bluuebunny/crossref_metadata_2025 huggingface dataset:
Persisting Consequences of Stroke Measured by the Stroke Impact Scale
Authors: Lai Sue-Min , Studenski Stephanie , Duncan Pamela W. , Perera Subashan
Published: July 2002

Background and Purpose

—

The purpose of this study was to compare disability and quality of life as measured by the Stroke Impact Scale (SIS) of stroke patients deemed recovered (Barthel Index ≥95) with 2 stroke-free populations of community-dwelling elderly.

Methods

—

Eighty-one stroke patients who participated in the Kansas City Stroke Registry and achieved a Barthel Index of ≥95 at 3 months after stroke and 246 stroke-free subjects enrolled in the Community Elders Study were enrolled in this study. The Community Elders Study group was further divided into 2 groups, those recruited from the Department of Veterans Affairs Health System (VA) and a those from a local health maintenance organization (HMO). Stroke patients were administered the SIS ≈90 days after stroke, and the stroke-free community dwellers were administered a version of the SIS adapted for nonstroke subjects, the Health Impact Scale (HIS). A general linear model was used to examine differences in health outcomes measured by the SIS or HIS between the KCSR stroke patients and VA and HMO community-dwelling elders after controlling for medical comorbidities and demographics.

Results

—

Kansas City Stroke Registry participants were significantly older than the community study groups (
P
=0.0052). Selected medical conditions were similar among the 3 study groups. Old age and a history of diabetes mellitus were more likely to be associated with more deficits and poor quality of life. In stroke patients deemed recovered, stroke still affected hand function, activities and independent activities of daily living, participation, and overall physical function compared with the stroke-free community dwellers in the HMO health system even after adjustment for age and diabetes status. Stroke-free community dwellers in the VA health system also had worse social participation than the stroke-free community dwellers in the HMO health system.

Conclusions

—

Research and clinicians have consistently underestimated the impact of stroke with the Barthel Index. This has major implications for the design of therapeutic trial designs and adequate assessments of social and economic sequelae of stroke.
Considering the Role of Heparin and Low-Molecular-Weight Heparins in Acute Ischemic Stroke
Authors: Moonis Majaz , Fisher Marc
Published: July 2002

Background and Purpose

—

The utility of parenteral anticoagulation therapy in acute ischemic stroke has engendered much controversy and discussion. Recent studies of low-molecular-weight heparins in multiple acute stroke subtypes have not demonstrated improved outcome or reduced recurrence risk. Beneficial treatment effects may occur in subgroups such as patients with large artery atherothrombotic stroke, but further studies will be needed to prove this possibility.

Summary of Review

—

The benefits of unfractionated intravenous heparin for reducing early stroke recurrence and improving outcome remain to be established, with the current lack of appropriately powered trials in stroke subgroups at high risk for such early recurrence. To most clinicians, the primary reason to use early intravenous anticoagulation is to prevent early stroke recurrence, not to improve outcome of an established stroke. Unfortunately, effects of reduction of recurrent stroke risk may be counterbalanced by a substantial increased risk of intracerebral hemorrhage with intravenous anticoagulation.

Conclusions

—

Unfractionated intravenous heparin should therefore not be used routinely in acute ischemic stroke, but it may be considered in select stroke groups at high risk for early recurrent ischemic events (ie, patients with atrial fibrillation or acute myocardial infarction and large mural thrombi). However, even in these select populations, new clinical trials will be needed to define the risk-benefit ratio.
Neuroprotective Effect of Delayed Moderate Hypothermia After Focal Cerebral Ischemia
Authors: Kollmar R. , Schäbitz W.R. , Heiland S. , Georgiadis D. , Schellinger P.D. , Bardutzky J. , Schwab S.
Published: July 2002

Background and Purpose

—

In contrast to early hypothermia, the effects of delayed hypothermia in focal cerebral ischemia have not been widely addressed. We examined the influence of delayed hypothermia on secondary ischemic injury, MRI lesion size, and neurological outcome after transient focal cerebral ischemia in a rat model.

Methods

—

Rats (n=30) were subjected to transient middle cerebral artery occlusion (MCAO, 120 minutes) by use of the intraluminal filament model. Animals of the treatment group (n=12) were exposed to whole-body hypothermia of 33°C for 5 hours starting 3 hours after MCAO, whereas the control group (n=18) was kept at 37°C throughout the whole experiment. The normothermia- and hypothermia-treated animals were investigated daily by using the Menzies neurological score. Serial MRI was performed 1, 3, and 6 hours after MCAO and on days 1, 2, 3, and 5. After the final MRI scan, the rats were euthanized, and brain slices were stained by 2,3,5-triphenyltetrazolium chloride.

Results

—

Delayed hypothermia resulted in a significant increase of survival rate and a significant improvement of the Menzies score. Moreover, a significant decrease in the extent of hyperintense volumes in T2-weighted scans and a reduction of cerebral edema as calculated from T2-weighted scans throughout the examination period were obvious. The extent of cerebral infarct volume and cerebral brain edema examined by MRI was consistent with 2,3,5-triphenyltetrazolium chloride staining.

Conclusions

—

Our results suggest that even delayed postischemic hypothermia can reduce the extent of infarct volume and brain edema after transient focal cerebral ischemia.
Tolerance Against Ischemic Neuronal Injury Can Be Induced by Volatile Anesthetics and Is Inducible NO Synthase Dependent
Authors: Kapinya Krisztian J. , Löwl Diana , Fütterer Carsten , Maurer Martin , Waschke Klaus F. , Isaev Nikolaj K. , Dirnagl Ulrich
Published: July 2002

Background and Purpose

—

We tested whether volatile anesthetics induce neuroprotection that is maintained for a prolonged time.

