bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravascular Ultrasound Findings in the Multicenter, Randomized, Double-Blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) Trial
Authors: Serruys Patrick W. , Degertekin Muzaffer , Tanabe Kengo , Abizaid Alexandre , Sousa J. Edouardo , Colombo Antonio , Guagliumi Giulio , Wijns William , Lindeboom Wietze K. , Ligthart Jurgen , de Feyter Pim J. , Morice Marie-Claude
Published: October 2002

Background—The goal of this intravascular ultrasound investigation was to provide a more detailed morphological analysis of the local biological effects of the implantation of a sirolimus-eluting stent compared with an uncoated stent.

Methods and Results—In the RAVEL trial, 238 patients with single de novo lesions were randomized to receive either an 18-mm sirolimus-eluting stent (Bx VELOCITY stent, Cordis) or an uncoated stent (Bx VELOCITY stent). In a subset of 95 patients (sirolimus-eluting stent=48, uncoated stent=47), motorized intravascular ultrasound pullback (0.5 mm/s) was performed at a 6-month follow-up. Stent volumes, total vessel volumes, and plaque-behind-stent volumes were comparable. However, the difference in neointimal hyperplasia (2±5 versus 37±28 mm3) and percent of volume obstruction (1±3% versus 29±20%) at 6 months between the 2 groups was highly significant (P<0.001), emphasizing the nearly complete abolition of the proliferative process inside the drug-eluting stent. Analysis of the proximal and distal edge volumes showed no significant difference between the 2 groups in external elastic membrane or lumen and plaque volume at the proximal and distal edges. There was also no evidence of intrastent thrombosis or persisting dissection at the stent edges. Although there was a higher incidence of incomplete stent apposition in the sirolimus group compared with the uncoated stent group (P<0.05), it was not associated with any adverse clinical events at 1 year.

Conclusions—Sirolimus-eluting stents are effective in preventing neointimal hyperplasia without creating edge effect and without affecting the plaque burden behind the struts.
Multiple Atherosclerotic Plaque Rupture in Acute Coronary Syndrome
Authors: Rioufol G. , Finet G. , Ginon I. , André-Fouët X. , Rossi R. , Vialle E. , Desjoyaux E. , Convert G. , Huret J.F. , Tabib A.
Published: October 2002

Background—

To test the hypothesis of general atherosclerotic plaque destabilization during acute coronary syndrome (ACS), the present study sought to analyze the 3 coronary arteries by systematic intravascular ultrasound scan (IVUS).

Methods and Results—

Seventy-two arteries were explored in 24 patients referred for percutaneous coronary intervention after a first ACS with troponin I elevation. Fifty plaque ruptures (mean, 2.08 per patient; range, 0 to 6) were diagnosed by the association of a ruptured capsule with intraplaque cavity. Plaque rupture on the culprit lesion was found in 9 patients (37.5%). At least 1 plaque rupture was found somewhere other than on the culprit lesion in 19 patients (79%). These lesions were in a different artery than the culprit artery in 70.8% and were in both other arteries in 12.5% of these 24 patients. Complete IVUS examination of all 3 coronary axes in patients who had experienced a first ACS revealed that multiple atherosclerotic plaque ruptures were detected by IVUS; these multiple ruptures were present simultaneously with the culprit lesion; they were frequent and located (in three quarters of cases) on the 3 principal coronary trunks; and the multiple plaque ruptures in locations other than on the culprit lesion were less severe, nonstenosing, and less calcified.

Conclusion—

Although one single lesion is clinically active at the time of ACS, the syndrome seems nevertheless associated with overall coronary instability.
Low-Output, Low-Gradient Aortic Stenosis in Patients With Depressed Left Ventricular Systolic Function
Authors: Nishimura Rick A. , Grantham J. Aaron , Connolly Heidi M. , Schaff Hartzell V. , Higano Stuart T. , Holmes David R.
Published: October 2002

Background—

Although aortic valve replacement can be performed at an acceptable risk level in selected patients with left ventricular systolic dysfunction and low-output, low-gradient aortic stenosis, not all patients presenting with these hemodynamics will benefit from the operation. Some patients may have only mild aortic stenosis, despite a small calculated valve area. We report on the clinical utility of diagnostic dobutamine stimulation during cardiac catheterization in these diagnostically challenging patients.

Methods and Results—

Thirty-two patients with low-output, low-gradient aortic stenosis and an ejection fraction <40% had dobutamine infusion in the catheterization laboratory. On the basis of the results of the dobutamine test, 21 patients underwent aortic valve replacement. All patients with a final aortic valve area ≤1.2 cm
2
at peak dobutamine infusion and a mean gradient of >30 mm Hg were found to have severe calcific aortic stenosis at operation. In the 15 patients in whom contractile reserve was identified during dobutamine challenge (increase in stroke volume >20%), 1 patient died perioperatively (7% mortality) and 12 patients were alive in New York Heart Association class I or II status at follow-up.

