bluuebunny/crossref_metadata_2025 huggingface dataset:
Impairment of Collateral Formation in Lipoprotein(a) Transgenic Mice
Authors: Morishita Ryuichi , Sakaki Minako , Yamamoto Kei , Iguchi Sota , Aoki Motokuni , Yamasaki Keita , Matsumoto Kunio , Nakamura Toshikazu , Lawn Richard , Ogihara Toshio , Kaneda Yasufumi
Published: July 2002

Background—

Although lipoprotein(a) (Lp[a]) is a risk factor for atherosclerosis, no study has documented the effects of Lp(a) on angiogenesis. In this study, we examined collateral formation in peripheral arterial disease (PAD) model in Lp(a) transgenic mice. In addition, we examined the feasibility of gene therapy by using an angiogenic growth factor, hepatocyte growth factor (HGF), to treat PAD in the presence of high Lp(a).

Methods and Results—

In Lp(a) transgenic mice, the degree of natural recovery of blood flow after operation was significantly lower than that in nontransgenic mice. Of importance, there was a significant negative correlation between serum Lp(a) concentration and the degree of natural recovery of blood flow (
P
<0.05). In addition, Lp(a) significantly stimulated the growth of vascular smooth muscle, accompanied by the phosphorylation of ERK. These data demonstrated the association of impairment of collateral formation with serum Lp(a) concentration. Thus, we examined the feasibility of therapeutic angiogenesis by using HGF, with the goal of progression to human gene therapy. Intramuscular injection of HGF plasmid resulted in a significant increase in blood flow even in Lp(a) transgenic mice, accompanied by the detection of human HGF protein. A significant increase in capillary density also was detected in Lp(a) transgenic mice transfected with human HGF compared with control (
P
<0.01).

Conclusions—

Overall, a high serum Lp(a) concentration impaired collateral formation. Although the delay of angiogenesis in high serum Lp(a) might diminish angiogenesis, intramuscular injection of HGF plasmid induced therapeutic angiogenesis in the Lp(a) transgenic ischemic hindlimb mouse model as potential therapy for PAD.
Acute Aortic Dissection Related to Crack Cocaine
Authors: Hsue Priscilla Y. , Salinas Cynthia L. , Bolger Ann F. , Benowitz Neal L. , Waters David D.
Published: July 2002

Background

—

Although single case reports have described acute aortic dissection in relation to cocaine use, this condition is not widely recognized, and the features of cocaine-related aortic dissection have not been defined.

Methods and Results

—

We reviewed all available hospital charts from 1981 to 2001 with the ICD-9 diagnosis of aortic dissection. Among the 38 cases of acute aortic dissection, 14 (37%) were related to cocaine use. Crack cocaine was smoked in 13 cases and powder cocaine was snorted in 1 case. The mean interval between cocaine use and the onset of symptoms was 12 hours (range, 0 to 24). Patients with cocaine-related dissection were much younger and more likely to undergo surgery compared with patients with aortic dissection without cocaine use. Most in the cocaine group were black, with a history of untreated hypertension. However, the two groups did not differ in other respects, including dissection type.

Conclusions

—

In an inner city population, acute aortic dissection in the setting of crack cocaine use is common, presumably as a consequence of abrupt, transient, severe hypertension and catecholamine release. This diagnosis should be considered in cocaine users with severe chest pain.
Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload
Authors: Chancey Amanda L. , Brower Gregory L. , Peterson J. Thomas , Janicki Joseph S.
Published: July 2002

Background

—

Left ventricular (LV) hypertrophy and dilatation are important compensatory responses to chronic volume overload. Although LV function is initially preserved by these responses, the continued structural remodeling of the myocardium ultimately becomes maladaptive, leading to the development of heart failure. We have shown previously that increased myocardial matrix metalloproteinase (MMP) activity precedes LV dilatation induced by a chronic volume overload. Accordingly, this study focused on the effects of MMP inhibition therapy (PD 166793, 1 mg · kg
−1
· d
−1
) on LV size and function in a rat model of volume overload–induced heart failure.

Methods and Results

—

Rats were divided into the following groups: treated and untreated infrarenal abdominal aortocaval fistula and treated and untreated sham-operated (control). LV weights of both fistula groups were increased above that of the control group (868±79 mg;
P
≤0.001); LV weights in the treated fistula group, however, were lower than in the untreated fistula group at 8 weeks (1447±186 versus 1715±279 mg, respectively;
P
≤0.012). The marked ventricular dilatation seen in the untreated fistula group was significantly diminished in the treated fistula group, although the increase in LV compliance was similar in both treated and untreated fistula hearts.

Conclusions

—

MMP inhibition significantly attenuates the myocardial remodeling associated with chronic volume overload, as evidenced by prevention of dilatation, a marked reduction in LV hypertrophy, and preservation of ventricular function.
Optical Imaging of Cardiac Reporter Gene Expression in Living Rats
Authors: Wu Joseph C. , Inubushi Masayuki , Sundaresan Gobalakrishnan , Schelbert Heinrich R. , Gambhir Sanjiv S.
Published: July 2002

Background

—

Studies of cardiac gene transfer rely on postmortem analysis using histologic staining or enzyme assays. Noninvasive imaging of the temporal and spatial characteristics of cardiac gene expression in the same subject offers significant advantages.

