bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of Metabolic Syndrome and Fibrinolytic Dysfunction to Cardiovascular Disease
Authors: Anand Sonia S. , Yi Qilong , Gerstein Hertzel , Lonn Eva , Jacobs Ruby , Vuksan Vlad , Teo Koon , Davis Bonnie , Montague Patty , Yusuf Salim
Published: July 2003

Background—

The clustering of impaired glucose metabolism, elevated triglycerides, low HDL cholesterol, and abdominal obesity is known as the metabolic syndrome. Individuals with this syndrome suffer an excess of cardiovascular disease (CVD) for reasons that are unclear.

Methods and Results—

We randomly sampled 1276 adults of South Asian, Chinese, European, and Native Indian ancestry from 4 communities in Canada. Participants provided fasting blood samples for glucose, lipids, and fibrinolytic measurements; had an oral glucose tolerance test; and underwent a B-mode carotid ultrasound examination. CVD was determined by history and ECG. The prevalence of the metabolic syndrome was 25.8% (95% CI, 23.5 to 28.2) and varied substantially by ethnic group: 41.6% among Native Indians, 25.9% among South Asians, and 22.0% among Europeans, compared with 11.0% among the Chinese (overall,
P
=0.0001). People with the metabolic syndrome had more atherosclerosis (maximum intimal medial thickness, 0.78±0.18 versus 0.74±0.18 mm;
P
=0.0005), CVD (17.2% versus 7.0%;
P
=0.0001), and elevated plasminogen activator inhibitor-1 (24.2 versus 14.6 U/mL;
P
=0.001) compared with levels among people without the metabolic syndrome. For the same amount of atherosclerosis, people with the metabolic syndrome had a greater prevalence of CVD, even among nondiabetic individuals. This difference in CVD prevalence among the groups was attenuated after adjustment for plasminogen activator inhibitor-1 levels, suggesting that fibrinolytic dysfunction mediates the increased risk of CVD in individuals with the metabolic syndrome.

Conclusion—

CVD among people with the metabolic syndrome is explained by their excess of atherosclerosis and impaired fibrinolysis. Interventions to prevent atherosclerosis progression and improve fibrinolytic function require evaluation in this high-risk group.
Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways
Authors: Shishehbor Mehdi H. , Brennan Marie-Luise , Aviles Ronnier J. , Fu Xiaoming , Penn Marc S. , Sprecher Dennis L. , Hazen Stanley L.
Published: July 2003

Background—

The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO
2
Tyr), a modification generated by nitric oxide–derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported.

Methods and Results—

As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO
2
Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO
2
Tyr, and dityrosine (30%, 25%, and 32%, respectively;
P
<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%,
P
<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively;
P
>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins.

Conclusions—

Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide–derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.
Prevalence and Spectrum of Thin Filament Mutations in an Outpatient Referral Population With Hypertrophic Cardiomyopathy
Authors: Van Driest Sara L. , Ellsworth Erik G. , Ommen Steve R. , Tajik A. Jamil , Gersh Bernard J. , Ackerman Michael J.
Published: July 2003

Background—

Thin filament mutations are reported to cause ≈20% of cases of hypertrophic cardiomyopathy (HCM), and they have been associated with specific phenotypes. However, the frequency of these mutations and their associated phenotype(s) from a large tertiary referral center population are unknown.

Methods and Results—

DNA was obtained from 389 unrelated patients with HCM. A mutational analysis of all protein coding exons of cardiac troponin T, cardiac troponin I, α-tropomyosin, and cardiac actin was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. The clinical data were extracted from patient records and maintained independent of the patient genotype. Overall, only 18 patients (4.6%) harbored isolated thin filament mutations: 8 had troponin T mutations, 6 had troponin I mutations, 3 had α-tropomyosin mutations, and 1 had an actin mutation. Of the 12 unique missense mutations identified, 9 (75%) were novel mutations. As a group, patients with thin filament mutations were not significantly different from the rest of the cohort in age at diagnosis, left ventricular wall thickness, left ventricular outflow tract obstruction, or family history of HCM or sudden cardiac death.

Conclusions—

Mutations in genes encoding thin filament proteins are less prevalent in HCM than previously estimated. Patients with mutations in troponin T, troponin I, α-tropomyosin, and actin do not invariably present with any distinct clinical feature, thus limiting the utility of gene status for risk stratification or of clinical phenotype in guiding individual genetic screening at this time.
Metabolic Syndrome With and Without C-Reactive Protein as a Predictor of Coronary Heart Disease and Diabetes in the West of Scotland Coronary Prevention Study
Authors: Sattar Naveed , Gaw Allan , Scherbakova Olga , Ford Ian , O’Reilly Denis St.J. , Haffner Steven M. , Isles Chris , Macfarlane Peter W. , Packard Chris J. , Cobbe Stuart M. , Shepherd James
Published: July 2003

Background—

The National Cholesterol Education Program (NCEP) recently proposed a simple definition for metabolic syndrome. Information on the prospective association of this definition for coronary heart disease (CHD) and type 2 diabetes is currently limited.

