mediated Delivery of Heme Oxygenase Gene
Authors: Melo Luis G. , Agrawal Reitu , Zhang Lunan , Rezvani Mojgan , Mangi Abeel A. , Ehsan Afshin , Griese Daniel P. , Dell’Acqua Giorgio , Mann Michael J. , Oyama Junichi , Yet Shaw-Fang , Layne Matthew D. , Perrella Mark A. , Dzau Victor J.
Published: July 2002

Background

—

Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury.

Methods and Results

—

Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1β protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death.

Conclusions

—

This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel “pre-event” gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.
Systemic Production of Vascular Endothelial Growth Factor and
fms
-Like Tyrosine Kinase-1 Receptor in Acute Kawasaki Disease
Authors: Yasukawa Kumi , Terai Masaru , Shulman Stanford T. , Toyozaki Tetsuya , Yajima Shigehiro , Kohno Yoichi , Rowley Anne H.
Published: July 2002

Background

—

Increased vascular permeability is an important event during the initial process of Kawasaki disease (KD). One potential responsible candidate for the induction of vascular hyperpermeability is vascular endothelial growth factor (VEGF).

Methods and Results

—

We investigated the expression of VEGF and its receptors (flt-1, KDR) in acute KD tissues at 7 days to 5 weeks of illness. Neuropilin-1, which enhances the binding of VEGF
165
to KDR, was also studied. Abundant expression of VEGF and flt-1 was documented immunohistochemically in many organs from acute KD, including heart and lung. VEGF and flt-1 were colocalized in all vessels that showed edema. These molecules resided in endothelium and vascular media and also in migrating smooth muscle cells in neointima and infiltrating macrophages. Compared with controls, coronary vessels of acute KD had upregulation of VEGF and flt-1 but not KDR or neuropilin-1. KDR was expressed by vessels at 7 days of illness but not later in the illness. Plasma proteins were more extensively bound to the extracellular matrix in coronary vessels in acute KD than controls. Furthermore, elevation of serum VEGF levels was correlated with low serum albumin in acute KD (n=220,
r
=−0.53,
P
<0.001).

Conclusions

—

These findings suggest that VEGF and flt-1 are upregulated in blood vessels in many organs of acute KD. Expression of KDR was limited to the early stage of acute KD. The roles of VEGF in acute KD may involve promotion of vascular permeability and macrophage activation. Low serum albumin may indicate overproduction of VEGF in acute KD.
Cell Membrane
Trans
-Fatty Acids and the Risk of Primary Cardiac Arrest
Authors: Lemaitre Rozenn N. , King Irena B. , Raghunathan Trivellore E. , Pearce Rachel M. , Weinmann Sheila , Knopp Robert H. , Copass Michael K. , Cobb Leonard A. , Siscovick David S.
Published: July 2002

Background

—

The relation of
trans
-fatty acid intake to life-threatening arrhythmias and primary cardiac arrest is unknown.

Methods and Results

—

We investigated the association of
trans
-fatty acid intake, assessed through a biomarker, with the risk of primary cardiac arrest in a population-based case-control study. Cases, aged 25 to 74 years, were out-of-hospital cardiac arrest patients attended by paramedics in Seattle, Washington from 1988 to 1999 (n=179). Controls, matched to cases by age and sex, were randomly identified from the community (n=285). Participants were free of previous clinically diagnosed heart disease. Blood was obtained at the time of cardiac arrest (cases) or at the time of an interview (controls) to assess
trans
-fatty acid intake. Higher total
trans
-fatty acids in red blood cell membranes was associated with a modest increase in the risk of primary cardiac arrest after adjustment for medical and lifestyle risk factors (odds ratio for interquintile range, 1.5; 95% CI, 1.0 to 2.1). However,
trans
isomers of oleic acid were not associated with risk (odds ratio for interquintile range, 0.8; 95% CI, 0.5 to 1.2), whereas higher levels of
trans
isomers of linoleic acid were associated with 3-fold increase in risk (odds ratio for interquintile range, 3.1; 95% CI, 1.7 to 5.4).