Methods

—

Rats were pretreated for 3 hours with 1 minimal anesthetic concentration of isoflurane or halothane in normal air (anesthetic preconditioning [AP]). The animals were subjected to permanent middle cerebral artery occlusion (MCAO) at 0, 12, 24, or 48 hours after AP. Halothane-pretreated animals were subjected to MCAO 24 hours after AP. Histological evaluation of infarct volumes was performed 4 days after MCAO. Cerebral glucose utilization was measured 24 hours after AP with isoflurane. Primary cortical neuronal cultures were exposed to 1.4% isoflurane for 3 hours. Oxygen-glucose deprivation (OGD) was performed 24 hours after AP. Injury was assessed 24 hours later by measuring the release of lactate dehydrogenase into the medium 24 hours after OGD.

Results

—

Isoflurane anesthesia at 0, 12, and 24 hours before MCAO or halothane anesthesia 24 hours before MCAO significantly reduced infarct volumes (125±42 mm
3
,
P
=0.024; 118±51 mm
3
,
P
=0.008; 120±49 mm
3
,
P
=0.009; and 121±48 mm
3
,
P
=0.018, respectively) compared with control volumes (180±51 mm
3
). Three hours of isoflurane anesthesia in rats did not have any effect on local or mean cerebral glucose utilization measured 24 hours later. Western blot analysis from cortical extracts of AP-treated animals revealed an increase of the inducible NO synthase (iNOS) protein beginning 6 hours after AP. The iNOS inhibitor aminoguanidine (200 mg/kg IP) eliminated the infarct-sparing effect of AP. In cultured cortical neurons, isoflurane exposure 24 hours before OGD decreased the OGD-induced release of lactate dehydrogenase by 49% (
P
=0.002).

Conclusions

—

Pretreatment with volatile anesthetics induces prolonged neuroprotection in vitro and in vivo, a process in which iNOS seems to be critically involved.
Intra-Arterial Thrombolysis in 100 Patients With Acute Stroke Due to Middle Cerebral Artery Occlusion
Authors: Arnold Marcel , Schroth Gerhard , Nedeltchev Krassen , Loher Thomas , Remonda Luca , Stepper Frank , Sturzenegger Matthias , Mattle Heinrich P.
Published: July 2002

Background and Purpose

—

The purpose of this study was to evaluate the safety and efficacy of local intra-arterial thrombolysis (LIT) using urokinase in patients with acute stroke due to middle cerebral artery (MCA) occlusion.

Methods

—

We analyzed clinical and radiological findings and functional outcome 3 months after LIT with urokinase of 100 consecutive patients. To measure outcome, the modified Rankin scale (mRs) score was used.

Results

—

Angiography showed occlusion of the M
1
segment of the MCA in 57 patients, of the M
2
segment in 21, and of the M
3
or M
4
segment in 22. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 14, and, on average, 236 minutes elapsed from symptom onset to LIT. Forty-seven patients (47%) had an excellent outcome (mRs score 0 to 1), 21 (21%) a good outcome (mRs score 2), and 22 (22%) a poor outcome (mRs score 3 to 5). Ten patients (10%) died. Excellent or good outcome (mRs score ≤2) was seen in 59% of patients with M
1
or M
2
and 95% of those with M
3
or M
4
MCA occlusions. Recanalization as seen on angiography was complete (thrombolysis in myocardial infarction [TIMI] grade 3) in 20% of patients and partial (TIMI grade 2) in 56% of patients. Age <60 years (
P
<0.05), low NIHSS score at admission (
P
<0.00001), and vessel recanalization (
P
=0.0004) were independently associated with excellent or good outcome and diabetes with poor outcome (
P
=0.002). Symptomatic cerebral hemorrhage occurred in 7 patients (7%).

Conclusions

—

LIT with urokinase that is administered by a single organized stroke team is safe and can be as efficacious as thrombolysis has been in large multicenter clinical trials.
Mouse Model of Cerebral Aneurysm
Authors: Morimoto Masafumi , Miyamoto Susumu , Mizoguchi Akira , Kume Noriaki , Kita Toru , Hashimoto Nobuo
Published: July 2002

Background and Purpose

—

Rupture of cerebral aneurysm (CA) is the major cause of subarachnoid hemorrhage. Molecular mechanisms of this disease, however, remain unknown. To make possible genetic analysis of CA formation with genetically altered mice, we have successfully established a mouse model of saccular CA that recapitulates the essential features of human saccular CA.

Methods

—

In C57black/6 male mice, various stages of CAs were experimentally induced at the right anterior cerebral artery–olfactory artery bifurcations by ligations of left common carotid arteries and posterior branches of bilateral renal arteries with high salt diet. Both light and electron microscopic studies were performed with the longitudinal sections of anterior cerebral artery–olfactory artery bifurcations.

Results

—

In the treated group, various aneurysmal changes were detected in 14 of 18 mice. On the other hand, in the control group, no aneurysmal changes were found in 15 mice. In microscopic studies, aneurysmal changes were shown to include mainly fragmentation of internal elastic lamina, thinning of the smooth muscle cell layer, and degeneration of adventitial tissue, which were very similar to critical changes in human saccular CA.