Methods and Results—

We used a modified NCEP definition with body mass index in place of waist circumference. Baseline assessments in the West of Scotland Coronary Prevention Study were available for 6447 men to predict CHD risk and for 5974 men to predict incident diabetes over 4.9 years of follow-up. Mean LDL cholesterol was similar but C-reactive protein was higher (
P
<0.0001) in the 26% of men with the syndrome compared with those without. Metabolic syndrome increased the risk for a CHD event [univariate hazard ratio (HR)=1.76 (95% CI, 1.44 to 2.15)] and for diabetes [univariate HR=3.50 (95% CI 2.51 to 4.90)]. Metabolic syndrome continued to predict CHD events (HR=1.30, 95% CI, 1.00 to 1.67,
P
=0.045) in a multivariate model incorporating conventional risk factors. Men with 4 or 5 features of the syndrome had a 3.7-fold increase in risk for CHD and a 24.5-fold increase for diabetes compared with men with none (both
P
<0.0001). C-reactive protein enhanced prognostic information for both outcomes. With pravastatin, men with the syndrome had similar risk reduction for CHD as compared with those without (HR, 0.73 and 0.69; pravastatin versus placebo).

Conclusions—

A modified NCEP metabolic syndrome definition predicts CHD events, and, more strikingly, new-onset diabetes, and thus helps identify individuals who may receive particular benefit from lifestyle measures to prevent these diseases.
Magnetic Resonance Perfusion Measurements for the Noninvasive Detection of Coronary Artery Disease
Authors: Nagel Eike , Klein Christoph , Paetsch Ingo , Hettwer Sabine , Schnackenburg Bernhard , Wegscheider Karl , Fleck Eckart
Published: July 2003

Background—

With MRI, an index of myocardial perfusion reserve (MPRI) can be determined. We assessed the value of this technique for the noninvasive detection of coronary artery disease (CAD) in patients with suspected CAD.

Methods and Results—

Eighty-four patients referred for a primary diagnostic coronary angiography were examined with a 1.5 T MRI tomograph (Philips-ACS). For each heartbeat, 5 slices were acquired during the first pass of 0.025 mmol gadolinium-diethylenetriamine pentaacetic acid/kg body weight before and during adenosine vasodilation by using a turbo-gradient echo/echo-planar imaging-hybrid sequence. MPRI was determined from the alteration of the upslope of the myocardial signal intensity curves for 6 equiangular segments per slice. Receiver operating characteristics were performed for different criteria to differentiate ischemic and nonischemic segments. Prevalence of CAD was 51%. Best results were achieved when only the 3 inner slices were assessed and a threshold value of 1.1 was used for the second smallest value as a marker for significant CAD. This approach yielded a sensitivity of 88%, specificity of 90%, and accuracy of 89%.

Conclusion—

The determination of MPRI with MRI yields a high diagnostic accuracy in patients with suspected CAD.
Clinical, Angiographic, and Interventional Follow-Up of Patients With Aortic-Saphenous Vein Graft Connectors
Authors: Traverse Jay H. , Mooney Michael R. , Pedersen Wesley R. , Madison James D. , Flavin Thomas F. , Kshettry Vibhu R. , Henry Timothy D. , Eales Frazier , Joyce Lyle D. , Emery Robert W.
Published: July 2003

Background—

The use of aortic connectors for proximal saphenous vein bypass graft anastomoses eliminates the need for aortic clamping during coronary artery bypass grafting (CABG) and may reduce the incidence of stroke in the elderly and in patients with severe aortic atherosclerosis.

Methods and Results—

We studied 74 consecutive patients who received the Symmetry Bypass System aortic connector at the time of CABG. A total of 131 of 144 proximal vein graft anastomoses were performed with this device. The left internal mammary artery was used in 62 patients, and 61 patients had “off-pump” coronary revascularization. A total of 11 patients were readmitted with chest pain consistent with unstable angina 173±39 days after CABG. Five of the 11 patients had previous in-stent restenosis before CABG. At angiography, 20 saphenous vein bypass grafts containing 19 connectors were found to have severe stenosis (n=12) or occlusion (n=6) and were treated with angioplasty and stenting or medical therapy. Seven of 11 patients were readmitted 76±11 days later with recurrent chest pain and were found to have severe stenosis at the previously stented connector site. Six patients underwent angioplasty followed by brachytherapy. Three of these patients redeveloped chest pain and were readmitted 151±71 days later. Two patients were started on oral Rapamune, and one patient underwent redo-CABG.