Methods and Results

—

Rats underwent direct myocardial injection via left thoracotomy with adenovirus-expressing firefly luciferase (Ad-CMV-Fluc; n=30). The reporter substrate
d
-luciferin was injected intraperitoneally. Serial images were acquired by use of a cooled charged couple detector (CCD) camera. Results are expressed as relative light unit per minute (RLU/min). Rats transduced with 1×10
9
plaque-forming units show decremental cardiac luciferase activity over time: 152 070±21 170 (day 2), 195 806±62 630 (day 5), 7250±2941 (day 8), and 2040±971 RLU/min (day 14). To assess the detection sensitivity, serially diluted titers of Ad-CMV-Fluc were injected: 1×10
9
(195 393±14 896), 1×10
8
(33 777±18 179), 1×10
7
(417±91), 1×10
6
(185±64), 1×10
5
(53±1), and control (54±1) (
P
<0.05 for 1×10
9
, 1×10
8
, and 1×10
7
plaque-forming units versus control adenovirus-expressing mutant thymidine kinase [Ad-CMV-HSV1-sr39tk]; n=3). Finally, rats were euthanized, and in vitro luciferase activity correlated with in vivo CCD signals (
r
2
=0.92).

Conclusions

—

This study demonstrates for the first time the feasibility of imaging the location, magnitude, and time course of cardiac reporter gene expression in living rats. Cardiac gene therapy studies could be aided with wider application of this approach.
Mitral Ratio of Peak Early to Late Diastolic Filling Velocity as a Predictor of Mortality in Middle-Aged and Elderly Adults
Authors: Bella Jonathan N. , Palmieri Vittorio , Roman Mary J. , Liu Jennifer E. , Welty Thomas K. , Lee Elisa T. , Fabsitz Richard R. , Howard Barbara V. , Devereux Richard B.
Published: July 2002

Background

—

With aging, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity (E/A). However, the prognostic significance of low or high E/A in older adults remains to be elucidated in population-based samples.

Methods and Results

—

Doppler echocardiograms were analyzed in 3008 American Indian participants in the second Strong Heart Study examination who had no more than mild mitral or aortic regurgitation. Participants were followed for a mean of 3 years after Doppler echocardiography to assess risks of all-cause and cardiac death associated with E/A <0.6 or >1.5; 2429 (81%) participants had normal E/A ratio, 490 (16%) had E/A <0.6, and 89 (3%) had E/A >1.5. All-cause mortality was higher with E/A <0.6 or E/A >1.5 (12% and 13% versus 6%), as was cardiac mortality (4.5% and 6.5% versus 1.6%; both
P
<0.001). Adjusting for age, sex, body mass index, systolic blood pressure, HDL and LDL cholesterol, smoking, hypertension, diabetes, coronary heart disease, left ventricular hypertrophy, and low ejection fraction (<40%), the relative risk of all-cause death with E/A >1.5 was 1.73 (95% CI, 0.99 to 3.03;
P
=0.05); the relative risk of cardiac death was 2.8 (95% CI, 1.19 to 6.75;
P
<0.05). E/A <0.6 was not independently associated with increased all-cause or cardiac mortality (
P
=0.19 and 0.31, respectively) after adjusting for covariates.

Conclusions

—

In a population-based sample of middle-aged and elderly adults, mitral E/A >1.5 at baseline Doppler echocardiography is associated with 2-fold increased all-cause and 3-fold increased cardiac mortality independent of covariates; mitral E/A <0.6 was also associated with 2-fold increased all-cause and cardiac mortality but not independent of covariates.
Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein
Authors: Verma Subodh , Li Shu-Hong , Badiwala Mitesh V. , Weisel Richard D. , Fedak Paul W.M. , Li Ren-Ke , Dhillon Bikramjit , Mickle Donald A.G.
Published: July 2002

Background

—

C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis. In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes.

Methods and Results

—

Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 μg/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (
P
<0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (
P
<0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (
P
<0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (
P
<0.01) and were attenuated by both bosentan and IL-6 antagonism (
P
<0.01).

Conclusions

—

CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET
A/B
receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.
Angiostatin Inhibits Coronary Angiogenesis During Impaired Production of Nitric Oxide
Authors: Matsunaga Toshiro , Weihrauch Dorothee W. , Moniz Melinda C. , Tessmer John , Warltier David C. , Chilian William M.
Published: July 2002

Background

—

The in vivo mechanism by which inhibition of NO synthase impairs ischemia-induced coronary vascular growth is unknown. We hypothesized that production of the growth inhibitor angiostatin increases during decreased NO production, blunting angiogenesis and collateral growth.

Methods and Results

—

Measurements were made in myocardial tissue or interstitial fluid (MIF) from dogs undergoing repetitive coronary occlusions under control conditions or during antagonism of NO synthase (
N
G
-nitro-
l
-arginine methyl ester [L-NAME]) for 7, 14, or 21 days. A sham group was instrumented identically but received no occlusions. In controls, capillary density in the ischemic zone increased initially but returned to baseline at the later times. In the L-NAME group, capillary density was lower at 7 days compared with that of controls. MIF from control dogs induced in vitro endothelial tube formation and cell proliferation, significantly greater than that from the L-NAME group. MIF from shams did not stimulate tube formation. In controls or shams, tube formation or cell proliferation did not change after administration of antiangiostatin, but this antibody restored the responses to control levels in the L-NAME group. Angiostatin expression in MIF was increased in the L-NAME group compared with controls and shams. The activities of tissue matrix metalloproteinases (MMPs) MMP-2 and MMP-9, which generate angiostatin, were increased in the L-NAME group.