Conclusions—

In patients with left ventricular systolic dysfunction and aortic stenosis with a low output and a low mean gradient, dobutamine challenge may aid in selecting those who would benefit from an aortic valve operation.
Mapping and Ablation of Idiopathic Ventricular Fibrillation
Authors: Haïssaguerre Michel , Shoda Morio , Jaïs Pierre , Nogami Akihiko , Shah Dipen C. , Kautzner Josef , Arentz Thomas , Kalushe Dietrich , Lamaison Dominique , Griffith Mike , Cruz Fernando , de Paola Angelo , Gaïta Fiorenzo , Hocini Mélèze , Garrigue Stéphane , Macle Laurent , Weerasooriya Rukshen , Clémenty Jacques
Published: October 2002

Background—

Ventricular fibrillation is the main mechanism of sudden cardiac death. The feasibility of eliminating recurrent episodes by catheter ablation has not been reported.

Methods and Results—

Twenty-seven patients without known heart disease (13 men, 14 women, 41±14 years of age) were studied after being resuscitated from recurrent (10±12) episodes of primary idiopathic ventricular fibrillation; 23 had received a defibrillator. The first initiating beat of ventricular fibrillation had an identical electrocardiographic morphology and coupling interval (297±41 ms) to preceding isolated premature beats typically noted in the aftermath of resuscitation. These triggers were localized by mapping the earliest electrical activity and ablated by local radiofrequency delivery. Outcome was assessed by Holter and defibrillator memory interrogation. Premature beats were elicited from the Purkinje conducting system in 23 patients: from the left ventricular septum in 10, from the anterior right ventricle in 9, and from both in 4. The interval from the Purkinje potential to the following myocardial activation varied from 10 to 150 ms during premature beat but was 11±5 ms during sinus rhythm, indicating location at peripheral Purkinje arborization. The premature beats originated from the right ventricular outflow tract muscle in 4 patients. The accuracy of mapping was confirmed by acute elimination of premature beats during local radiofrequency delivery. During a follow-up of 24±28 months, 24 patients (89%) had no recurrence of ventricular fibrillation without drug.

Conclusions—

Primary idiopathic ventricular fibrillation is a syndrome characterized by dominant triggers from the distal Purkinje system. These sources can be eliminated by focal energy delivery.
Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure
Authors: Packer Milton , Califf Robert M. , Konstam Marvin A. , Krum Henry , McMurray John J. , Rouleau Jean-Lucien , Swedberg Karl
Published: October 2002

Background—

Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone.

Methods and Results—

We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point—the combined risk of death or hospitalization for heart failure requiring intravenous treatment—was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03,
P
=0.187)—a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (
P
=0.024) and a 6% lower risk of death (
P
=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal
P
=0.012).

Conclusion—

Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.
A Self-Fulfilling Prophecy
Authors: Verma Subodh , Wang Chao-Hung , Li Shu-Hong , Dumont Aaron S. , Fedak Paul W.M. , Badiwala Mitesh V. , Dhillon Bikramjit , Weisel Richard D. , Li Ren-Ke , Mickle Donald A.G. , Stewart Duncan J.
Published: October 2002

Background—

Given the central importance of nitric oxide (NO) in the development and clinical course of cardiovascular diseases, we sought to determine whether the powerful predictive value of C-reactive protein (CRP) might be explained through an effect on NO production.

Methods and Results—

Endothelial cells (ECs) were incubated with recombinant CRP (0 to 100 μg/mL, 24 hours), and NO and cyclic guanosine monophosphate (cGMP) production was assessed. The effects of CRP on endothelial NO synthase (eNOS) protein, mRNA expression, and mRNA stability were also examined. In a separate study, the effects of CRP (25 μg/mL) on EC cell survival, apoptosis, and in vitro angiogenesis were evaluated. Incubation of ECs with CRP resulted in a significant inhibition of basal and stimulated NO release, with concomitant reductions in cGMP production. CRP caused a marked downregulation of eNOS mRNA and protein expression. Actinomycin D studies suggested that eNOS downregulation was related to decreased mRNA stability. In conjunction with a decrease in NO production, CRP inhibited both basal and vascular endothelial growth factor–stimulated angiogenesis as assessed by EC migration and capillary-like tube formation. CRP did not induce EC survival but did, however, promote apoptosis in a NO-dependent fashion.

Conclusions—

CRP, at concentrations known to predict adverse vascular events, directly quenches the production of the NO, in part, through posttranscriptional effect on eNOS mRNA stability. Diminished NO bioactivity, in turn, inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. Through decreasing NO synthesis, CRP may facilitate the development of diverse cardiovascular diseases. Risk reduction strategies designed to lower plasma CRP may be effective by improving NO bioavailability.
Angiotensin II–Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense
Authors: Kagiyama Shuntaro , Eguchi Satoru , Frank Gerald D. , Inagami Tadashi , Zhang Yuan Clare , Phillips M. Ian
Published: October 2002

Background—

Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via “
trans”
-activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II–induced cardiovascular hypertrophic effects.

Methods and Results—

The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II–induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II–infused hypertensive rats. In VSMCs, EGFR-AS (2.5 μmol/L) reduced EGFR expression and inhibited the Ang II–induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184±6 mm Hg versus 122±3 mm Hg; n=7;
P
<0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169±8 mm Hg; n=8;
P
<0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75±0.08 versus 2.33±0.07;
P
<0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II–infused rats (2.32±0.06;
P
<0.01) and attenuated Ang II–enhanced EGFR expression and ERK phosphorylation.