Conclusion—

Eleven of 74 patients who received aortic connectors at the time of CABG developed symptomatically significant stenosis or occlusion at the connector site shortly after CABG, requiring multiple repeat interventions, including brachytherapy.
Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans
Authors: Koyama Hidenori , Maeno Takaaki , Fukumoto Shinya , Shoji Takuhito , Yamane Takahisa , Yokoyama Hisayo , Emoto Masanori , Shoji Tetsuo , Tahara Hideki , Inaba Masaaki , Hino Masayuki , Shioi Atsushi , Miki Takami , Nishizawa Yoshiki
Published: July 2003

Background—

Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects.

Methods and Results—

Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index β) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index β. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectin–positive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol.

Conclusions—

Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.
Tissue Discontinuities Affect Conduction Velocity Restitution
Authors: Derksen Richard , van Rijen Harold V.M. , Wilders Ronald , Tasseron Sara , Hauer Richard N.W. , Rutten Willem L.C. , de Bakker Jacques M.T.
Published: July 2003

Background—

The mechanism by which structural barriers promote wave break and fibrillation is unclear. Conduction velocity (CV) restitution is an important determinant of wave break. Abnormal CV restitution is associated with ventricular fibrillation in patients with heart disease and arises preferentially in fibrotic myocardium. We hypothesize that tissue discontinuities imposed by structural barriers cause abnormal CV restitution.

Methods and Results—

Tissue discontinuities were simulated in cultures of neonatal rat heart cells grown in 8-armed star patterns. Premature stimulation was applied at the extremity of 1 arm (n=12) while extracellular electrograms were recorded at 24 sites throughout the star. Action potentials were recorded at the following 3 sites: in the stimulated arm and at the discontinuity both proximal to and distal from the star center. Extracellular recordings revealed progressive increases in activation delay (indicative for abnormal CV restitution) only at the discontinuity from arms proximal to the star center. The mean increase in delay was 0.81±0.41 ms/10 ms for recording sites proximal to and 3.13±0.58 ms/10 ms for sites distal from this discontinuity. Depolarizing currents were determined in single cells during premature stimulation and for voltage configurations similar to those arising at the discontinuity. Both voltage-clamp measurements and computer simulations showed that delay at the discontinuity was associated with biphasic, prolonged activation and delayed inactivation of depolarizing current.

Conclusions—

Tissue discontinuities cause abnormal CV restitution. Rapid increase in activation after an initial slow activation and delayed inactivation at the discontinuity lengthen the duration of depolarizing current and cause the abnormal restitution.
Leukemia Inhibitory Factor Enhances Survival of Cardiomyocytes and Induces Regeneration of Myocardium After Myocardial Infarction
Authors: Zou Yunzeng , Takano Hiroyuki , Mizukami Miho , Akazawa Hiroshi , Qin Yingjie , Toko Haruhiro , Sakamoto Masaya , Minamino Tohru , Nagai Toshio , Komuro Issei
Published: July 2003

Background—

Myocardial infarction (MI) is a leading cause of cardiac morbidity and mortality in many countries; however, the treatment of MI is still limited.

Methods and Results—

We demonstrate a novel gene therapy for MI using leukemia inhibitory factor (LIF) cDNA. We injected LIF plasmid DNA into the thigh muscle of mice immediately after inducing MI. Intramuscular injection of LIF cDNA resulted in a marked increase in circulating LIF protein concentrations. Two weeks later, left ventricular remodeling, such as infarct extent and myocardial fibrosis, was markedly attenuated in the LIF cDNA–injected mice compared with vehicle-injected mice. More myocardium was preserved and cardiac function was better in the LIF-treated mice than in the vehicle-injected mice. Injection of LIF cDNA not only prevented the death of cardiomyocytes in the ischemic area but also induced neovascularization in the myocardium. Furthermore, LIF cDNA injection increased the number of cardiomyocytes in cell cycle and enhanced mobilization of bone marrow cells to the heart and their differentiation into cardiomyocytes.

Conclusions—

The intramuscular injection of LIF cDNA may induce regeneration of myocardium and provide a novel treatment for MI.
Low Birth Weight Is Associated With Increased Sympathetic Activity
Authors: IJzerman Richard G. , Stehouwer Coen D.A. , de Geus Eco J. , van Weissenbruch Mirjam M. , Delemarre-van de Waal Henriette A. , Boomsma Dorret I.
Published: July 2003

Background—

Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs.