Conclusions

—

Inhibition of NO synthase increased expression of angiostatin and activities of MMP-2 and MMP-9. Our findings indicate that angiostatin inhibits coronary angiogenesis during compromised NO production and may underscore the impairment of coronary angiogenesis during endothelial dysfunction.
Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium
Authors: Andreka Peter , Aiyar Nambi , Olson Leslie C. , Wei Jian Qin , Turner Mark S. , Webster Keith A. , Ohlstein Eliot H. , Bishopric Nanette H.
Published: July 2002

Background

—

Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium.

Methods and Results

—

Myocardial strips (≈1 mm
3
) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by ≈25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64±0.25-fold and 2.00±0.27-fold over control, respectively,
P
<0.01 for human tissue).

Conclusions

—

Bucindolol exhibits ≈60% of the β-adrenergic agonist activity of xamoterol in normal human myocardial tissue.
Intracoronary Thrombectomy With the X-Sizer Catheter System Improves Epicardial Flow and Accelerates ST-Segment Resolution in Patients With Acute Coronary Syndrome
Authors: Beran Gilbert , Lang Irene , Schreiber Wolfgang , Denk Stefan , Stefenelli Thomas , Syeda Bonni , Maurer Gerald , Glogar Dietmar , Siostrzonek Peter
Published: July 2002

Background

—

In patients with acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) may cause thrombus dislodgment followed by reduced flow and impaired microcirculatory function. We prospectively compared conventional PCI to a strategy of additional pretreatment using the X-sizer thrombectomy system.

Methods and Results

—

Sixty-six patients (51 [77%] men; 54.9±9.9 years) with ACS (49 with ST-elevation infarction [STEMI]) and suspected intracoronary thrombus were randomized 1:1 to pretreatment with X-sizer and conventional PCI alone. Various aspects of epicardial flow and microvascular function were studied. Baseline data were similar in both groups. Postprocedural TIMI 3 flow was obtained in 90% of X-sizer–treated patients and in 84% of controls (NS); however, corrected TIMI frame count was lower in X-sizer– treated patients (18.3±10.2 versus 24.7±14.1;
P
<0.05). No significant group differences were observed in final coronary flow reserve, myocardial blush grade, and myocardial dye intensity. In STEMI, the sum of ST elevation was significantly lower in X-sizer–treated patients immediately after (2.78±3.05 versus 6.15±6.32 mm;
P
<0.03) and 6 hours after (2.17±2.31 versus 4.14±3.7 mm;
P
<0.05) intervention. ST-segment resolution >50% was observed in 83% of X-sizer–treated patients and in 52% of controls (
P
<0.03). Multivariate analysis identified X-sizer treatment as the single independent predictor of ST-segment resolution >50% (OR 4.35; 95% CI, 1.13 to 16.9;
P
<0.04). Major adverse cardiac events after 30 days occurred in 2 patients in each group.

Conclusions

—

In ACS with suspected thrombus, pretreatment with the X-sizer catheter system improves epicardial flow and accelerates ST-segment resolution compared with conventional PCI alone.
Ventricular Afterload and Ventricular Work in Fontan Circulation
Authors: Senzaki Hideaki , Masutani Satoshi , Kobayashi Jun , Kobayashi Toshiki , Sasaki Nozomu , Asano Haruhiko , Kyo Shunei , Yokote Yuji , Ishizawa Akira
Published: July 2002

Background
—

Recent studies have indicated that there are inherent limitations associated with Fontan physiology. However, there have been no quantitative analyses of the effects of right heart bypass on ventricular afterload, hydraulic power, and resultant overall hemodynamics.

Methods and Results
—

During routine cardiac catheterization, aortic impedance and ventricular hydraulic power were determined, both at rest and under increased ventricular work induced by dobutamine, in 17 patients with Fontan circulation, 15 patients with a single ventricle whose pulmonary circulation was maintained only by Blalock-Taussig shunts, and 13 patients who had normal 2-ventricle circulation. Both vascular resistance (nonpulsatile load on the ventricle) and pulsatile components of ventricular afterload (represented by low-frequency impedance) were significantly higher in the Fontan group than in the other groups (
P
<0.01), and this was associated with decreased cardiac output in the Fontan patients. In addition, hydraulic power cost per unit forward flow was 40% lower in the 2-ventricle circulation than in the single-ventricle circulation, suggesting lower ventricular efficiency in single-ventricle circulation attributable to the lack of a pulmonary ventricle. Furthermore, in the Fontan group, β-adrenergic reserve was markedly decreased because of a limited preload reserve.

Conclusions
—

Fontan physiology is associated with disadvantageous ventricular power and afterload profiles and has limited ventricular reserve capacity. Thus, to improve the long-term prognosis of patients after Fontan surgery, future research should be conducted into medical interventions that can overcome these limitations inherent in Fontan circulation.
Antithrombin-Heparin Covalent Complex
Authors: Chan Anthony K.C. , Rak Janusz , Berry Leslie , Liao Peng , Vlasin Michal , Weitz Jeffrey , Klement Petr
Published: July 2002

Background

—

The anticoagulant effect of heparinoids is attributed to their cofactor activity for antithrombin (AT) and heparin cofactor II. In patients with thrombosis, however, thrombin is often protected from AT-dependent, heparin-mediated inactivation. The purpose of this study was to compare the properties of unfractionated/standard heparin (UFH/SH) and those of a novel covalent AT-heparin complex (ATH) in a rabbit arterial thrombosis prevention and bleeding model.