Conclusion—

Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.
Efficacy of Eplerenone Added to Renin-Angiotensin Blockade in Hypertensive Patients
Authors: Krum Henry , Nolly Hector , Workman Diane , He Weizhong , Roniker Barbara , Krause Scott , Fakouhi Kaffa
Published: October 2002

The efficacy and tolerability of eplerenone, a selective aldosterone blocker, was assessed when added to existing antihypertensive therapy with an ACE inhibitor or an angiotensin II receptor blocker (ARB). Hypertensive patients (n=341) whose blood pressure (BP) was not controlled despite ACE inhibitor or ARB were randomized (double-blind) to receive 50 mg eplerenone (increasing to 100 mg if required) once daily or placebo for 8 weeks. Diastolic and systolic BP and adverse events were recorded. By study end (week 8), mean seated diastolic BP was significantly reduced from week 0 among patients receiving eplerenone/ARB (−12.7±0.81 mm Hg) compared with those receiving placebo/ARB (−9.3±0.83 mm Hg). The change in mean seated diastolic BP was −9.9±0.88 mm Hg in eplerenone/ACE inhibitor patients and −8.0±0.86 mm Hg in placebo/ACE inhibitor patients (
P
=NS). Systolic BP levels were also significantly lower at week 8 for eplerenone/ACE inhibitor (−13.4±1.35 mm Hg) and eplerenone/ARB (−16.0±1.37 mm Hg) patients, respectively, compared with placebo/ACE inhibitor (−7.5±1.31 mm Hg) and placebo/ARB patients (−9.2±1.41 mm Hg). Adverse events were generally nonsevere and not significantly different between eplerenone and placebo. This study demonstrated that in patients whose BP was not controlled with an ACE inhibitor or ARB, the addition of eplerenone over an 8-week period significantly lowered systolic BP in both groups and diastolic BP in ARB patients. Selective aldosterone blockade with eplerenone, therefore, may be useful add-on therapy in hypertensive patients inadequately controlled on ACE inhibitor or ARB alone.
Norepinephrine Enhances Fibrosis Mediated by TGF-β in Cardiac Fibroblasts
Authors: Akiyama-Uchida Yuri , Ashizawa Naoto , Ohtsuru Akira , Seto Shinji , Tsukazaki Tomoo , Kikuchi Hiroshi , Yamashita Shunichi , Yano Katsusuke
Published: October 2002

Cardiac fibrosis results from proliferation of interstitial fibroblasts and concomitant increased biosynthesis of extracellular matrix (ECM) components and is often complicated by cardiac hypertrophy. This study was conducted to investigate whether norepinephrine (NE) potentiates transforming growth factor-β (TGF-β)–induced cardiac fibrosis. The expression of the cardiac ECM proteins, plasminogen activator inhibitor-1 (PAI-1), fibronectin, and collagen type I, was examined by Western blotting using extracts from neonatal rat primary cardiac fibroblasts. In cardiac fibroblasts, treatment with a combination of NE and TGF-β1 increased cell proliferation and ECM expression. Luciferase assays were conducted to clarify the effect of NE on TGF-β signaling. TGF-β1 (1 ng/mL) increased the specific signaling activity 2-fold, whereas the combination of NE (10 μmol/L) and TGF-β1 (1 ng/mL) resulted in an approximate 10-fold increase in specific signaling activity. We confirmed that treatment with NE markedly enhances TGF-β–induced phosphorylation of activating transcription factor 2 (ATF-2). These results indicated that NE has a synergistic effect on TGF-β signaling. To determine whether this activation by NE was mediated by the TGF-β1 receptor, we used a dominant negative vector of the TGF-β1 type II receptor, and the synergistic effects were inhibited. Furthermore, this synergistic effect was attenuated by a specific inhibitor of p38, SB203680. These data indicate that NE enhances cardiac fibrosis through TGF-β1 post-receptor signaling, predominantly via the p38 MAP kinase pathway.
N
-Acetyl-Ser-Asp-Lys-Pro Inhibits Phosphorylation of Smad2 in Cardiac Fibroblasts
Authors: Pokharel Saraswati , Rasoul Saman , Roks Anton J.M. , van Leeuwen Rick E.W. , van Luyn Marja J.A. , Deelman Leo E. , Smits Jos F. , Carretero Oscar , van Gilst Wiek H. , Pinto Yigal M.
Published: October 2002

N
-Acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a specific substrate for the N-terminal site of ACE and increases 5-fold during ACE inhibitor therapy. It is known to inhibit the proliferation of hematopoietic stem cells and has also recently been reported to inhibit the growth of cardiac fibroblasts. We investigated its mode of action in cardiac fibroblasts by assessing its influence on transforming growth factor β
1
(TGFβ1)–mediated Smad signaling. AcSDKP inhibited the proliferation of isolated cardiac fibroblasts (
P
<0.05) but significantly stimulated the proliferation of vascular smooth muscle cells. Flow cytometry of rat cardiac fibroblasts treated with AcSDKP showed significant inhibition of the progression of cells from G
0
/G
1
phase to S phase of the cell cycle. In cardiac fibroblasts transfected with a Smad-sensitive luciferase reporter construct, AcSDKP decreased luciferase activity by 55±9.7% (
P
=0.01). Moreover, phosphorylation and nuclear translocation of Smad2 was decreased in cardiac fibroblasts treated with AcSDKP. To conclude, AcSDKP inhibits the growth of cardiac fibroblasts and also inhibits TGFβ1-stimulated phosphorylation of Smad2. Because AcSDKP increases substantially during ACE inhibitor therapy, this suggests a novel pathway independent of angiotensin II, by which ACE inhibitors can inhibit cardiac fibrosis.
Heart Rate Variability and Baroreflex Function in AT
2
Receptor-Disrupted Mice
Authors: Gross Volkmar , Plehm Ralph , Tank Jens , Jordan Jens , Diedrich Andre , Obst Michael , Luft Friedrich C.
Published: October 2002