Methods and Results—

Birth weight of the twins was obtained from the mothers. Pre-ejection period and respiratory sinus arrhythmia were measured with electrocardiography and impedance cardiography at rest, during a reaction time task, and during a mental arithmetic task. In the overall sample, lower birth weight was significantly associated with shorter pre-ejection period at rest, during the reaction time task, and during the mental arithmetic task (
P
=0.0001,
P
<0.0001, and
P
=0.0001, respectively) and with larger pre-ejection period reactivity to the stress tasks (
P
=0.02 and
P
=0.06, respectively). In within-pair analyses, differences in birth weight were associated with differences in pre-ejection period at rest and during both stress tasks in dizygotic twin pairs (
P
=0.01,
P
=0.06, and
P
=0.2, respectively) but not in monozygotic twin pairs (
P
=0.9,
P
=1.0, and
P
=0.5, respectively). Shorter pre-ejection period explained approximately 63% to 84% of the birth weight and blood pressure relation.

Conclusions—

Low birth weight is associated with increased sympathetic activity, and this explains a large part of the association between birth weight and blood pressure. In addition, our findings suggest that the association between birth weight and sympathetic activity depends on genetic factors.
Antiremodeling Effect of Long-Term Exercise Training in Patients With Stable Chronic Heart Failure
Authors: Giannuzzi Pantaleo , Temporelli Pier Luigi , Corrà Ugo , Tavazzi Luigi
Published: July 2003

Background—

The effects of exercise training (ET) on left ventricular (LV) remodeling in chronic heart failure are not definitively established, and the safety of ET in these patients is still debated.

Methods and Results—

This multicenter study investigated the long-term effect of moderate ET on LV remodeling, work capacity, and quality of life (QoL) in 90 patients with stable chronic heart failure caused by LV systolic dysfunction, randomized to a 6-month ET program (T, n=45) or a control group (C, n=45). All patients underwent resting echocardiography, a cardiopulmonary exercise test, 6-minute walking test, and QoL assessment at entry and after 6 months. At entry, end-diastolic (EDV) and end-systolic (ESV) volume, ejection fraction, work capacity, peak V̇
o
2
, and walking distance were similar in the 2 groups. After 6 months, LV volumes diminished in T (EDV, from 142±26 to 135±26 mL/m
2
,
P
<0.006; ESV, from 107±24 to 97±24 mL/m
2
,
P
<0.05) but increased in C (EDV, from 147±41 to 156±42 mL/m
2
,
P
<0.01; ESV, from 110±34 to 118±34 mL/m
2
,
P
<0.01). Ejection fraction improved in T (
P
<0.001) but was unchanged in C (
P
=NS). Significant improvement in work capacity (
P
<0.001), peak V̇
o
2
(
P
<0.006), walking distance (
P
<0.001), and QoL (
P
<0.01) was observed in T but not in C (
P
=NS). T showed a trend toward fewer (
P
=0.05) hospital readmissions for worsening dyspnea in the absence of other adverse cardiac events.

Conclusions—

In stable chronic heart failure, long-term moderate ET has no detrimental effect on LV volumes and function; rather, it attenuates abnormal remodeling. Furthermore, ET is safe and effective in improving exercise tolerance and QoL.
Additive Protection of the Ischemic Heart Ex Vivo by Combined Treatment With δ-Protein Kinase C Inhibitor and ε-Protein Kinase C Activator
Authors: Inagaki Koichi , Hahn Harvey S. , Dorn Gerald W. , Mochly-Rosen Daria
Published: July 2003

Background—

Protein kinase C (PKC) plays a major role in cardioprotection from ischemia/reperfusion injury. Using an HIV-1 Tat protein–derived peptide to mediate rapid and efficient transmembrane delivery of peptide regulators of PKC translocation and function, we examined the cardioprotective effect of selective δ-PKC inhibitor (δV1-1) and ε-PKC activator (ψεRACK) peptides for ischemia/reperfusion damage in isolated perfused rat hearts. Furthermore, we examined the protective effects of these PKC isozymes in isolated perfused hearts subjected to ischemia/reperfusion damage using transgenic mice expressing these peptides specifically in their cardiomyocytes.

Methods and Results—

In isolated perfused rat hearts, administration of δV1-1 but not ψεRACK during reperfusion improved cardiac function and decreased creatine phosphokinase release. In contrast, pretreatment with ψεRACK but not δV1-1, followed by a 10-minute washout before ischemia/reperfusion, also improved cardiac function and decreased creatine phosphokinase release. Furthermore, administration of ψεRACK before ischemia followed by δV1-1 during reperfusion only conferred greater cardioprotective effects than that obtained by each peptide treatment alone. Both the δ-PKC inhibitor and ε-PKC activator conferred cardioprotection against ischemia/reperfusion injury in transgenic mice expressing these peptides in the heart, and coexpression of both peptides conferred greater cardioprotective effects than that obtained by the expression of each peptide alone.