Conclusions

—

These findings suggest that dietary intake of total
trans
-fatty acids is associated with modest increase and
trans
isomers of linoleic acid with a larger increase in the risk of primary cardiac arrest. These associations need to be confirmed in future studies that distinguish between
trans
isomers of linoleic acid and
trans
isomers of oleic acid.
Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention
Authors: Chan Albert W. , Bhatt Deepak L. , Chew Derek P. , Quinn Martin J. , Moliterno David J. , Topol Eric J. , Ellis Stephen G.
Published: July 2002

Background

—

Long-term administration of statin therapy has been shown to reduce major coronary events and cardiac mortality within randomized clinical trials. In addition to lowering lipids, statins favorably affect platelet adhesion, thrombosis, endothelial function, inflammation, and plaque stability, which may potentially improve outcome after percutaneous coronary intervention (PCI). Therefore, we hypothesized that statin therapy has an early beneficial effect among patients undergoing PCI.

Methods and Results

—

Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non–statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were treated with statin at the time of the procedure. Statin therapy was associated with a mortality reduction at 30 days (0.8% versus 1.5%; hazard ratio, 0.53;
P
=0.048) and at 6 months (2.4% versus 3.6%; hazard ratio, 0.67;
P
=0.046). After adjusting for the propensity to receive statin therapy before the procedure and other confounders, statin therapy remained an independent predictor for survival at 6 months after coronary intervention (hazard ratio, 0.65; 95% CI, 0.42 to 0.99;
P
=0.045).

Conclusions

—

In this large study cohort, statin therapy among PCI patients seems to be associated with a significant mortality advantage at early and intermediate-term follow-up.
Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration
Authors: Iwaguro Hideki , Yamaguchi Jun-ichi , Kalka Christoph , Murasawa Satoshi , Masuda Haruchika , Hayashi Shin-ichiro , Silver Marcy , Li Tong , Isner Jeffrey M. , Asahara Takayuki
Published: July 2002

Background

—

Previous studies have established that bone marrow–derived endothelial progenitor cells (EPCs) are present in the systemic circulation. In the current study, we investigated the hypothesis that gene transfer can be used to achieve phenotypic modulation of EPCs.

Methods and Results

—

In vitro, ex vivo murine vascular endothelial growth factor (VEGF) 164 gene transfer augmented EPC proliferative activity and enhanced adhesion and incorporation of EPCs into quiescent as well as activated endothelial cell monolayers. To determine if such phenotypic modulation may facilitate therapeutic neovascularization, heterologous EPCs transduced with adenovirus encoding VEGF were administered to athymic nude mice with hindlimb ischemia; neovascularization and blood flow recovery were both improved, and limb necrosis/autoamputation were reduced by 63.7% in comparison with control animals. The dose of EPCs used for the in vivo experiments was 30 times less than that required in previous trials of EPC transplantation to improve ischemic limb salvage. Necropsy analysis of animals that received DiI-labeled VEGF-transduced EPCs confirmed that enhanced EPC incorporation demonstrated in vitro contributed to in vivo neovascularization as well.

Conclusions

—

In vitro, VEGF EPC gene transfer enhances EPC proliferation, adhesion, and incorporation into endothelial cell monolayers. In vivo, gene-modified EPCs facilitate the strategy of cell transplantation to augment naturally impaired neovascularization in an animal model of experimentally induced limb ischemia.
Isthmus Characteristics of Reentrant Ventricular Tachycardia After Myocardial Infarction
Authors: de Chillou Christian , Lacroix Dominique , Klug Didier , Magnin-Poull Isabelle , Marquié Christelle , Messier Marc , Andronache Marius , Kouakam Claude , Sadoul Nicolas , Chen Jian , Aliot Etienne , Kacet Salem
Published: July 2002

Background

—

The reentrant mechanism of postinfarct ventricular tachycardia (VT) has been documented by surgical mapping analysis, but little is known about postinfarct VT circuits and the characteristics of their related protected isthmus with the use of 3D catheter mapping systems.