Methods and Results

—

Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored with a flow probe placed distal to the constrictor. Rabbits were given doses of SH (62.5 to 187.5 IU · kg
−1
· 90 min
−1
) or ATH (16 to 65 IU · kg
−1
· 90 min
−1
). Cumulative blood loss from skin incisions was used to assess drug safety. The antithrombotic effects of ATH were greater than those of SH as measured by clot weight, blood flow, and vessel patency; eg, complete thrombus resolution was achieved with ATH (33 to 65 IU/kg), but not SH (125.0 to 187.5 IU/kg). At doses that produced equivalent vessel patency (50% to 60%), blood loss induced by ATH (60.2 μL) was 2.6-fold lower (
P
<0.05) than that induced by SH (154.6 μL).

Conclusions

—

In our experimental system, ATH was able to control arterial thrombosis more effectively than its SH precursor, without pronounced bleeding.
Left Atrial Appendage Activity Masquerading as Pulmonary Vein Potentials
Authors: Shah Dipen , Haissaguerre Michel , Jais Pierre , Hocini Meleze , Yamane Teiichi , Macle Laurent , Choi Kee Joon , Clementy Jacques
Published: July 2002

Background
—

Despite extensive proximal ablation, all potentials frequently cannot be eliminated from the left pulmonary veins (PV).

Methods and Results
—

PV electrograms were analyzed during sinus rhythm, coronary sinus, and left atrial appendage (LAA) pacing, and PV and LAA angiography performed. During pacing, an initial low-amplitude slow potential was recorded on the anterior aspect of the left superior PV and anticipated with shortest activation time by LAA pacing. Its timing coincided with posterior LAA activation, shown to be immediately adjacent to the left superior PV by angiography. In the left inferior PV, the first potential was smaller and less sharp, coinciding with adjacent low LA activation. Angiographically, the LAA was at least 15 mm from the left inferior PV. The second sharper potential in both left PVs was eliminated by proximal ablation.

Conclusion
—

Far field LAA activity consistently adds to PV myocardial electrograms in the left superior PV whereas lower, less sharp extravenous potentials in the left inferior PV originate from the inferior LA. They can be identified by LAA and coronary sinus pacing.
Direct Assessment of Coronary Steal and Associated Changes of Collateral Hemodynamics in Chronic Total Coronary Occlusions
Authors: Werner Gerald S. , Figulla Hans R.
Published: July 2002

Background

—

Coronary steal can occur in collateral-dependent myocardium during pharmacologically induced vasodilation. This study assessed coronary steal invasively in chronic total coronary occlusions (TCOs).

Methods and Results

—

In 35 consecutive patients with a percutaneous transluminal coronary angioplasty of a TCO (duration >4 weeks), coronary flow velocity (APV) by a Doppler wire and distal pressure (P
D
) by a pressure wire were assessed in the collateral-dependent vascular bed before dilatation. Indexes of peripheral resistance (R
P
) and for the collateral pathway, including the donor artery segment (R
CP
), were calculated. Changes of these parameters were assessed during intravenous adenosine (140 μg · kg
−1
· min
−1
). Adenosine caused a decrease of APV, ie, coronary steal, in 13 patients (37%; group S), an increase in 11 patients (group R), and no change in 11 patients (group N). Angiographic analysis of collateral pathways showed no difference between the groups, except that in group S all collateral connections were continuously visible but no large collaterals (>0.5 mm) were found. In group N, collaterals were least developed. The increase of APV in group R was associated with a decrease of R
P
, whereas R
CP
remained unchanged. In contrast, group S showed no change in R
P
but a significant increase of R
CP
, indicating an increased resistance of the donor segment.

Conclusions

—

Coronary steal is observed in about one third of TCOs and is associated with specific hemodynamic changes of R
P
and R
CP
. Steal occurred only with well-developed angiographically visible collaterals but not with very large collaterals.
Age-Dependent Spontaneous Coronary Arterial Thrombosis in Transgenic Mice That Express a Stable Form of Human Plasminogen Activator Inhibitor-1
Authors: Eren Mesut , Painter Corrie A. , Atkinson James B. , Declerck Paul J. , Vaughan Douglas E.
Published: July 2002

Background

—

Plasminogen activator inhibitor-1 (PAI-1) regulates fibrinolysis and has been reported to be an independent risk factor for ischemic cardiovascular events. This study describes the age-dependent development of spontaneous coronary arterial thrombi that are associated with evidence of subendocardial myocardial infarction in mice transgenic for human PAI-1.

Methods and Results

—

We generated two independent transgenic mice founder lines that express a stable variant of active human PAI-1 under control of the murine preproendothelin-1 (mPPET-1) promoter. Backcrossed homozygous transgenic animals from founder line I had plasma PAI-1 levels of 23±12 ng/mL. PAI-1 transgenic animals younger than 4 months do not exhibit any evidence of arterial or venous thrombosis. Ninety percent of transgenic animals (n=10) older than 6 months developed spontaneous occlusions of typically multiple, penetrating coronary arteries, with histological evidence of subendocardial infarction identified in 50% of animals.