Conclusions—

δ-PKC inhibitor prevents reperfusion injury, and ε-PKC activator mimics ischemic preconditioning. Furthermore, treatment with both peptides confers additive cardioprotective effects. Therefore, these peptides mediate cardioprotection by regulating ischemia/reperfusion damage at distinct time points.
Aging, Progenitor Cell Exhaustion, and Atherosclerosis
Authors: Rauscher Frederick M. , Goldschmidt-Clermont Pascal J. , Davis Bryce H. , Wang Tao , Gregg David , Ramaswami Priya , Pippen Anne M. , Annex Brian H. , Dong Chunming , Taylor Doris A.
Published: July 2003

Background—

Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries.

Methods and Results—

Here we show that chronic treatment with bone marrow–derived progenitor cells from young nonatherosclerotic ApoE
−/−
mice prevents atherosclerosis progression in ApoE
−/−
recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE
−/−
mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE
−/−
mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury.

Conclusions—

Our data indicate that progressive progenitor cell deficits may contribute to the development of atherosclerosis.
Coronary Restenosis After Sirolimus-Eluting Stent Implantation
Authors: Lemos Pedro A. , Saia Francesco , Ligthart Jurgen M.R. , Arampatzis Chourmouzios A. , Sianos Georgios , Tanabe Kengo , Hoye Angela , Degertekin Muzaffer , Daemen Joost , McFadden Eugene , Hofma Sjoerd , Smits Pieter C. , de Feyter Pim , van der Giessen Willem J. , van Domburg Ron T. , Serruys Patrick W.
Published: July 2003

Background—

We describe the clinical and morphological patterns of restenosis after sirolimus-eluting stent (SES) implantation.

Methods and Results—

From 121 patients with coronary angiography obtained >30 days after SES implantation, restenosis (diameter stenosis >50%) was identified in 19 patients and 20 lesions (located at the proximal 5-mm segment in 30% or within the stent in 70%). Residual dissection after the procedure or balloon trauma outside the stent was identified in 83% of the proximal edge lesions. Lesions within the stent were focal, and stent discontinuity was identified in some lesions evaluated by intravascular ultrasound.

Conclusions—

Sirolimus-eluting stent edge restenosis is frequently associated with local trauma outside the stent. In-stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Local conditions instead of intrinsic drug-resistance to sirolimus are likely to play a major role in post-SES restenosis.
Hydroxymethylglutaryl Coenzyme A Reductase Inhibition Reduces
Chlamydia pneumoniae
-Induced Cell Interaction and Activation
Authors: Dechend Ralf , Gieffers Jens , Dietz Rainer , Joerres Achim , Rupp Jan , Luft Friedrich C. , Maass Matthias
Published: July 2003

Background—

Chlamydia pneumoniae
stimulates chronic inflammation in vascular cells. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may have an ameliorating effect. We investigated possible mechanisms.

Methods and Results—

We infected human macrophages that in coculture spread infection to vascular smooth muscle cells (VSMCs). Cerivastatin (250 nmol/L) reduced VSMC infection by 33%. Western blotting made it apparent that VSMC infection resulted in increased cell membrane-associated RhoA and Rac1, implying increased prenylation of these proteins. This effect was blocked by statin but circumvented by mevalonate. Cytochrome C assays showed that infected VSMCs produced increased reactive oxygen species that was blocked by statin. Infection increased nuclear transcription factor-κB expression in VSMCs that was dose-dependently suppressed by statin. Infected VSMCs produced and released RANTES and MCP-1. Statin dose-dependently blocked this production both at the mRNA and protein levels. Mevalonate and M geranylgeranylpyrophosphate circumvented these effects.

Conclusions—

C pneumoniae
can be transmitted from macrophages to VSMCs. VSMCs showed an activation profile typical of atherosclerosis, namely Rac1 and RhoA prenylation, nuclear transcription factor-κB activation, reactive oxygen species production, and chemokine production. Statin reduces macrophage-mediated
C pneumoniae
-induced signaling and transmission.
Cardiac Resynchronization Therapy Improves Heart Rate Variability in Patients with Symptomatic Heart Failure
Authors: Adamson Philip B. , Kleckner Karen J. , VanHout Warren L. , Srinivasan Sriram , Abraham William T.
Published: July 2003

Background—

Cardiac resynchronization therapy (CRT) using biventricular pacing improves symptoms and functional capacity in patients with moderate to severe heart failure. The present study examined whether an improvement in ventricular performance from resynchronization therapy changes the autonomic control of heart rate.