Conclusions

—

This mouse model of CA will be useful for studying the effects of complex determinants on CA formation and makes it possible to understand the pathogenesis of CA at the molecular level.
Adenovirus-Mediated Heme Oxygenase-1 Gene Expression Stimulates Apoptosis in Vascular Smooth Muscle Cells
Authors: Liu Xiao-ming , Chapman Gary B. , Wang Hong , Durante William
Published: July 2002

Background
—

Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into biliverdin, iron, and carbon monoxide (CO). Although HO-1 is induced in vascular smooth muscle cells (SMCs), the biological role of HO-1 in these cells has not been completely characterized.

Methods and Results
—

In the present study, we overexpressed HO-1 in rat aortic SMCs by generating a recombinant defective adenovirus containing the rat HO-1 gene (AdHO-1) and examined the effect on SMC proliferation. Infection of SMCs with AdHO-1 resulted in a dose-dependent increase in the expression of HO-1 mRNA, protein, and activity. Infection of SMCs with AdHO-1 inhibited serum-stimulated SMC proliferation in a dose-dependent manner. In contrast, the control adenovirus expressing the green fluorescent protein failed to induce HO-1 expression and had minimal effects on SMC growth. Infection with AdHO-1 stimulated SMC apoptosis in a dose-dependent fashion, as demonstrated by DNA fragmentation, positive annexin V labeling, and caspase-3 activation. HO-1–mediated apoptosis was associated with a marked increase in the expression of the proapoptotic protein p53. Finally, the exogenous administration of biliverdin and bilirubin stimulated SMC apoptosis. In contrast, the administration of CO or iron failed to induce cell death.

Conclusions
—

These results demonstrate that overexpression of HO-1 or the exogenous administration of biliverdin or bilirubin stimulates SMC apoptosis. Adenovirus-mediated transfer of the HO-1 gene may provide a novel therapeutic approach in treating occlusive vascular disease.
Selective Attenuation of Isoproterenol-Stimulated Arrhythmic Activity by a Partial Agonist of Adenosine A
1
Receptor
Authors: Song Yejia , Wu Lin , Shryock John C. , Belardinelli Luiz
Published: July 2002

Background
—

The goal of this study was to examine the hypothesis that a partial agonist of the adenosine A
1
receptor (A
1
AdoR) may cause a greater attenuation of catecholamine-induced ventricular arrhythmic activity than of contractility.

Methods and Results
—

The effects of CVT-2759 and adenosine, a partial and a full agonist of the A
1
AdoR, on isoproterenol-stimulated arrhythmic activity and contractility of guinea pig isolated ventricular myocytes were determined. CVT-2759 (10 μmol/L) and adenosine (10 μmol/L) significantly inhibited isoproterenol-induced arrhythmic activity (aftercontraction and transient inward current) but did not reduce the amplitudes of twitch shortening and L-type Ca
2+
current. Increasing the concentration of the full agonist adenosine from 10 to 100 μmol/L, however, caused significant attenuation of twitch shortening as well as aftercontractions, whereas increasing the concentration of the partial agonist CVT-2759 from 10 to 100 μmol/L did not. CVT-2759 also significantly inhibited isoproterenol-induced spontaneous ventricular beats in isolated hearts. In contrast to adenosine, CVT-2759 neither activated adenosine-sensitive K
+
current nor shortened the duration of the atrial APD.

Conclusions
—

The present results support the hypothesis and suggest a potential role for a partial agonist of the A
1
AdoR in the treatment of cardiac arrhythmias.
Analysis of Mural Cell Recruitment to Tumor Vessels
Authors: Abramsson Alexandra , Berlin Örjan , Papayan Hayk , Paulin Denise , Shani Moshe , Betsholtz Christer
Published: July 2002

Background
—

Tumor blood vessels are both structurally and functionally abnormal compared with normal vessels. A limited support of mural cells may contribute to these abnormalities. Here, we characterized mural cell recruitment in 2 mouse tumor models and addressed the question of why tumor vessels fail to recruit a proper coat of mural cells.

Methods and Results
—

We studied mural cell recruitment to the vasculature of 2 transplantable mouse tumor models, T241 fibrosarcoma and KRIB osteosarcoma. We found that both tumors formed a vessel network with heterogeneous and highly abnormal organization of mural cells. Transplantation of tumors to mice expressing lacZ in mural cells demonstrated that these cells were host-derived. Although tumor vessel endothelium expressed PDGF-B, an embryonic mitogen for mural cells, only very few PDGFRβ-positive cells were found to be associated with the developing tumor vasculature, suggesting a limited pool of recruitable mural cells. We tested whether exogenous mural cells could be recruited to tumor vessels by injecting mixtures of T241 tumor cells and embryonic mesenchymal cells isolated from mice expressing lacZ in mural cells. In the tumors that arose, lacZ-positive cells were efficiently recruited to the tumor vessels.

Conclusions
—

T241 and KRIB tumors show a similar highly abnormal organization of vessel-associated mural cells. T241 tumor vessels seem highly capable of recruiting exogenously added mural cells. The sparse mural cell coat of tumor vessels may result from a limited pool of mural cells available for recruitment.
Gas Exchange Detection of Exercise-Induced Right-to-Left Shunt in Patients With Primary Pulmonary Hypertension
Authors: Sun Xing-Guo , Hansen James E. , Oudiz Ronald J. , Wasserman Karlman
Published: July 2002

Background
—

Because of high pulmonary vascular resistance in patients with primary pulmonary hypertension (PPH), right atrial pressure may exceed left atrial pressure during exercise, resulting in a right-to-left shunt via a patent foramen ovale (PFO). This shunting would disturb arterial P
co
2
and H
+
homeostasis if the pulmonary blood were not simultaneously hyperventilated to compensate for the high CO
2
and H
+
in the shunted blood. This article first hypothesizes and then describes unique changes in gas exchange when right-to-left exercise-induced shunting (EIS) occurs.