We adapted telemetry and sequence analysis employed in humans to mice and measured heart rate variability and the spontaneous baroreflex sensitivity in angiotensin II type 2 (AT
2
) receptor–deleted (AT
2
−/−) and wild-type (AT
2
+/+) mice with either deoxycorticosterone acetate (DOCA)-salt hypertension or Nω-nitro-
l
-arginine methylester hydrochloride (L-NAME) hypertension. Mean arterial pressure leveled during the day at 101±1 mm Hg and during the night at 109±1 mm Hg in AT
2
receptor–deleted mice, compared with 98±2 mm Hg (day) and 104±2 mm Hg (night) in wild-type mice. Mean arterial pressure increased in AT
2
receptor–deleted mice with L-NAME to 114±1 mm Hg (day) and 121±1 mm Hg (night), compared with 105±2 mm Hg (day) and 111±2 mm Hg (night), respectively. DOCA-salt also increased day and night blood pressures in AT
2
receptor–deleted mice to a greater degree than in wild-type mice. Heart rate variability in the time and frequency domain was not different between AT
2
receptor–deleted mice and AT
2
receptor–deleted mice at baseline. Systolic blood pressure variability in the low frequency band was lower in AT
2
receptor–deleted mice (0.6±0.1 ms
2
versus 3.9±1.3 ms
2
) than in wild-type mice. Baroreceptor-heart rate reflex sensitivity was significantly increased in AT
2
receptor–deleted mice compared with wild-type mice (3.4±0.6 versus 2.1±0.5 ms/mm Hg). These differences remained after DOCA-salt and L-NAME treatments. We conclude that activation of the AT
2
receptor impairs arterial baroreceptor reflex function, probably by a central action. These data support the existence of an inhibitory central effect of the AT
2
receptor on baroreflex function.
Comparison of Sphingosine 1-Phosphate–Induced Intracellular Signaling Pathways in Vascular Smooth Muscles
Authors: Coussin Frederic , Scott Roderick H. , Wise Alan , Nixon Graeme F.
Published: October 2002

Sphingosine 1-phosphate (S1P), a lipid released from activated platelets, influences physiological processes in the cardiovascular system via activation of the endothelial differentiation gene (EDG/S1P) family of 7 transmembrane G protein–coupled receptors. In cultured vascular smooth muscle (VSM) cells, S1P signaling has been shown to stimulate proliferative responses; however, its role in vasoconstriction has not been examined. In the present study, the effects of S1P and EDG/S1P receptor expression were determined in rat VSM from cerebral artery and aorta. S1P induced constriction of cerebral artery, which was partly dependent on activation of p160
ROCK
(Rho-kinase). S1P also induced activation of RhoA in cerebral artery with a similar time course to contraction. In aorta, S1P did not produce a constriction or RhoA activation. In VSM myocytes from cerebral arteries, stimulation with S1P gives rise to a global increase in [Ca
2+
]
i
, initially generated via Ca
2+
release from the sarcoplasmic reticulum by an inositol 1,4,5-trisphosphate–dependent pathway. In aorta VSM, a small increase in [Ca
2+
]
i
was observed after stimulation at higher concentrations of S1P. S1P induced activation of p42/p44
mapk
in aorta and cerebral artery VSM. Subtype-specific S1P receptor antibodies revealed that the expression of S1P
3
/EDG-3 and S1P
2
/EDG-5 receptors is 4-fold higher in cerebral artery compared with aorta. S1P
1
/EDG-1 receptor expression was similar in both types of VSM. Therefore, the ability of S1P to act as a vasoactive mediator is dependent on the activation of associated signaling pathways and may vary in different VSM. This differential signaling may be related to the expression of S1P receptor subtypes.
Atorvastatin Attenuates Remnant Lipoprotein-Induced Monocyte Adhesion to Vascular Endothelium Under Flow Conditions
Authors: Kawakami Akio , Tanaka Akira , Nakajima Katsuyuki , Shimokado Kentaro , Yoshida Masayuki
Published: October 2002