Methods and Results—

Heart rate variability (HRV) was examined in 50 patients implanted with the InSync biventricular pacing system who were randomized to therapy-on (n=25) or therapy-off (n=25). HRV was computed as the standard deviation of the atrial cycle length sensed from the system over 2 months of continuous monitoring. HRV was compared between CRT-on and CRT-off groups. HRV was higher in patients randomized to CRT-on compared with CRT-off (148±47 ms for CRT-on versus 118±45 ms for CRT-off;
P
=0.02), despite the lack of difference in mean atrial cycle length (844±129 ms for CRT-on versus 851±110 ms for CRT-off;
P
=0.82). Changes in plasma catecholamines were not different between the CRT-on and CRT-off groups from baseline to the 3-month follow-up.

Conclusions—

Improvement in ventricular performance from CRT shifts cardiac autonomic balance toward a more favorable profile that is less dependent on sympathetic activation.
Acute Release of Plasminogen Activator Inhibitor-1 in ST-Segment Elevation Myocardial Infarction Predicts Mortality
Authors: Collet J.P. , Montalescot G. , Vicaut E. , Ankri A. , Walylo F. , Lesty C. , Choussat R. , Beygui F. , Borentain M. , Vignolles N. , Thomas D.
Published: July 2003

Background—

A few studies have suggested that von Willebrand factor (vWF) or plasminogen activator inhibitor-1 (PAI-1) can be associated with outcomes of acute coronary syndromes. The present study was designed to assess the acute release of these markers in ST-segment elevation myocardial infarction (STEMI) and their relations to death.

Methods and Results—

In 153 consecutive patients with STEMI, vWF and PAI-1 antigens were measured on admission (H0) and 24 hours later (H24). At 30 days, the death rate was 7.2%. Heart failure (Killip stage ≥3) on admission was present in 13.7% of patients. The acute release of PAI-1 (H24−H0, in ng/mL) and of vWF (H24−H0, in %) was dramatically higher in patients who died than in those who survived (46.9±26.3 versus −0.6±2.8 ng/mL,
P
=0.0001 and 65.8±20.0% versus 10.0±5.1%,
P
=0.004 for PAI-1 and vWF, respectively) and in patients developing heart failure compared with those without (24.8±10.1 versus −1.1±3.3 ng/mL,
P
=0.004 and 47.3±11.0% versus 8.1±5.6%,
P
=0.005 for PAI-1 and vWF, respectively). The release of PAI-1 correlated weakly with the left ventricular ejection fraction (
R
=−0.195,
P
=0.01) and the peak of troponin (
R
=0.149,
P
=0.045). Postangioplasty TIMI-3 flow and the acute release of PAI-1 were the only 2 independent predictors of death at 30 days.

Conclusions—

The acute release of vWF and PAI-1 over the first 24 hours of STEMI is associated with death and heart failure. The acute rise of PAI-1 is also a strong independent predictor of death at 30 days.
Tissue Doppler Imaging Predicts the Development of Hypertrophic Cardiomyopathy in Subjects With Subclinical Disease
Authors: Nagueh Sherif F. , McFalls Judy , Meyer Denise , Hill Rita , Zoghbi William A. , Tam James W. , Quiñones Miguel A. , Roberts Robert , Marian A.J.
Published: July 2003

Background—

Systolic (Sa) and diastolic (Ea) myocardial velocities measured by tissue Doppler (TD) imaging (TDI) recently were shown to be decreased in subjects who have mutations causing hypertrophic cardiomyopathy (HCM) but who do not have left ventricular (LV) hypertrophy. By studying these subjects at a later date, we sought to determine whether TDI predicts the subsequent evolution of the HCM phenotype.

Methods and Results—

Serial 2D and Doppler echocardiography were performed in 12 subjects (age range, 17 to 51 years) with HCM-causing mutations on 2 occasions: before development of hypertrophy and 2 years later. Twelve age- and gender-matched family members without mutations were included as control subjects. In those with mutations, mean septal thickness and LV mass were 1.07±0.14 cm and 103.0±11 g at baseline, respectively, and increased to 1.30±0.36 cm and 193.0±78 g at follow-up (
P
<0.01), with 6 subjects satisfying HCM diagnostic criteria. Sa and Ea velocities in those with mutations were lower compared with control subjects at baseline and follow-up (lateral Sa, 15±1.2 versus 8.2±2.1 cm/s; lateral Ea, 16.5±2.8 versus 8.1±2.3 cm/s;
P
<0.01). At 2 years, left atrial volume and pulmonary venous flow indices of LV filling pressures increased, whereas TD early and late diastolic velocities decreased (all
P
<0.05) in those with the mutations. Control subjects had no significant interval changes of the above parameters.