Methods and Results
—

Retrospectively, the cardiopulmonary exercise tests of 71 PPH patients were studied. Criteria postulated to document hyperventilation of the pulmonary blood flow due to a right-to-left EIS were (1) an abrupt and sustained increase in end-tidal O
2
with a simultaneous sustained decrease in end-tidal CO
2
; (2) an abrupt and sustained increase in the respiratory exchange ratio; and (3) usually, an associated decline in pulse oximetry saturation. Each patient was evaluated for a PFO with resting echocardiography. The investigators interpreting the gas exchange evidence of EIS were blinded to the echocardiographic readings. Forty-five percent of the patients had demonstrable EIS by gas exchange criteria. Almost all were also positive for a PFO by echocardiography. Using the resting echocardiograph as the reference, the sensitivity, specificity, positive and negative predictive values, and accuracy were all between 90% to 96%.

Conclusions
—

Exercise-induced right-to-left shunting can be detected by noninvasive, cardiopulmonary exercise testing in patients with PPH.
Determination of Successful Reperfusion After Thrombolysis for Acute Myocardial Infarction
Authors: Hancock J. E. , Cooke J. C. , Chin D. T. , Monaghan M. J.
Published: July 2002

Background
—

The aim of the present study was to determine the use of cyclic variation in ultrasonic integrated backscatter (IBS), which is reduced in ischemic myocardium, to predict an occluded infarct-related artery (IRA) after thrombolysis for acute myocardial infarction (AMI). This is important, because patency of the IRA 90 minutes after thrombolysis has been shown to predict outcome.

Methods and Results
—

One hundred thirteen patients with AMI had peak-to-peak cyclic IBS measured in the myocardial territory supplied by their IRA as well as a remote territory with normal function from the parasternal long- or short-axis view. This analysis took 5 to 10 minutes. Wall motion score index was assessed, and coronary angiography, to determine patency of the IRA, was performed in all patients. Cyclic IBS in the IRA territory was much lower in segments supplied by an occluded IRA (3.3 versus 4.6 dB,
P
<0.00001). Using a difference in cyclic IBS between infarcted and normal segments of 15% (or 1.5 dB) as a cutoff, the sensitivity, specificity, positive and negative predictive values to determine an occluded IRA were 92%, 75%, 81%, and 89%, respectively.

Conclusions
—

The difference in cyclic IBS between IRA and remote normal segments, which can be analyzed rapidly, can be used to predict patency of the IRA in patients with AMI. This provides a noninvasive method to determine those patients who may require urgent invasive investigation.
Sonodynamic Therapy Decreased Neointimal Hyperplasia After Stenting in the Rabbit Iliac Artery
Authors: Arakawa Koh , Hagisawa Kousukue , Kusano Hiroyuki , Yoneyama Satoru , Kurita Akira , Arai Tsunenori , Kikuchi Makoto , Sakata Isao , Umenura Shin-ichirou , Ohsuzu Fumitaka
Published: July 2002

Background
—

In-stent restenosis remains a pivotal problem after coronary and peripheral stenting. Sonodynamic therapy inhibits tumor growth by means of cytotoxicity after the activation of sonochemical sensitizers by ultrasound. PAD-S31 is known to be a water-soluble, chlorin-derivative sonochemical sensitizer. We assessed the efficacy of sonodynamic therapy using this sensitizer on neointimal hyperplasia in a rabbit stent model.

Methods and Results
—

Stents were implanted in the iliac arteries of 16 rabbits. A total of 32 stented arteries were randomized to sonodynamic therapy, control, ultrasound exposure, and PAD-S31 groups. One hour after the intravenous administration of PAD-S31 (25 mg/kg body weight), ultrasound energy (1 MHz, 0.3 W/cm
2
) was delivered transdermally to the sonodynamic therapy group. At 28 days, all stent sites were analyzed morphometrically. The size of the intimal cross-sectional area was smaller in the sonodynamic therapy group than in the control, ultrasound, and PAD-S31 groups (0.31±0.07 versus 1.38±0.47, 1.66±0.71, and 1.61±0.42 mm
2
, respectively;
P
<0.05). The ratio of the intimal and medial cross-sectional area was smaller in the sonodynamic therapy group than in the control, ultrasound, and PAD-S31 groups (0.71±0.22 versus 2.53±1.39, 2.48±0.60, and 3.45±1.42 mm
2
;
P
<0.05).

Conclusions
—

Sonodynamic therapy with PAD-S31 is considered to be a feasible treatment modality for noninvasively inhibiting neointimal hyperplasia in a rabbit iliac stent model.
Outcomes of Patients With Acute Coronary Syndromes and Prior Coronary Artery Bypass Grafting
Authors: Labinaz Marino , Kilaru Rakhi , Pieper Karen , Marso Steven P. , Kitt Michael M. , Simoons Maarten L. , Califf Robert M. , Topol Eric J. , Armstrong Paul W. , Harrington Robert A.
Published: July 2002

Background

—

Patients with prior CABG with a subsequent non–ST-segment elevation acute coronary syndrome (ACS) pose an increasingly important clinical problem. Although GP IIb/IIIa inhibitors have improved the outcome of patients with ACS, their efficacy in patients with prior CABG has not been previously evaluated.