Remnant lipoproteins have been reported to play a causative role in atherogenesis. We investigated the effect of remnant-like lipoprotein particles (RLPs) on monocyte-endothelial interaction and their potential regulation by atorvastatin. Monocytic U937 cells were incubated with RLPs isolated from hypertriglyceridemia subjects and their adhesion to human umbilical vein endothelial cells (HUVECs) was examined under flow conditions. Incubation of U937 cells with 15 μg protein/mL RLPs increased their adhesion to HUVECs activated with IL-1β (untreated: 6.8±1.6 cells/HPF versus RLPs: 16.2±3.3 cells/HPF,
P
<0.05). Flow cytometric analysis revealed that incubation with RLPs increased expression levels of CD11a, CD18, and CD49d in U937 cells. Moreover, RLP-induced RhoA activation as well as FAK activation was seen in U937 cells, and RLP-induced RhoA activation seemed to be involved with PKC-dependent signaling. To explore the effect of atorvastatin on RLP-induced U937 cell adhesion to HUVECs, U937 cells were incubated with RLPs in the presence of atorvastatin. Pretreatment of U937 cells with 10 μmol/L atorvastatin significantly decreased RLP-induced U937 cell adhesion to activated HUVECs (RLP 15.2±1.5 cells/HPF versus atorvastatin+RLP 10.2±1.0 cells/HPF;
P
<0.05) and decreased the enhanced integrin expression in RLP-treated U937 cells. Atorvastatin also inhibited RLP-induced RhoA activation and FAK activation in U937 cells. In summary, RLPs induced monocyte adhesion to vascular endothelium by sequential activation of PKC, RhoA, FAK, and integrins, indicating a role of remnant lipoproteins in vascular inflammation during atherogenesis. Atorvastatin attenuated this enhanced monocyte adhesion to HUVECs, suggesting an antiinflammatory role for this compound.
Enhanced Basal Activity of a Cardiac Ca
2+
Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death
Authors: Jiang Dawei , Xiao Bailong , Zhang Lin , Chen S.R. Wayne
Published: October 2002

Mutations in the human cardiac Ca
2+
release channel (ryanodine receptor, RyR2) gene have recently been shown to cause effort-induced ventricular arrhythmias. However, the consequences of these disease-causing mutations in RyR2 channel function are unknown. In the present study, we characterized the properties of mutation R4496C of mouse RyR2, which is equivalent to a disease-causing human RyR2 mutation R4497C, by heterologous expression of the mutant in HEK293 cells. [
3
H]ryanodine binding studies revealed that the R4496C mutation resulted in an increase in RyR2 channel activity in particular at low Ca
2+
concentrations. This increased basal channel activity remained sensitive to modulation by caffeine, ATP, Mg
2+
, and ruthenium red. In addition, the R4496C mutation enhanced the sensitivity of RyR2 to activation by Ca
2+
and by caffeine. Single-channel analysis showed that single R4496C mutant channels exhibited considerable channel openings at low Ca
2+
concentrations. HEK293 cells transfected with mutant R4496C displayed spontaneous Ca
2+
oscillations more frequently than cells transfected with wild-type RyR2. Substitution of a negatively charged glutamate for the positively charged R4496 (R4496E) further enhanced the basal channel activity, whereas replacement of R4496 by a positively charged lysine (R4496K) had no significant effect on the basal activity. These observations indicate that the charge and polarity at residue 4496 plays an essential role in RyR2 channel gating. Enhanced basal activity of RyR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia.
Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis
Authors: Hansson Göran K. , Libby Peter , Schönbeck Uwe , Yan Zhong-Qun
Published: October 2002

This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro- and antithrombotic processes. Various established and emerging risk factors for atherosclerosis modulate aspects of immune responses, including lipoproteins and their modified products, vasoactive peptides, and infectious agents. As we fill in the molecular details, new potential targets for therapies will doubtless emerge.
Microtubule Involvement in the Adaptation to Altered Mechanical Load in Developing Chick Myocardium
Authors: Schroder Elizabeth A. , Tobita Kimimasa , Tinney Joseph P. , Foldes Jane K. , Keller Bradley B.
Published: October 2002

Mechanical load regulates ventricular growth, function, and structure from the earliest stages of cardiac morphogenesis through senescence. Dramatic changes in cardiac form and function have been defined for developing cardiovascular systems, and changes in mechanical loading conditions can produce structural malformations such as left heart hypoplasia. To date, relatively little is known regarding the interactions between changes in mechanical load, morphogenesis, and the material properties of the embryonic heart. We tested the hypothesis that passive material properties in the embryonic heart change in response to altered mechanical load and that microtubules play an important role in this adaptive response. We measured biaxial passive stress-strain relations in left ventricular (LV) myocardial strips in chick embryos at Hamburger-Hamilton stage 27 following left atrial ligation (LAL) at stage 21 to reduce LV volume load and create left heart hypoplasia. Following LAL, myocardial stresses at given strains and circumferential stiffness increased versus control strips. Western blot analysis of LAL embryos showed an increase in both total and polymerized β-tubulin and confocal microscopy confirmed an increase in microtubule density in the LV compact layer versus control. Following colchicine treatment, LV stresses and stiffness normalized in LAL specimens and microtubule density following colchicine was similar in LAL to control. In contrast, Taxol treatment increased myocardial stresses and stiffness in control strips to levels beyond LAL specimens. Thus, the material properties of the developing myocardium are regulated by mechanical load and microtubules play a role in this adaptive response during cardiac morphogenesis.
Telephone Intervention With Family Caregivers of Stroke Survivors After Rehabilitation
Authors: Grant Joan S. , Elliott Timothy R. , Weaver Michael , Bartolucci Alfred A. , Giger Joyce Newman
Published: October 2002

Background and Purpose

—

Social problem-solving therapy shows promise as an intervention to improve the well-being of family caregivers. There is some evidence that training in problem solving may be effectively delivered by telephone. The purpose of this study was to quantify the impact of social problem-solving telephone partnerships on primary family caregiver outcomes after stroke survivors are discharged home from a rehabilitation facility.