Conclusions—

Subsequent development of HCM in subjects with initially reduced TD velocities establishes TDI as a reliable method for early identification of HCM mutation carriers.
Intracellular Renin and the Nature of Intracrine Enzymes
Authors: Re Richard N.
Published: July 2003

Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term
intracrine
for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. The relation of prorenin/renin to other intracrine enzymes, and to intracrines in general, is discussed.
Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature
Authors: Schmidt Bernhard M.W. , Oehmer Sebastian , Delles Christian , Bratke Renate , Schneider Markus P. , Klingbeil Arnfried , Fleischmann Erwin H. , Schmieder Roland E.
Published: July 2003

The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest. Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine,
N
G
-monomethyl-
l
-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow (
P
<0.001, ANOVA). The maximum effect was an increase in forearm blood flow with aldosterone of 7.9±2.6% compared with 0.1±1.9% with placebo treatment after 8 minutes. With aldosterone, L-NMMA induced a greater vasoconstriction (
P
<0.05, ANOVA), sodium nitroprusside induced an attenuated vasoconstriction (
P
<0.01, ANOVA), and phenylephrine induced an exaggerated vasoconstriction (
P
<0.01, ANOVA) within minutes as compared with placebo. These data suggest that aldosterone acts through rapid nongenomic effects at the endothelium by increasing NO release and at the vascular smooth muscle cells by promoting vasoconstriction. This is consistent with in vitro data showing an increase in intracellular calcium in both cell types. Disturbances of these aldosterone effects on both levels might be important in promoting hypertension.
Late-Onset Apparent Mineralocorticoid Excess Caused by Novel Compound Heterozygous Mutations in the HSD11B2 Gene
Authors: Lavery Gareth G. , Ronconi Vanessa , Draper Nicole , Rabbitt Elizabeth H. , Lyons Val , Chapman Karen E. , Walker Elizabeth A. , McTernan Claire L. , Giacchetti Gilberta , Mantero Franco , Seckl Jonathan R. , Edwards Christopher R.W. , Connell John M.C. , Hewison Martin , Stewart Paul M.
Published: July 2003

Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2, 11β-HSD2 (
HSD11B2
), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11β-HSD2–mediated cortisol to cortisone inactivation. In this study, we describe mutations in the
HSD11B2
gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the
HSD11B2
gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from “essential” hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the
HSD11B2
locus can have on blood pressure in later life.
Association of Hypoadiponectinemia With Impaired Vasoreactivity
Authors: Ouchi Noriyuki , Ohishi Mitsuru , Kihara Shinji , Funahashi Tohru , Nakamura Tadashi , Nagaretani Hiroyuki , Kumada Masahiro , Ohashi Koji , Okamoto Yoshihisa , Nishizawa Hitoshi , Kishida Ken , Maeda Norikazu , Nagasawa Azumi , Kobayashi Hideki , Hiraoka Hisatoyo , Komai Norio , Kaibe Masaharu , Rakugi Hiromi , Ogihara Toshio , Matsuzawa Yuji
Published: July 2003

Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total (
r
=0.257,
P
<0.001) and no-medication (
r
=0.296,
P
=0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout (KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.
Peroxisome Proliferator-Activated Receptor-α and Receptor-γ Activators Prevent Cardiac Fibrosis in Mineralocorticoid-Dependent Hypertension
Authors: Iglarz Marc , Touyz Rhian M. , Viel Emilie C. , Paradis Pierre , Amiri Farhad , Diep Quy N. , Schiffrin Ernesto L.
Published: July 2003