Conclusions

—

This study shows that chronically elevated levels of PAI-1 are associated with age-dependent coronary arterial thrombosis in mice transgenic for human PAI-1. This is the first study of a murine model of coronary thrombosis that occurs in the absence of severe hypercholesterolemia or multiple genetic manipulations. These findings provide new evidence to support the hypothesis that PAI-1 excess contributes to the development of coronary arterial thrombosis.
Positron Emission Tomography Imaging of Cardiac Reporter Gene Expression in Living Rats
Authors: Wu Joseph C. , Inubushi Masayuki , Sundaresan Gobalakrishnan , Schelbert Heinrich R. , Gambhir Sanjiv S.
Published: July 2002

Background

—

Imaging reporter gene expression is useful for noninvasive monitoring of gene therapy. In this study, we imaged cardiac reporter gene expression in living rats using micro positron emission tomography (microPET).

Methods and Results

—

Rats (n=10) underwent intramyocardial injection with 1×10
9
pfu of adenovirus carrying cytomegalovirus promoter-driving herpes simplex virus type 1 mutant thymidine kinase (Ad-CMV-HSV1-sr39tk) as PET reporter gene. Control rats (n=4) received 1×10
9
pfu of adenovirus carrying cytomegalovirus promoter-driving firefly luciferase (Ad-CMV-Fluc). On days 2 to 4, microPET images were obtained after a tail vein injection of nitrogen-13 ammonia ([
13
N]-NH
3
) as myocardial perfusion tracer, followed by 9-(4-[
18
F]-fluoro-3 hydroxymethylbutyl) guanine ([
18
F]-FHBG) to assess HSV1-sr39tk expression. After imaging, hearts were removed for ex vivo [
18
F] gamma counting and thymidine kinase enzyme assay. Results show homogenous myocardial distribution of [
13
N]-NH
3
on all microPET images. Rats injected with Ad-CMV-HSV1-sr39tk have significant [
18
F]-FHBG uptake in the anterolateral wall compared with background signal in controls. Gamma counting shows 20.0±4.4-fold increase of radioactivity, whereas enzyme assay shows 22.1±6.1-fold increase of thymidine kinase activity in Ad-CMV-HSV1-sr39tk injected rats (
P
<0.05).

Conclusions

—

Successful imaging of cardiac HSV1-sr39tk expression was performed in living rats with microPET. The presence of [
18
F]-FHBG uptake is confirmed by gamma counting and the presence of HSV1-sr39TK protein by thymidine kinase enzyme assay. Cardiac reporter gene imaging by PET may eventually be applied toward human gene therapy studies.
Acute Effect of Nonsurgical Septal Reduction Therapy on Regional Left Ventricular Asynchrony in Patients With Hypertrophic Obstructive Cardiomyopathy
Authors: Park Tae-Ho , Lakkis Nasser M. , Middleton Katherine J. , Franklin Jennifer , Zoghbi William A. , Quiñones Miguel A. , Spencer William H. , Nagueh Sherif F.
Published: July 2002

Background

—

Patients with hypertrophic obstructive cardiomyopathy have left ventricular (LV) diastolic dysfunction due, in part, to temporal heterogeneity in regional function. The acute effect of the relief of LV outflow tract obstruction is unknown. Therefore, we investigated the effects of nonsurgical septal reduction therapy (NSRT) on regional function.

Methods and Results

—

Twenty-two patients (aged 56±17 years) underwent echocardiographic examination, including tissue Doppler imaging, simultaneously with left heart catheterization before and after NSRT. LV regional function was assessed in 12 segments from which myocardial strain was obtained. Asynchrony was calculated as the coefficient of variation of the time interval from the QRS complex to the onset of expansion and to early diastolic strain. After NSRT, a significant reduction in LV outflow tract obstruction (from 57±5 to 12±3 mm Hg) occurred with shortening of the time constant of LV relaxation (71±4 to 61±3 ms; both
P
<0.05). The coefficient of variation of the time interval to onset of regional expansion decreased significantly and related well to the changes in the time constant of LV relaxation (
r
=0.81,
P
<0.01).

Conclusions

—

NSRT has a favorable effect on LV regional asynchrony, which accounts for the acute changes in LV relaxation.
The Impact of JNC-VI Guidelines on Treatment Recommendations in the US Population
Authors: Muntner Paul , He Jiang , Roccella Edward J. , Whelton Paul K.
Published: July 2002