Methods and Results

—

A 3D electroanatomic mapping was performed in 21 patients with well-tolerated, postinfarct, sustained VT. In total, 33 episodes of tachycardia (mean cycle length 432±74 ms) were induced and mapped. Complete maps demonstrated macroreentrant circuits with 1 loop (n=8) or 2 loops (n=25) rotating around a protected isthmus bounded by 2 approximately parallel conduction barriers that consisted of a line of double potentials, a scar area, or the mitral annulus. A total of 26 critical isthmi were identified for the 33 VTs mapped, with the same isthmus being shared by 2 to 4 different tachycardic morphologies in 5 patients. On average, isthmi were 31±7 mm long (ranging from 18 to 41 mm) and 16±8 mm wide (ranging from 6 to 36 mm) and harbored diastolic electrograms. The isthmus axis was oriented parallel to the mitral annulus plane in perimitral circuits and perpendicular to the mitral annulus plane in all other circuits. Linear radiofrequency ablation performed across the most accessible part of the isthmus prevented the recurrence of tachycardia in 19 patients (90%) with a follow-up at 16±8 months.

Conclusions

—

Detailed 3D electroanatomic mapping is helpful in reconstructing postinfarct VT circuits and in defining the characteristics of their related protected isthmi. The wide range of isthmus width values supports the need of linear radiofrequency lesions to eliminate the reentrant substrate of postinfarct VTs.
Cardiac Autonomic Dysfunction in Brugada Syndrome
Authors: Wichter Thomas , Matheja Peter , Eckardt Lars , Kies Peter , Schäfers Klaus , Schulze-Bahr Eric , Haverkamp Wilhelm , Borggrefe Martin , Schober Otmar , Breithardt Günter , Schäfers Michael
Published: July 2002

Background

—

Patients with Brugada syndrome present with characteristic ECG abnormalities (atypical right bundle-branch block and ST-segment elevation) and life-threatening ventricular tachyarrhythmias despite structurally normal hearts. Involvement of the autonomic nervous system is suggested by the occurrence of ventricular tachyarrhythmias and sudden death at rest or during sleep and by changes of typical ECG signs under pharmacological modulation of the myocardial autonomic tone.

Methods and Results

—

This study investigated the presynaptic cardiac neuronal reuptake of norepinephrine (uptake 1) in 17 patients with Brugada syndrome and 10 age-matched control subjects with the use of the norepinephrine analogue [
123
I]
m
-iodobenzylguanidine (
123
I-MIBG), single-photon emission CT (SPECT), and quantitative 33-segment bull’s-eye analysis. Regionally reduced
123
I-MIBG uptake was present in 8 (47%) of 17 patients with Brugada syndrome but in none of the control subjects. Quantitative analysis showed segmental reduction of
123
I-MIBG uptake in the inferior and septal left ventricular wall in patients with Brugada syndrome compared with control subjects (
P
<0.05). No correlation was found between the findings of
123
I-MIBG-SPECT and clinical characteristics of the study patients.

Conclusions

—

The present study demonstrated an abnormal
123
I-MIBG uptake in patients with Brugada syndrome, indicating presynaptic sympathetic dysfunction of the heart. These findings may have potential impact on the pathophysiology and arrhythmogenesis in patients with Brugada syndrome. Future quantitative investigations of the presynaptic and postsynaptic sympathetic and parasympathetic branches of the cardiac autonomic nervous system may clarify whether these observations represent a primary adrenergic dysfunction or an imbalance between sympathetic and parasympathetic innervation of the heart.
Effect of Hypercholesterolemia on Expression and Function of Vascular Soluble Guanylyl Cyclase
Authors: Laber Ute , Kober Thorsten , Schmitz Verena , Schrammel Astrid , Meyer Wilfried , Mayer Bernd , Weber Martina , Kojda Georg
Published: July 2002

Background
—

Vasorelaxation to endothelial NO is mediated by activation of soluble guanylyl cyclase (sGC) and impaired by hypercholesterolemia in animals and humans. We investigated whether hypercholesterolemia impacts expression and function of sGC.