Methods and Results

—

We analyzed the 30- and 180-day outcomes of patients with prior CABG enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. In this trial, which evaluated the efficacy of eptifibatide in patients with ACS, 1134 patients (12%) with prior CABG and 8321 without prior CABG were enrolled. After adjusting for differences in baseline characteristics and treatment, patients with prior CABG had a significantly higher mortality rates at 30 days (hazard ratio [HR], 1.45 [95% CI, 1.06 to 1.98];
P
=0.019) and at 180 days (HR, 1.32 [95% CI, 1.04 to 1.67];
P
=0.021). At 30 days, there was a similar effect on the primary end point of death or myocardial infarction in the eptifibatide group versus the placebo group in prior CABG patients (unadjusted HR, 0.90 [95% CI, 0.67 to 1.20]) and in patients without a history of CABG (unadjusted HR, 0.89 [95% CI, 0.80 to 0.99]).

Conclusions

—

Patients with prior CABG with non–ST-segment elevation ACS have a significantly worse prognosis than do patients without a history of CABG. The treatment effect of eptifibatide in the prior CABG group was similar to the effect seen in patients without prior CABG.
Improved Endothelium-Dependent Vasodilation After Blockade of Endothelin Receptors in Patients With Essential Hypertension
Authors: Cardillo Carmine , Campia Umberto , Kilcoyne Crescence M. , Bryant Melissa B. , Panza Julio A.
Published: July 2002

Background
—

Hypertensive patients have both impaired endothelium-dependent vasodilation and increased activity of the endothelin (ET-1) system, which participate in their increased vascular tone and may predispose them to atherosclerosis. This study investigated the contribution of increased ET-1 activity to the impaired endothelium-dependent vasodilator function of hypertensive patients.

Methods and Results
—

Forearm blood flow (FBF) responses to intraarterial infusion of acetylcholine (ACh; 7.5, 15, and 30 μg/min) and sodium nitroprusside (SNP; 0.8,1.6, and 3.2 μg/min) were assessed by strain-gauge plethysmography before and after nonselective blockade of ET
A
and ET
B
receptors by combined infusion of BQ-123 (ET
A
blocker; 100 nmol/min) and BQ-788 (ET
B
blocker; 50 nmol/min). During saline administration, the vasodilator response to ACh was significantly blunted in hypertensive patients compared with controls (
P
<0.001), whereas the vasodilator effect of SNP was not different between groups (
P
=0.74). Blockade of ET-1 receptors resulted in a significant increase in FBF from baseline in hypertensive patients (
P
<0.008) but not in controls (
P
=0.15). In hypertensive patients, a combined ET
A/B
blockade resulted in a significant potentiation of the vasodilator response to ACh compared with saline (
P
=0.01), whereas the response to SNP was unchanged (
P
=0.44). In contrast, the response to ACh was not significantly modified by ET-1 receptor antagonism in healthy subjects (
P
=0.14 compared with saline).

Conclusions
—

These findings indicate that blockade of ET-1 receptors improves endothelium-dependent vasodilator function in hypertensive patients, thereby suggesting that an increased ET-1 activity may play a role in the pathophysiology of this abnormality.
Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly
Authors: Niimura Hideshi , Patton Kristen K. , McKenna William J. , Soults Johann , Maron Barry J. , Seidman J.G. , Seidman Christine E.
Published: July 2002

Background
—

Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown.

Methods and Results
—

Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (±12.3) years, and diagnosis was made at 62.8 (±10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9±3.8 mm, systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63±42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and α-cardiac myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac myosin binding protein-C Arg326Gln) also occurred in a healthy adult.

Conclusions
—

Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (
P
<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in β-cardiac myosin heavy chain, cardiac troponin T, and α-tropomyosin account for >45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and α-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.
Passage of Inhaled Particles Into the Blood Circulation in Humans
Authors: Nemmar A. , Hoet P.H.M. , Vanquickenborne B. , Dinsdale D. , Thomeer M. , Hoylaerts M.F. , Vanbilloen H. , Mortelmans L. , Nemery B.
Published: July 2002

Background
—

Pollution by particulates has been consistently associated with increased cardiovascular morbidity and mortality. However, the mechanisms responsible for these effects are not well-elucidated.

Methods and Results
—

To assess to what extent and how rapidly inhaled pollutant particles pass into the systemic circulation, we measured, in 5 healthy volunteers, the distribution of radioactivity after the inhalation of “Technegas,” an aerosol consisting mainly of ultrafine
99m
Technetium-labeled carbon particles (<100 nm). Radioactivity was detected in blood already at 1 minute, reached a maximum between 10 and 20 minutes, and remained at this level up to 60 minutes. Thin layer chromatography of blood showed that in addition to a species corresponding to oxidized
99m
Tc, ie, pertechnetate, there was also a species corresponding to particle-bound
99m
Tc. Gamma camera images showed substantial radioactivity over the liver and other areas of the body.