Methods

—

Using a randomized 3-group repeated-measures experimental design, 74 stroke survivors with an admitting diagnosis of ischemic stroke and their primary family caregivers were entered into the study. The intervention consisted of an initial 3-hour home visit between a trained nurse and the family caregiver within 1 week after discharge to begin problem-solving skill training. This initial session was followed by weekly (the first month) and biweekly (the second and third month) telephone contacts.

Results

—

Compared with the sham intervention and control groups, family caregivers who participated in the social problem-solving telephone partnership intervention group had better problem-solving skills; greater caregiver preparedness; less depression; and significant improvement in measures of vitality, social functioning, mental health, and role limitations related to emotional problems. There were no significant differences among the groups in caregiver burden. Satisfaction with healthcare services decreased over time in the control group while remaining comparable in the intervention and sham intervention groups.

Conclusion

—

These results indicate that problem-solving training may be useful for family caregivers of stroke survivors after discharge from rehabilitative facilities.
Middle Cerebral Artery Function After Stroke
Authors: Cipolla Marilyn J. , Curry Amy B.
Published: October 2002

Background and Purpose

—

Myogenic activity of the cerebral arteries is an important contributor to autoregulation of cerebral blood flow. Previous studies have demonstrated that increasing periods of ischemia diminished the amount of myogenic tone in cerebral arteries. In the present study, we investigated the effect of different periods of postischemic reperfusion on the myogenic behavior of middle cerebral arteries (MCAs). We measured both the amount of spontaneous myogenic tone that developed at 75 mm Hg and the contractile response to increased transmural pressure (TMP), ie, myogenic reactivity.

Methods

—

The MCA occlusion model was used in male Wistar rats (n=45) to induce 30 minutes of temporary ischemia, followed by different periods of reperfusion (0 or sham; 30 minutes; and 6, 12, 18, 20, and 22 hours), confirmed by laser Doppler flowmetry. MCAs were studied in vitro using an arteriograph system that allowed control of TMP and measurement of lumen diameter. After equilibration for 1 hour at 75 mm Hg, TMP was increased stepwise in 25–mm Hg increments to 125 mm Hg and lumen diameter measured at each pressure. The amount of spontaneous myogenic tone was determined in both ischemic and contralateral arteries for each reperfusion period and compared with the right and left MCAs in the sham group. Arteries were then fixed with 10% formalin pressurized in the arteriograph bath and stained for filamentous (F)–actin with fluorescently labeled phalloidin, a specific probe for F-actin. The amount of F-actin was quantified using confocal microscopy.

Results

—

MCAs from the sham-operated control group possessed considerable myogenic tone (35%). However, the amount of tone in ischemic MCAs progressively diminished as the reperfusion duration increased. In addition, sham-operated control arteries responded myogenically to increases in TMP, decreasing diameter as pressure increased. There was a similar response in arteries exposed to 30 minutes and 6 hours of reperfusion, all producing a negative slope on the pressure-diameter curve; however, myogenic reactivity was diminished at the longer periods of reperfusion, producing a positive slope of the graph. The slopes of the pressure-diameter curves were as follows: −0.10±−0.06 (sham), −0.07±−0.12 (30 minutes), −0.08±−0.11 (6 hours), +0.09±0.09 (12 hours), +0.25±0.16 (18 hours), +0.38±0.09 (20 hours), and +0.57±0.09 (22 hours). F-actin content was significantly less only in ischemic MCAs at 6 and 12 hours of reperfusion.

Conclusions

—

These results demonstrate that longer periods of reperfusion significantly diminish myogenic activity of MCAs. Understanding how different periods of ischemia and reperfusion affect the function of the cerebral circulation may promote more effective treatment of ischemic stroke.
Etiologic Study of Young Ischemic Stroke in Taiwan
Authors: Lee Tsong-Hai , Hsu Wen-Chuin , Chen Chi-Jen , Chen Sien-Tsong
Published: October 2002

Background and Purpose

—

The etiologic mechanisms of young ischemic stroke in Chinese are largely unknown. This work thus studied the etiologies of young ischemic stroke in Taiwan Chinese and made a comparison with previous reports.

Methods

—

From January 1997 to October 2001, a total of 264 consecutive young ischemic stroke patients (18 to 45 years old) were admitted to the Department of Neurology in our hospital. The risk factors for stroke and the distribution of stroke subtype were studied. The vascular ultrasound and angiographic findings of these patients were also studied.

Results

—

The sample contained 188 men and 76 women. Cerebral infarction was diagnosed in 241 patients and transient ischemic attack in 23 (8.7%). Regarding stroke subtype, stroke of small-vessel occlusion was diagnosed in 20.5% of cases, large-artery atherosclerosis in 7.2%, cardioembolism in 17.8%, other determined etiology in 22.3%, and undetermined etiology in 23.5%. The 4 most common risk factors were hyperlipidemia (53.1%), smoking (49.8%), hypertension (45.8%), and family history of stroke (29.3%). Twenty-three patients (9.6%) had significant stenosis (≥50%) of the carotid (7.5%) and vertebral arteries (2.1%), the most common cause of which was dissection (60.9%). Forty-five patients (26.5%) had significant intracranial stenosis with 18.8% in the carotid and 10.6% in the vertebrobasilar system, and 5 (2.9%) had stenosis in both systems. Premature atherosclerosis (33.3%) was the most common cause of intracranial stenosis.