Methods and Results
—

White New Zealand rabbits (n=10 per group) received a standard diet for 16 weeks (SD16) (n=20) or 32 weeks (SD32) and a cholesterol diet (7.5 g/kg) for 16 weeks (CD16) (n=20) or 32 weeks (CD32), respectively. Another group received cholesterol diet for 16 weeks followed by standard diet for 16 weeks (CD/SD). Aortic expression of the α
1
-subunit of sGC (sGC-α
1
) and β
1
-subunit of sGC (sGC-β
1
) was assessed by Western blot. Function was measured by aortic relaxation to S-Nitroso-
N
-acetyl-D, L-penicillamine (SNAP) and sGC activity in aortic cytosols. Hypercholesterolemia induced an upregulation of sGC-β
1
in CD16 (3.5±0.4-fold,
P
<0.001 versus SD16) and CD32 (4.0±0.4-fold,
P
<0.001 versus SD32). A similar increase was found for sGC-α
1
. In striking contrast, basal and NO-stimulated sGC activities in aortic cytosols of CD16 were only slightly enhanced (1.4-fold,
P
<0.05). Furthermore, the vasodilator potency of SNAP (EC
50
in −logM) was 10-fold lower in CD16 (6.76±0.09) than in SD16 (7.66±0.14,
P
<0.01). The increase of sGC expression was completely reversible, as indicated by comparable sGC-β
1
amounts in SD32 and CD/SD (1.2±0.1-fold,
P
>0.05). Immunohistochemical analysis suggests that a great portion of the overexpressed sGC is located in intimal lesions. Additional experiments showed that increased vascular superoxide production induced by 6-anilino-5,8-quinolinedione (LY85385) reduces sGC-activity but increases sGC-expression.

Conclusions
—

These results suggest that hypercholesterolemia induces a reversible overexpression of a dysfunctional vascular sGC, which may contribute to the pathogenesis of atherosclerosis.
Relationship Between Treatment-Induced Changes in Left Ventricular Mass and Blood Pressure in Black African Hypertensive Patients
Authors: Skudicky Daniel , Sareli Pinhas , Libhaber Elena , Candy Geoffrey , Radevski Ivo , Valtchanova Zdravska , Tshele Elizabeth , Thijs Lutgarde , Wang Ji-Guang , Staessen Jan A.
Published: July 2002

Background
—

In a single-center study, we compared to what extent changes in conventional and ambulatory blood pressure (BP) predicted regression of left ventricular mass (LVM) index in response to antihypertensive treatment in previously untreated and treated patients with sustained hypertension.

Methods and Results
—

We enrolled 173 black African patients who, off treatment, had a daytime diastolic BP ranging from 90 to 114 mm Hg. Antihypertensive drugs were titrated and combined to reduce the daytime diastolic BP below 90 mm Hg. Echocardiograms were obtained at baseline and follow-up. Mean systolic/diastolic clinic BP, 24-hour BP, and LVM index were similar in previously untreated (n=64) and previously treated (n=109) patients and averaged 171/102 mm Hg, 151/97 mm Hg, and 118 g/m
2
, respectively. At 4 months, these values had decreased (
P
<0.001) by 26/12 mm Hg, 23/14 mm Hg, and 14 g/m
2
in previously untreated patients and by 22/9 mm Hg, 21/13 mm Hg, and 19 g/m
2
in previously treated patients. In the previously untreated patients, the regression in LVM index correlated to a similar degree (
P
=0.09) with the decreases in the conventional (
r
=0.34;
P
=0.005) and the 24-hour (
r
=0.26;
P
=0.04) systolic BP. In the previously treated patients, the corresponding correlations were 0.02 (
P
=0.82) and −0.10 (
P
=0.32), respectively. Compared with the 24-hour systolic BP, automated oscillometric measurements of systolic BP obtained at the clinic yielded similar results.