Conclusions
—

We conclude that inhaled
99m
Tc-labeled ultrafine carbon particles pass rapidly into the systemic circulation, and this process could account for the well-established, but poorly understood, extrapulmonary effects of air pollution.
Department of Veterans Affairs Cooperative Studies Program Clinical Trial Comparing Combined Warfarin and Aspirin With Aspirin Alone in Survivors of Acute Myocardial Infarction
Authors: Fiore Louis D. , Ezekowitz Michael D. , Brophy Mary T. , Lu David , Sacco Joseph , Peduzzi Peter
Published: July 2002

Background

—

Both aspirin and warfarin when used alone are effective in the secondary prevention of vascular events and death after acute myocardial infarction. We tested the hypothesis that aspirin and warfarin therapy, when combined, would be more effective than aspirin monotherapy.

Methods and Results

—

We conducted a randomized open-label study to compare the efficacy of warfarin (target international normalized ratio 1.5 to 2.5 IU) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5059 patients enrolled within 14 days of infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank
P
=0.76). Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank
P
=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank
P
=0.52). Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively;
P
<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups.

Conclusions

—

In post–myocardial infarction patients, warfarin therapy (at a mean international normalized ratio of 1.8) combined with low-dose aspirin did not provide a clinical benefit beyond that achievable with aspirin monotherapy.
Principal Component Analysis of the T Wave and Prediction of Cardiovascular Mortality in American Indians
Authors: Okin Peter M. , Devereux Richard B. , Fabsitz Richard R. , Lee Elisa T. , Galloway James M. , Howard Barbara V.
Published: July 2002

Background

—

Increased QT interval dispersion (QTd) is a proposed ECG marker of vulnerability to ventricular arrhythmias and of cardiovascular (CV) mortality. However, principal component analysis (PCA) of the T-wave vector loop may more accurately represent repolarization abnormalities than QTd.

Methods and Results

—

Predictive values of QTd and PCA were assessed in 1839 American Indian participants in the first Strong Heart Study examination. T-wave loop morphology was quantified by the ratio of the second to first eigenvalues of the T-wave vector by PCA (PCA ratio); QTd was quantified as the difference between maximum and minimum QT intervals. After 3.7±0.9 years mean follow-up, there were 55 CV deaths. In univariate analyses, an increased PCA ratio predicted CV mortality in women (χ
2
=7.8,
P
=0.0053) and men (χ
2
=9.5,
P
=0.0021). In contrast, increased QTd was a significant predictor of CV mortality in women (χ
2
=30.6,
P
<0.0001) but not in men (χ
2
=2.0,
P
=NS). In multivariate Cox analyses controlling for risk factors and rate-corrected QT interval, the PCA ratio remained a significant predictor of CV mortality in women (χ
2
=4.0
P
=0.043) and men (χ
2
=6.4,
P
=0.011); QTd was a significant predictor in women only (χ
2
=11.0,
P
=0.0009). PCA ratios >90th percentile (32% in women and 24.6% in men) identified women with a 3.68-fold increased risk of CV mortality (95% CI, 1.54 to 8.83) and men with a 2.77-fold increased risk (95% CI, 1.18 to 6.49).

Conclusions

—

Abnormalities of repolarization measured by PCA of the T-wave loop predict CV death in men and women, supporting use of PCA for quantifying repolarization abnormalities.
Altered Expression of ADAMs (
A D
isintegrin
A
nd
M
etalloproteinase) in Fibrillating Human Atria
Authors: Arndt Marco , Lendeckel Uwe , Röcken Christoph , Nepple Karen , Wolke Carmen , Spiess Antje , Huth Christof , Ansorge Siegfried , Klein Helmut U. , Goette Andreas
Published: July 2002

Background

—

ADAMs (
A D
isintegrin
A
nd
M
etalloproteinase) are ectoproteases that have recently been reported to be expressed in cardiac tissue. Although they are known to regulate cell-cell and cell-matrix interactions, their pathophysiological role in various cardiac diseases is unclear. The purpose of the present study was to determine whether structural remodeling of the atria during atrial fibrillation (AF) is associated with altered ADAM expression.

Methods and Results

—

Atrial tissue samples of 30 patients undergoing open-heart surgery were examined. Fifteen patients had persistent AF (≥6 months), and the remaining 15 patients had no history of AF. ADAM9, ADAM10, and ADAM15 expression was analyzed quantitatively at the mRNA and protein levels. ADAM expression was localized by immunohistochemistry. ADAM expression was correlated with amounts of integrins β
1
and β
3
. The amount of ADAM10 protein more than doubled during AF (82±15 versus 36±8 U;
P
<0.01). Amounts of ADAM15 protein (102±12 versus 40±6 U;
P
<0.01) and mRNA (24.0±5.6 versus 10.5±2.5 U;
P
<0.05) increased significantly during AF compared with sinus rhythm. ADAM9 protein was not detected in any sample. ADAM/integrin ratios showed an increase of 4- to 6-fold (
P
<0.05) in patients with AF who had significantly dilated atria (4.94±0.6 versus 4.3±0.7 cm;
P
<0.05). ADAM/integrin ratios correlated with atrial diameter.

Conclusions

—

AF is associated with an increase in the expression of ADAM10 and ADAM15. Enhanced ADAM-dependent disintegrin and metalloproteinase activity may be a molecular mechanism that contributes to the dilation of fibrillating human atria.
Calcineurin Inhibition Attenuates Mineralocorticoid-Induced Cardiac Hypertrophy
Authors: Takeda Yoshiyu , Yoneda Takashi , Demura Masashi , Usukura Mikiya , Mabuchi Hiroshi
Published: July 2002

Background

—

It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis.