Using epidemiological and clinical trial evidence, the sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC-VI) updated previous guidelines to suggest that in addition to blood pressure, decisions on initial treatment should emphasize absolute cardiovascular disease risk. We estimated the impact of using cardiovascular disease risk on treatment recommendations for the US population using data from 16 527 participants in the Third National Health and Nutrition Examination Survey. In the US population ≥20 years of age, 36% (62 million) had high-normal blood pressure or greater (systolic/diastolic blood pressure ≥130 mm Hg/≥85 mm Hg) or were taking antihypertensive medication. Of this population, 5.1% (3.2 million) were stratified into risk group A (no cardiovascular disease risk factors or prevalent cardiovascular disease), 66.3% (41.4 million) into risk group B (≥1 major risk factor), and 28.6% (17.9 million) into risk group C (diabetes mellitus, clinical cardiovascular disease, target organ damage). Also, 26% of this group (16.2 million) had high-normal blood pressure and were in risk groups A or B, a context in which vigorous lifestyle modification is recommended in the JNC-VI guidelines. Additionally, 11% (7.0 million) had high-normal blood pressure (systolic/diastolic, 130 to 139 mm Hg/85 to 89 mm Hg, respectively) or stage-1 hypertension (140 to 159 mm Hg/90 to 99 mm Hg), and at least 1 factor, placing them in risk group C, but they were not currently on antihypertensive medication. JNC-VI, but not previous JNC guidelines, specifically recommends drug therapy as initial treatment for these patients. We conclude that JNC-VI refines cardiovascular risk and enfranchises more Americans to undertake more aggressive risk reduction maneuvers.
Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure
Authors: Fujii Masanori , Wada Atsuyuki , Tsutamoto Takayoshi , Ohnishi Masato , Isono Takahiro , Kinoshita Masahiko
Published: July 2002

Both systolic and diastolic cardiac dysfunction coexist in various degrees in the majority of patients with heart failure. Although ACE inhibitors are useful in the treatment of heart failure, the roles of bradykinin in the systolic and diastolic properties of left ventricular function under long-term treatment of ACE inhibitor have not been fully elucidated. We therefore evaluated the changes in left ventricular function, histomorphometry, and the expression of several failing heart related genes, by use of an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg per day), with an ACE inhibitor, enalapril (1 mg/kg per day), in dogs with tachycardia-induced heart failure (270 ppm, 22 days) and compared the effects to enalapril alone. Although there were no differences observed in blood pressure, left ventricular dimension, and percentage of fractional shortening, FR173657 significantly increased left ventricular filling pressure (
P
<0.01), prolonged the time constant of relaxation (
P
<0.05), and suppressed the expression of endothelial NO synthase and sarcoplasmic reticulum Ca
2+
-ATPase mRNA (
P
<0.05). FR173657 also upregulated collagen type I and III mRNA (
P
<0.05) and increased the total amount of cardiac collagen deposits (
P
<0.05) in left ventricle compared with that in the enalapril-treated group. In conclusion, endogenous bradykinin contributes to the cardioprotective effect of ACE inhibitor, improving left ventricular diastolic dysfunction rather than systolic dysfunction, via modification of NO release and Ca
2+
handling and suppression of collagen accumulation.
Effects of Mild Exercise on Insulin Sensitivity in Hypertensive Subjects
Authors: Rhéaume Caroline , Waib Paulo H. , Lacourcière Yves , Nadeau André , Cléroux Jean
Published: July 2002

Physical exercise increases insulin sensitivity in conditions associated with insulin resistance, such as obesity and diabetes, but little is known in this regard in hypertension. Whether postexercise changes in hemodynamics and/or changes in insulin-induced vasodilatation could contribute to a postexercise increase in insulin sensitivity in hypertensive subjects is unknown. We investigated the effects of acute physical exercise on insulin sensitivity in 10 hypertensive and 10 normotensive subjects during a control evaluation (CTRL), during lower body negative pressure (LBNP), after 30 minutes of mild bicycle exercise (POSTEX), and during LBNP after exercise (POSTEX+LBNP). Insulin-induced vasodilatation was assessed from peak forearm blood flow during the intravenous glucose tolerance test. Cardiac output (4.9±0.3 versus 5.3±0.4 L/min, mean±SEM) and insulin sensitivity (the glucose disappearance rate over insulin area under the curve: 0.91±0.07 versus 1.38±0.25 min
−1
/[pmol · L
−1
] · minute) were lower (both
P
<0.05) in hypertensive than in normotensive subjects, respectively. Cardiac output decreased during LBNP, increased during POSTEX, and was similar to control during POSTEX+LBNP in both groups. Insulin sensitivity was unchanged during LBNP, increased during POSTEX, and remained elevated during POSTEX+LBNP in hypertensive subjects, whereas it remained unchanged in normotensives. Peak forearm blood flow was significantly lower in hypertensive than in normotensive subjects, despite higher insulin levels in hypertensives, and was not modified by LBNP or exercise. In conclusion, insulin sensitivity increases after exercise in hypertensive subjects, and the increase in cardiac output does not contribute to this effect. Endogenous insulin-induced vasodilatation is reduced in hypertensive subjects, and this insulin action is not affected by physical exercise.
Brain Sodium Channels Mediate Increases in Brain “Ouabain” and Blood Pressure in Dahl S Rats
Authors: Wang Hao , Leenen Frans H.H.
Published: July 2002