Conclusions
—

In previously untreated patients with sustained hypertension followed at a single center, reductions in clinic and ambulatory systolic pressure in response to antihypertensive treatment equally predicted the regression in LVM index.
Maternal Anti-Ro and Anti-La Antibody–Associated Endocardial Fibroelastosis
Authors: Nield Lynne E. , Silverman Earl D. , Taylor Glenn P. , Smallhorn Jeffrey F. , Mullen J. Brendan M. , Silverman Norman H. , Finley John P. , Law Yuk M. , Human Derek G. , Seaward P. Gareth , Hamilton Robert M. , Hornberger Lisa K.
Published: July 2002

Background
—

Maternal anti-Ro and anti-La antibodies are associated with congenital heart block (CHB). Although endocardial fibroelastosis (EFE) has been described in isolated cases of autoantibody-mediated CHB, the natural history and pathogenesis of this disease are poorly understood.

Methods and Results
—

We retrospectively reviewed the clinical history, echocardiography, and pathology of fetuses and children with EFE associated with CHB born to mothers positive for anti-Ro or anti-La antibodies at 5 centers. Thirteen patients were identified, 6 with a prenatal and 7 with a postnatal diagnosis. Six mothers were positive for anti-Ro and anti-La antibodies, and 7 were positive for anti-Ro antibodies only. Only 1 mother had autoimmune disease. Severe ventricular dysfunction was seen in all fetal and postnatal cases. Four fetal and 3 postnatal cases had EFE at initial presentation. However, 2 fetal and 4 postnatal cases developed EFE 6 to 12 weeks and 7 months to 5 years from CHB diagnosis, respectively, even despite ventricular pacing in 6 postnatal cases. Eleven (85%) either died (n=9) or underwent cardiac transplantation (n=2) secondary to the EFE. Pathologic assessment of the explanted heart, available in 10 cases, revealed moderate to severe EFE in 7 and mild EFE in 3 cases, predominantly involving the left ventricle. Immunohistochemistry in 4 cases (including 3 fetuses) demonstrated deposition of IgG in 4 and IgM in 3 and T-cell infiltrates in 3 cases, suggesting an immune response by the affected fetus or child.

Conclusions
—

EFE occurs in the presence of autoantibody-mediated CHB despite adequate ventricular pacing. Autoantibody-associated EFE has a very high mortality rate, whether developing in fetal or postnatal life.
Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functions in Obese Women After Weight Loss Over One Year
Authors: Ziccardi Patrizia , Nappo Francesco , Giugliano Giovanni , Esposito Katherine , Marfella Raffaele , Cioffi Michele , D’Andrea Francesco , Molinari Anna Maria , Giugliano Dario
Published: July 2002

Background
—

Visceral fat is a key regulator site for the process of inflammation, and atherosclerotic lesions are essentially an inflammatory response.

Methods and Results
—

Fifty-six healthy premenopausal obese women (age range 25 to 44 years, body mass index 37.2±2.2, waist to hip ratio range 0.78 to 0.92) and 40 age-matched normal weight women were studied. Compared with nonobese women, obese women had increased basal concentrations of tumor necrosis factor-α (TNF-α,
P
<0.01), interleukin-6 (IL-6,
P
<0.01), P-selectin (
P
<0.01), intercellular adhesion molecule-1 (ICAM-1,
P
<0.02), and vascular adhesion molecule-1 (VCAM-1,
P
<0.05). Vascular responses to
l
-arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure (
P
<0.02), platelet aggregation to adenosine diphosphate (
P
<0.05), and blood viscosity (
P
<0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-α and IL-6 were related (
P
<0.01) to visceral obesity, as well as to adhesin levels and responses to
l
-arginine. After 1 year of a multidisciplinary program of weight reduction (diet, exercise, behavioral counseling), all obese women lost at least 10% of their original weight (9.8±1.5 kg, range 7.5 to 13 kg). Compared with baseline, sustained weight loss was associated with reduction of cytokine (
P
<0.01) and adhesin (
P
<0.02) concentrations and with improvement of vascular responses to
l
-arginine.

Conclusion
—

In obese women, endothelial activation correlates with visceral body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating endothelial dysfunction in obese women.