Methods and Results

—

Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 μg · h
−1
) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg · kg
−1
· d
−1
) or cyclosporine A (10 mg · kg
−1
· d
−1
). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg · kg
−1
· d
−1
)on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity and its mRNA expression were also increased in aldosterone-induced hypertrophic heart. Treatment with losartan, FK506, or cyclosporine partially prevented aldosterone-induced cardiac hypertrophy and fibrosis.

Conclusion

—

These results suggest that calcineurin is involved in the development of cardiac hypertrophy and fibrosis induced by mineralocorticoid excess. Inhibition of calcineurin may therefore prevent cardiac hypertrophy and fibrosis in mineralocorticoid hypertension.
Cigarette Smoke Exposure and Hypercholesterolemia Increase Mitochondrial Damage in Cardiovascular Tissues
Authors: Knight-Lozano Cynthia A. , Young Christal G. , Burow David L. , Hu Zhao Yong , Uyeminami Dale , Pinkerton Kent E. , Ischiropoulos Harry , Ballinger Scott W.
Published: July 2002

Background
—

A shared feature among cardiovascular disease risk factors is increased oxidative stress. Because mitochondria are susceptible to damage mediated by oxidative stress, we hypothesized that risk factors (secondhand smoke and hypercholesterolemia) are associated with increased mitochondrial damage in cardiovascular tissues.

Methods and Results
—

Atherosclerotic lesion formation, mitochondrial DNA damage, protein nitration, and specific activities of mitochondrial proteins in cardiovascular tissues from age-matched C57 and apoE
−/−
mice exposed to filtered air or secondhand smoke were quantified. Both secondhand smoke and hypercholesterolemia were associated with significantly increased mitochondrial DNA damage and protein nitration. Tobacco smoke exposure also resulted in significantly decreased specific activities of mitochondrial enzymes. The combination of secondhand smoke and hypercholesterolemia resulted in increased atherosclerotic lesion formation and even greater levels of mitochondrial damage.

Conclusions
—

These data are consistent with the hypothesis that cardiovascular disease risk factors cause mitochondrial damage and dysfunction.
Effects of Selective Autonomic Blockade on T-Wave Alternans in Humans
Authors: Rashba Eric J. , Cooklin Michael , MacMurdy Karen , Kavesh Neal , Kirk Malcolm , Sarang Samantha , Peters Robert W. , Shorofsky Stephen R. , Gold Michael R.
Published: July 2002

Background
—

T-wave alternans (TWA) is an important noninvasive measure of ventricular arrhythmia vulnerability. This study tested the hypothesis that the autonomic nervous system influences TWA measurement in high-risk subjects with coronary artery disease.

Methods and Results
—

T-wave alternans was measured in 60 patients with coronary artery disease, left ventricular dysfunction, and inducible sustained ventricular tachycardia during electrophysiological studies. All patients had TWA measured at baseline with atrial pacing at 100 bpm (600 ms), 109 bpm (550 ms), and 120 bpm (500 ms). After a 10-minute recovery period, TWA was measured again after sympathetic blockade (esmolol, n=20), parasympathetic blockade (atropine, n=20), or no intervention (control subjects, n=20). The prevalence of significant TWA was unchanged compared with baseline after atropine infusion and in the control group. In contrast, the amplitude of TWA in the vector magnitude lead was significantly reduced after esmolol infusion (
P
<0.001), and the number of positive TWA tests was reduced by 50% (70% versus 35%,
P
<0.05).

Conclusions
—

Our findings have important implications for the use of TWA to risk-stratify patients for life-threatening ventricular arrhythmias and provide a new potential mechanism for the reduction in sudden cardiac death conferred by β-blockers among patients with coronary artery disease and congestive heart failure.
Increased Nitric Oxide Bioavailability in Endothelial Cells Contributes to the Pleiotropic Effect of Cerivastatin
Authors: Kalinowski Leszek , Dobrucki Lawrence W. , Brovkovych Viktor , Malinski Tadeusz
Published: July 2002

Background

—

Although statins preserve endothelial function by reducing serum cholesterol levels, it has been suggested they may also stimulate nitric oxide (NO) synthase in endothelium with concurrent increase in superoxide (O
2
−
) generation, leading to impairment of NO activity. Therefore, measurements of biologically active NO and O
2
−
in endothelium after exposure to the HMG-CoA reductase inhibitor cerivastatin were undertaken to evaluate its potential effect on NO biological activity.

Methods and Results

—

Highly sensitive electrochemical NO and O
2
−
microsensors were placed near the surface of a single human umbilical vein endothelial cell, and the kinetics of NO and O
2
−
release were recorded in vitro. Cerivastatin demonstrated a time-dependent effect on NO release in endothelial cells. The initial release (approximately the first 3 minutes) was concentration-dependent (0.01 to 10 μmol/L) and was similar to that observed for typical NO synthase agonists calcium ionophore or acetylcholine. Cerivastatin stimulated NO release at a favorable rate and scavenged O
2
−
, which led to the preservation of the active concentration of NO. The sustained effect (after ≈6 hours) of cerivastatin on endothelium was associated with an ≈35% increase in NO release as compared with the initial effect. In contrast to the initial effect, the sustained effect of cerivastatin was shown at concentrations ≈100-fold lower and was dependent on inhibition of endothelial HMG-CoA reductase.