Conclusions

—

Our study found that strokes of other determined etiology and undetermined etiology were most common among the sample group, and a battery of extensive examinations is indicated to elucidate the etiology for further stroke prevention. Intracranial stenosis is more common than extracranial stenosis in both the carotid and vertebrobasilar systems.
Inflammatory Cell Adhesion Molecules in Ischemic Cerebrovascular Disease
Authors: Frijns C.J.M. , Kappelle L.J.
Published: October 2002

Background

—

In this review we discuss the role of inflammatory cell adhesion molecules (CAMs) in ischemic stroke and in delayed cerebral ischemia after subarachnoid hemorrhage. Vascular endothelial cells and leukocytes express several inflammatory adhesion receptors, the most important of which are the selectins, immunoglobulin gene superfamily CAMs, and β2 integrins. They mediate the transmigration process of leukocytes to the abluminal side of the endothelium.

Summary of Review

—

There is ample evidence from animal models of middle cerebral artery occlusion that expression of CAMs is associated with cerebral infarct size. Absence of CAMs in knockout animals resulted in reduced infarct size. When middle cerebral artery occlusion in experimental stroke was followed by reperfusion, administration of anti-CAM antibodies decreased infarct size. Thus far, anti-CAM treatment has not been successful in patients with ischemic stroke. Inflammatory CAM may also play a role in the pathogenesis of delayed cerebral ischemia after subarachnoid hemorrhage. In animal models, increased expression of CAMs has been observed in vasospastic arteries. Increased concentrations of CAMs have also been found in cerebrospinal fluid of patients with subarachnoid hemorrhage.

Conclusions

—

Further research on the role of inflammatory CAMs in the pathogenesis of ischemic cerebrovascular disorders should lead to new diagnostic and therapeutic strategies.
Two Types of Lacunar Infarcts
Authors: de Jong G. , Kessels F. , Lodder J.
Published: October 2002

Background and Purpose

—

Earlier, we found that lacunar stroke patients with ≥1 asymptomatic lacunar infarcts on CT had leukoaraiosis and hypertension significantly more often than patients without such lesions, and we hypothesized that 2 types of small-vessel disease could be distinguished during life: arteriolosclerosis and microatheromatosis, respectively. Differences in prognosis might sustain this hypothesis of 2 lacunar stroke entities. Therefore, we performed a follow-up in 333 patients with first lacunar stroke, distinguishing those with ≥1 asymptomatic lacunar lesions (LACI+) from those without such lesions (LACI−).

Methods

—

Cross-sectional follow-up was performed after 785±479 days (mean±SD) in 104 LACI+ patients and 865±545 days in 229 LACI− patients.

Results

—

Mortality at the end of follow-up was 33% in LACI+ and 21% in LACI− patients [odds ratio (OR), 1.74; 95% confidence interval (CI), 1.01 to 3.01]. Stroke recurrence rate was 21% in LACI+ and 11% in LACI− (OR, 2.09; 95% CI, 1.08 to 4.06). Forty percent of LACI+ and 26% of LACI− patients had unfavorable outcome at the end of follow-up (OR, 1.95; 95% CI, 1.17 to 3.26). Kaplan-Meier curves showed less favorable survival in LACI+ (log-rank test,
P
=0.0218) and survival free of stroke (log-rank test,
P
=0.0121) than in LACI−. When we restricted the analysis to patients with both silent lesions and leukoaraiosis (n=63) compared with those without (n=196), differences were even more pronounced.

Conclusions

—

Prognosis for mortality, recurrent stroke, and overall functional outcome in lacunar stroke patients with ≥1 silent lacunar lesions is more unfavorable than in patients without such lesions. These findings sustain the idea of 2 lacunar stroke entities.
Long-Term Prognosis of Vascular Hemiballismus
Authors: Ristic Aleksandar , Marinkovic Jelena , Dragasevic Natasa , Stanisavljevic Dejana , Kostic Vladimir
Published: October 2002

Background and Purpose

—

The aim of this study was to prospectively evaluate the long-term prognosis of hemiballismus due to first-ever ischemic strokes.

Methods

—

A cohort of 27 patients with hemiballismus due to first-ever ischemic strokes was followed for a mean period of 30 months (range, 5 days to 150 months).

Results

—

During the follow-up period there were 11 deaths (44%). The survival rate was 85% (95% CI, 71% to 99%) at 6 months, 81% (95% CI, 65% to 97%) at 15 months, 51% (95% CI, 24% to 78%) at 36 months, and only 32% (95% CI, 4% to 60%) at 150 months. The survival rate free from recurrent stroke was 96% (95% CI, 87% to 100%) at 6 months, 91% (95% CI, 79% to 100%) at 12 months, 80% (95% CI, 61% to 99%) at 24 months, and 27% (95% CI, 0% to 71%) at 150 months.