Central infusions of benzamil prevent/reverse salt-induced hypertension in genetic models of salt-sensitive hypertension. Benzamil acts by blockade of ion—presumably sodium—channels. In the present study, we assessed in Dahl salt-sensitive (S) rats on high salt intake whether these channels mediate increases in brain “ouabain” and, thereby, hypertension. Intracerebroventricular (icv) infusions of a low (1.2 μg/kg per hour) or high (4.0 μg/kg per hour) dose of benzamil were given to Dahl S rats on high salt diet (1370 μmol Na
+
/g food) for 2 or 4 weeks. “Ouabain” content was measured using a specific enzyme-linked immunosorbent assay (ELISA). Systolic blood pressure (BP) in Dahl S rats on high salt for 4 weeks increased markedly (188±10 versus 128±4 mm Hg, n=8,
P
<0.05). Benzamil fully blocked this increase (131±7 mm Hg after the high dose of benzamil). Hypothalamic and pituitary “ouabain” increased significantly (22±7 versus 12±3 and 151±38 versus 69±6 ng/g tissue, respectively,
P
<0.05) in Dahl S rats on high salt versus regular salt diet for 2 weeks. Benzamil blocked these increases of brain “ouabain” to high salt intake. Similarly, high salt intake for 4 weeks increased hypothalamic (18±2 versus 13±1 ng/g tissue,
P
<0.05) and pituitary (183±30 versus 78±8 ng/g tissue,
P
<0.05) “ouabain.” Benzamil also inhibited these increases of brain “ouabain.” Both hypothalamic and pituitary “ouabain” showed significant positive correlations with BP. In contrast, high salt intake did not affect “ouabain” levels in the adrenal gland or plasma in Dahl S rats on high salt for either 2 or 4 weeks. These findings indicate that in Dahl S rats high salt intake only increases brain and not peripheral “ouabain” and that benzamil-blockable brain sodium channels mediate the increases in brain “ouabain” and the subsequent hypertension.
Disruption of Inducible Nitric Oxide Synthase Improves β-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy
Authors: Funakoshi Hajime , Kubota Toru , Kawamura Natsumi , Machida Yoji , Feldman Arthur M. , Tsutsui Hiroyuki , Shimokawa Hiroaki , Takeshita Akira
Published: July 2002

Abstract—

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-α develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates β-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt
max
was significantly suppressed, and its β-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved β-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of β-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.
Informal Care for Stroke Survivors
Authors: Dewey H.M. , Thrift A.G. , Mihalopoulos C. , Carter R. , Macdonell R.A.L. , McNeil J.J. , Donnan G.A.
Published: July 2002

Background and Purpose—Informal caregivers play an important role in the lives of stroke patients, but the cost of providing this care has not been estimated. The purpose of this study was to determine the nature and amount of informal care provided to stroke patients and to estimate the economic cost of that care.

Methods—The primary caregivers of stroke patients registered in the North East Melbourne Stroke Incidence Study (NEMESIS) were interviewed at 3, 6, and 12 months after stroke, and the nature and amount of informal care provided were documented. The opportunity and replacement costs of informal care for all first-ever-in-a-lifetime strokes (excluding subarachnoid hemorrhages) that occurred in 1997 in Australia were estimated.

Results—Among 3-month stroke survivors, 74% required assistance with activities of daily living and received informal care from family or friends. Two thirds of primary caregivers were women, and most primary caregivers (>90%) provided care during family or leisure time. Total first-year caregiver time costs for all first-ever-in-a-lifetime strokes were estimated to be A$21.7 million (opportunity cost approach) or A$42.5 million (replacement cost approach), and the present values of lifetime caregiver time costs were estimated to be A$171.4 million (opportunity cost approach) or A$331.8 million (replacement cost approach).

Conclusions—Informal care for stroke survivors represents a significant hidden cost to Australian society. Because our community is rapidly aging, this informal care burden may increase significantly in the future.
Subarachnoid Hemorrhage
Authors: Kissela Brett M. , Sauerbeck Laura , Woo Daniel , Khoury Jane , Carrozzella Janice , Pancioli Arthur , Jauch Edward , Moomaw Charles J. , Shukla Rakesh , Gebel James , Fontaine Robert , Broderick Joseph
Published: July 2002

Background and Purpose

—

Subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysm affects approximately 16 000 Americans annually, and almost 40% of affected patients die within 30 days despite the best current therapy. Prevention of SAH is therefore of paramount importance. We present a preliminary analysis of risk factors for SAH from our population-based, case-control study.

Methods

—

Cases were prospectively collected and matched 2:1 by age, race, and gender to controls using random digit dialing. Personal risk factor history, family history, neuroimaging data, and genetic samples were obtained. Univariate and bivariate analyses were performed and population-attributable risks estimated. Multivariable analysis was performed using conditional logistic regression.

Results

—

Between June 1997 and February 2000, 107 cases and 197 controls were enrolled. In bivariate analyses, a large proportion of population-attributable risk for SAH could be explained by modifiable risk factors: smoking, hypertension, and heavy alcohol use. In multivariable analysis, current cigarette smoking, history of hypertension, frequent alcohol use, lower body mass index, and a family history of a relative with SAH or intracranial aneurysm were found to be significant, independent risk factors for SAH.

Conclusion

—

Our data confirm previous reports that SAH clusters within some families independent of environmental risk factors, suggesting that SAH has a significant genetic component. Yet, even among families at increased risk of SAH, smoking cessation, treatment of hypertension, and reduced alcohol intake may substantially decrease SAH risk. The independent associations with heavy alcohol use and low body mass index with SAH may be confounded by smoking and require further study.
Genetic and Environmental Risk Factors for Intracerebral Hemorrhage
Authors: Woo Daniel , Sauerbeck Laura R. , Kissela Brett M. , Khoury Jane C. , Szaflarski Jerzy P. , Gebel James , Shukla Rakesh , Pancioli Arthur M. , Jauch Edward C. , Menon Anil G. , Deka Ranjan , Carrozzella Janice A. , Moomaw Charles J. , Fontaine Robert N. , Broderick Joseph P.
Published: July 2002

Background and Purpose

—

Intracerebral hemorrhage (ICH) has a 30-day mortality rate of 40% to 50% and lacks a proven treatment. We report a preplanned, midpoint analysis of the first population-based, case-control study that examines both genetic and environmental risk factors of ICH.