Conclusions

—

These data provide direct evidence to prove that in the presence of cerivastatin, the NOS system in endothelium operates with high efficiency toward increasing NO activity by activation of NO release and by concurrent inactivation of O
2
−
.
Relationship Between Coronary Artery Remodeling and Plaque Vulnerability
Authors: Varnava Amanda M. , Mills Peter G. , Davies Michael J.
Published: July 2002

Background

—

In vivo studies with intravascular ultrasound have shown that complex plaque anatomy and plaque rupture are more frequent in the presence of marked outward remodeling. A large lipid core and a high macrophage count are recognized histological markers for plaque vulnerability. The link between plaque vulnerability in terms of these markers and remodeling in coronary arteries has not been explored.

Methods and Results

—

In 88 male subjects who died suddenly with coronary artery disease, 108 plaques were studied. The percent remodeling was calculated. Lesions with remodeling ≥0% were considered to have positive remodeling, and those in which remodeling was <0% were considered to have negative remodeling. Percent lipid core and macrophage count at the plaque were assessed. Of 108 plaque sites, 64 (59.2%) had undergone no remodeling or positive remodeling, and 44 (40.7%) had negative remodeling (vessel shrinkage). Lesions with positive remodeling, compared with lesions with vessel shrinkage, had a larger lipid core (percent mean lipid core was 39.0±21.0% versus 22.3±23.1%, respectively;
P
<0.0001) and a higher macrophage count (mean macrophage count was 15.6±12.3 versus 8.9±11.6, respectively;
P
=0.005).

Conclusions

—

We have shown that coronary artery plaques with positive remodeling have a higher lipid content and macrophage count, both markers of plaque vulnerability. These results may explain why plaque rupture is often apparent at sites with only modest luminal stenoses (but marked positive remodeling).
Effect of Abciximab on Prothrombin Activation and Thrombin Generation in Acute Coronary Syndromes Without ST-Segment Elevation
Authors: Merlini Piera Angelica , Repetto Alessandra , Lombardi Alessandro , Vetrano Alfredo , Fetiveau Raffaela , Cavallini Claudio , Sappè Diego , Salvioni Alessandro , Canziani Roberto , Savonitto Stefano , Mannucci Pier Mannuccio , Ardissino Diego
Published: July 2002

Background
—

Abciximab is very effective in reducing major cardiac events in patients undergoing interventional procedures. Its antithrombotic effect is primarily attributable to the blocking of platelet glycoprotein IIb/IIIa receptors, but recent evidence suggests that it may have a direct antithrombin effect. No data are available concerning the effect of abciximab on the in vivo markers of prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation.

Methods and Results

—

We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and the thrombin/antithrombin complex (a marker of thrombin generation) in 167 patients with acute coronary syndromes without ST elevation enrolled in the GUSTO IV ACS trial who were randomized to receive abciximab for 24 hours (52 patients), abciximab for 48 hours (59 patients), or placebo (56 patients) in addition to heparin. Blood samples were obtained at baseline (before any treatment), after 24 and 48 hours (before study drug discontinuation), and 1 month later. There was a significant increase in the plasma levels of prothrombin fragment 1+2 after 48 hours and after 1 month in all 3 groups, placebo (
P
=0.0001), 24-hour abciximab (
P
=0.0002), and 48-hour abciximab (
P
=0.0001). The plasma thrombin/antithrombin complex levels were similar in the 3 groups at all time points and did not change during the study drug infusions.

Conclusions

—

Abciximab does not decrease prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation not undergoing interventional procedures.
Targeting Phospholamban by Gene Transfer in Human Heart Failure
Authors: del Monte Federica , Harding Sian E. , Dec G. William , Gwathmey Judith K. , Hajjar Roger J.
Published: July 2002

Background

—

Myocardial cells from failing human hearts are characterized by abnormal calcium handling, a negative force-frequency relationship, and decreased sarcoplasmic reticulum Ca
2+
ATPase (SERCA2a) activity. In this study, we tested whether contractile function can be improved by decreasing the inhibitory effects of phospholamban on SERCA2a with adenoviral gene transfer of antisense phospholamban (asPL).

Methods and Results

—

Myocardial cells isolated from 9 patients with end-stage heart failure and 18 donor nonfailing hearts were infected with adenoviruses encoding for either the antisense of phospholamban (Ad.asPL), the SERCA2a gene (Ad.SERCA2a), or the reporter genes β-galactosidase and green fluorescent protein (Ad.βgal-GFP). Adenoviral gene transfer with Ad.asPL decreased phospholamban expression over 48 hours, increasing the velocity of both contraction and relaxation. Compared with cardiomyocytes infected with Ad.asPL (n=13), human myocytes infected with Ad.βgal-GFP (n=8) had enhanced contraction velocity (20.3±3.9% versus 8.7±2.6% shortening/second;
P
<0.01) and relaxation velocity (26.0±6.2% versus 8.6±4.3% shortening/second;
P
<0.01). The improvement in contraction and relaxation velocities was comparable to cardiomyocytes infected with Ad.SERCA2a. Failing human cardiomyocytes had decreased contraction and Ca
2+
release with increasing frequency (0.1 to 2 Hz). Phospholamban ablation restored the frequency response in the failing cardiomyocytes to normal; increasing frequency resulted in enhanced sarcoplasmic reticulum Ca
2+
release and contraction.

Conclusion

—

These results show that gene transfer of asPL can improve the contractile function in failing human myocardium. Targeting phospholamban may provide therapeutic benefits in human heart failure.