Conclusions

—

The long-term prognosis of patients with vascular hemiballismus is similar to that of other stroke patients, ie, it follows the etiologic pattern of hemiballismus.
Automatic Online Embolus Detection and Artifact Rejection With the First Multifrequency Transcranial Doppler
Authors: Brucher Rainer , Russell David
Published: October 2002

Background and Purpose

—

The goal of this study was to assess the first multifrequency transcranial Doppler system specially developed for online automatic detection of cerebral microemboli.

Methods

—

The multifrequency Doppler instrumentation insonates simultaneously with 2.0- and 2.5-MHz frequencies. The detection threshold for embolus detection used in this study was a relative Doppler energy increase of >20 dB · ms, at which point the Doppler power increase was at least 5 dB and lasted >4 ms above the background energy. Four parameters were used in an optimized binary decision tree to recognize emboli: quarter Doppler shift, maximum duration limit, reference gate, and bidirectional enhancement. In in vitro studies, 200 plastic microspheres (80 μm), 200 gas bubbles (8 to 25 μm), and 600 artifacts were studied in a pulsatile closed-loop system. In vivo studies were carried out for 1 hour in 15 patients with mechanical heart valves and in 45 patients with carotid stenosis. This gave a total of 60 hours of online automatic monitoring in patients.

Results

—

All 400 plastic spheres and microbubbles were automatically detected and correctly classified. Of the 600 artifacts, 596 (99.3%) were correctly classified as artifacts, and 4 (0.7%) were incorrectly identified as emboli (κ=0.992,
P
<0.001). The experienced observer detected a total of 554 emboli and 800 artifacts in the heart valve (521 emboli, 400 artifacts) and carotid stenosis (33 emboli, 400 artifacts) patients. With multifrequency Doppler, 546 of these emboli (98.6%) and 791 of these artifacts (98.9%) were automatically detected and correctly classified as embolus or artifact (κ=0.953,
P
<0.0001).

Conclusions

—

We found that multifrequency transcranial Doppler had a relatively high sensitivity and specificity when used to automatically detect cerebral microemboli and reject artifacts online.
Occurrence of Hemispheric and Retinal Ischemia in Atrial Fibrillation Compared With Carotid Stenosis
Authors: Anderson D.C. , Kappelle L.J. , Eliasziw M. , Babikian V.L. , Pearce L.A. , Barnett H.J.M.
Published: October 2002

Background and Purpose

—

The goal of this study was to examine the hypotheses that retinal ischemia is caused more often by carotid atherosclerosis than by atrial fibrillation and that the odds of retinal events compared with hemispheric events increase with worsening carotid stenosis.

Methods

—

We used data from the Stroke Prevention in Atrial Fibrillation (SPAF) I through III trials and North American Symptomatic Carotid Endarterectomy Trial (NASCET), calculating hemispheric:retinal (H:R) odds for the territory of ischemic events during follow-up in patients with atrial fibrillation and medically treated 50% to 99% carotid stenosis or occlusion in the respective trials.

Results

—

The H:R odds were 25:1 in the SPAF aspirin-assigned patients and 2:1 for NASCET vessels. In NASCET patients, the H:R odds of recurrent ischemic events were 1:4 for vessels randomized initially for retinal symptoms compared with 6:1 for those randomized for hemispheric events (significant difference;
P
<0.001). Moreover, the H:R odds of first events in the territory of the contralateral asymptomatic artery were 1:1 if the randomized vessel had retinal symptoms compared with 4:1 if the randomized vessel had hemispheric symptoms (significant difference;
P
<0.01). Increasing carotid stenosis in the 50% to 99% range had no effect on H:R odds (
P
=0.8).

Conclusions

—

These findings confirm that retinal symptoms are more typical of carotid stenosis. Hemodynamic effects do not appear to be more important in the pathogenesis of retinal events than hemispheric ones in carotid stenosis. The retinal versus hemispheric location of initial symptoms is strongly predictive of the location of subsequent events in patients with carotid stenosis, even when new symptoms are contralateral to the original ones.
Incidence and Short-Term Outcome of Cerebral Infarction in Young Adults in Western Norway
Authors: Naess H. , Nyland H.I. , Thomassen L. , Aarseth J. , Nyland G. , Myhr K-M.
Published: October 2002

Background and Purpose

—

We sought to determine the incidence and short-term outcome of people aged 15 to 49 years with first-ever cerebral infarction in 1988–1997 in Hordaland County, Norway.

Methods

—

Cases were found from computer search of hospital registries and detailed review of patient records. Stroke subtype was classified according to the major intracranial artery affected. Short-term outcome was evaluated by the modified Rankin Scale (mRS).

Results

—

A total of 96 women and 136 men met the inclusion criteria. The average annual incidence was 11.4/100 000. Women outnumbered men among those aged <30 years (
P
=0.059); men predominated among those aged ≥30 years (
P
=0.004). A total of 148 patients had anterior circulation infarction (64%), and 84 had posterior circulation infarction (36%) (
P
<0.001). Patients with posterior circulation infarction had better mRS score at discharge (
P
=0.005). Eighty percent had favorable outcome (mRS score ≤2). The 30-day case fatality rate was 3.4%. The recurrence rate in hospital was 2.2%.

Conclusions

—

The incidence was in the lower range compared with other reports from western Europe. Although men predominated, there was a strong trend toward more women among patients aged <30 years. Short-term outcome was generally good. Patients with posterior circulation infarction had significantly better short-term outcome.