Methods

—

We prospectively identified cases of hemorrhagic stroke at all 16 hospitals in the Greater Cincinnati/Northern Kentucky region. All cases underwent medical record and neuroimaging review. Cases enrolled in the direct interview and genetic sampling arm of the study were matched to population-based control subjects by age, race, and sex. Multivariable logistic regression was performed to identify significant independent risk factors.

Results

—

We enrolled 188 cases of ICH (67 lobar, 121 nonlobar) and 366 control subjects in the direct interview arm of the study. Significant independent risk factors for lobar ICH included the presence of an apolipoprotein E2 or E4 allele, frequent alcohol use, prior stroke, and first-degree relative with ICH. Significant independent risk factors for nonlobar ICH were hypertension, prior stroke, and first-degree relative with ICH. An increasing level of education was associated with a decreased risk of nonlobar ICH. The attributable risk of apolipoprotein E2 or E4 for lobar ICH was 29%, and the attributable risk of hypertension for nonlobar ICH was 54%.

Conclusions

—

There is significant epidemiological evidence that the pathophysiology of ICH varies by location. We estimate that a third of all cases of lobar ICH are attributable to possession of an apolipoprotein E4 or E2 allele and that half of all cases of nonlobar ICH are attributable to hypertension.
Cerebral Infarction Due to Carotid Occlusion Caused by Cervical Vagal Neurilemmoma
Authors: Matsuo Ryu , Kamouchi Masahiro , Inoue Tooru , Okada Yasushi , Ibayashi Setsuro
Published: July 2002

Background

—

We report a case of a 71-year-old woman with cerebral infarction due to occlusion of the internal carotid artery (ICA) caused by a neck tumor.

Case Description

—

In 1998, the patient complained of mild hoarseness, and a diagnostic workup showed a cervical mass that was considered a benign neck tumor. In September 2000, she developed right-sided weakness. Diffusion-weighted MRI showed a high-intensity area in the territory of the left middle cerebral artery. Carotid angiography and ultrasonography revealed occlusion of the left ICA, which was due to compression by the neck tumor. Superficial temporal artery–middle cerebral artery anastomosis was performed to prevent critical reduction of cerebral blood flow in the left ICA territory; this was followed by tumor resection. The occluded ICA recanalized after tumor resection. Microscopic examination showed that the tumor was a vagal neurilemmoma.

Conclusions

—

This is the first case of cerebral infarction due to left ICA occlusion by a cervical neurilemmoma. Even when the neck tumor is benign, it may occlude the ICA and thereby cause cerebral infarction.
Carotid Intima-Media Thickness Is Associated With Allelic Variants of Stromelysin-1, Interleukin-6, and Hepatic Lipase Genes
Authors: Rundek Tanja , Elkind Mitchell S. , Pittman John , Boden-Albala Bernadette , Martin Steve , Humphries Steve E. , Juo Suh-Hang Hank , Sacco Ralph L.
Published: July 2002

Background and Purpose

—

Atherosclerosis is a complex disorder with hereditary and environmental causes. Carotid artery intima-media wall thickness (IMT) is a useful measure of atherosclerosis. The objective of this study was to determine the association between carotid IMT and functional promoter variants of stromelysin-1 (
MMP3
: −1612 5A>6A), interleukin-6 (
IL6
: −174G>C), and hepatic lipase (
HL
: −480C>T) genes.

Methods

—

B-mode carotid ultrasound was performed among 87 subjects (mean age, 70±12 years; 55% women; 60% Caribbean-Hispanic, 25% black, and 13% white) from the Northern Manhattan Prospective Cohort Study. Carotid IMT was calculated as a composite measure (mean of the maximum IMT in the bifurcation, the common carotid artery, and the internal carotid artery).

Results

—

For all polymorphisms, genotype distribution was not significantly different from Hardy-Weinberg equilibrium. The frequencies of the rare alleles were as follows:
MMP3
−1612 5A>6A, 0.31 (95% CI, 0.25 to 0.39);
IL6
−174 G>C, 0.20 (95% CI, 0.13 to 0.25); and
HL
−480 C>T, 0.45 (95% CI, 0.35 to 0.50). Carotid IMT in the sample was 0.78±0.18 mm. Subjects with the
MMP3
genotype
6A6A
had 8% greater mean carotid IMT than the other
MMP3
genotypes combined (0.95±0.17 versus 0.87±0.15 mm;
P
=0.04). Subjects with the
IL6
genotype
GG
had 11% greater IMT (0.85±0.17 versus 0.76±0.16 mm;
P
=0.03), and those with the
HL
genotype
CC
had 13% greater IMT (0.87±20 versus 0.76±0.18 mm;
P
=0.02) than the other genotypes combined. Adjustment for other risk factors did not change these associations.

Conclusions

—

Carotid IMT is higher among subjects homozygous for functional variants in genes related to matrix deposition (
MMP3
−16126A), inflammation (
IL6
−174G), and lipid metabolism (
HL
−480C). These associations were independent of race-ethnicity and some environmental exposures. Further studies are needed to confirm these genotype-phenotype associations.