Peroxisome proliferator-activated receptor (PPAR) activation may prevent cardiac hypertrophy and inhibit production of endothelin-1 (ET-1), a hypertrophic agent. The aim of this in vivo study was to investigate the effects of PPAR activators on cardiac remodeling in DOCA-salt rats, a model overexpressing ET-1. Unilaterally nephrectomized 16-week-old Sprague-Dawley rats (Uni-Nx) were randomly divided into 4 groups: control rats, DOCA-salt, DOCA-salt+rosiglitazone (PPAR-γ activator, 5 mg/kg per day), and DOCA-salt+fenofibrate (PPAR-α activator, 100 mg/kg per day). After 3 weeks of treatment, mean arterial blood pressure was significantly increased in DOCA-salt by 36 mm Hg. Mean arterial blood pressure was normalized by coadministration of rosiglitazone but not by fenofibrate. Both PPAR activators prevented cardiac fibrosis and abrogated the increase in prepro–ET-1 mRNA content in the left ventricle of DOCA-salt rats. Coadministration of rosiglitazone or fenofibrate failed to prevent thickening of left ventricle (LV) walls as measured by echocardiography and the increase in atrial natriuretic peptide mRNA levels. However, rosiglitazone and fenofibrate prevented the decrease in LV internal diameter and thus concentric remodeling of the LV found in DOCA-salt rats. Taken together, these data indicate a modulatory role of PPAR activators on cardiac remodeling in mineralocorticoid-induced hypertension, in part associated with decreased ET-1 production.
Hypertensive Target-Organ Damage in the Very Elderly
Authors: O’Sullivan Cianán , Duggan Joe , Lyons Simon , Thornton John , Lee Michael , O’Brien Eoin
Published: July 2003

In people aged >80 years, the so-called very elderly, there is uncertainty about the relation between hypertension and cardiovascular morbidity. The aims of this study were to investigate whether hypertension in people aged >80 years is associated with target-organ damage, over and above the effects of age, and to determine whether ambulatory blood pressure monitoring (ABPM) could improve on conventional blood pressure monitoring (CBPM) in predicting target-organ damage. Investigations included echocardiographic measurement of left ventricular mass index (LVMI), brain magnetic resonance imaging assessment of periventricular hyperintensity (PVH), urinary albumin-creatinine ratio (ACR), aortic pulse wave velocity (PWV), and 24-hour ABPM. Forty-three subjects, at a mean age 84.3 years, were studied, 22 normotensive (NT) and 21 hypertensive (HT). CBP was 184/89 and 145/76 mm Hg in the HT and NT groups, respectively. In men, LVMI was significantly greater in HT subjects, 157±37 vs 123±15 g/m
2
in NT subjects (
P
<0.05). In women, LVMI was similar in both groups. Urinary ACR was greater in HT than in NT subjects (log ACR, 1.21±0.50 vs 0.95±0.23;
P
<0.05). Cerebral PVH grade was higher in the HT subjects (2.6±0.8 vs 2.2±0.9), although this difference was not significant. Aortic PWV did not differ between the 2 groups. ABPM was positively associated with urinary ACR and cerebral PVH, independent of its correlation with CBPM. In advanced old age, HT is associated with evidence of target-organ damage. ABPM can improve on CBPM in predicting very elderly subjects with HT target-organ damage.
Clinical Utility of Aortic Pulses and Pressures Calculated From Applanated Radial-Artery Pulses
Authors: Smulyan Harold , Siddiqui Danish S. , Carlson Raymond J. , London Gerard M. , Safar Michel E.
Published: July 2003

Brachial artery cuff blood pressures are but approximations of central aortic pressures. The actual pressures against which the left ventricle must pump would be useful clinical information if obtained noninvasively. Our aim was to determine the clinical utility of aortic pulses and pressures calculated from noninvasively obtained radial-artery pulses. Radial-arterial pulses were recorded by applanation and calibrated with arm/cuff oscillometric pressures. Aortic pulses and pressures were calculated from the radial pulses by Fourier analysis and transfer functions. These calculated aortic pulses were compared with directly recorded aortic pulses by a transducer-tip catheter in a series of 50 patients undergoing cardiac catheterization. The correlation coefficient (
r
) of the measured versus the calculated aortic systolic blood pressure was +0.89, but the scatter was large (standard deviation of the differences=±11.3 mm Hg). The pulse pressure correlations were less good (
r
=+0.79) and also had a large scatter (±13.6 mm Hg). The average calculated pulse pressure was 11.5 mm Hg lower than the measured value because the cuff diastolic blood pressures, used to calibrate the radial pulses, were systematically higher than those in the aorta (8.9 mm Hg). Multivariable analysis incorporating height, age, heart rate, and ejection fraction as additional, independent variables eliminated mean differences between the new “predicted” and measured pressures, significantly improved correlation coefficients, and reduced the scatter. However, the improvements were small. The inaccuracy of the oscillometric cuff method for measuring arm blood pressure appears to be the limiting factor in the prediction of clinically useful, noninvasive aortic pressures.
Activation of gp130 Transduces Hypertrophic Signal Through Interaction of Scaffolding/Docking Protein Gab1 With Tyrosine Phosphatase SHP2 in Cardiomyocytes
Authors: Nakaoka Yoshikazu , Nishida Keigo , Fujio Yasushi , Izumi Masahiro , Terai Kazuo , Oshima Yuichi , Sugiyama Shoko , Matsuda Satoshi , Koyasu Shigeo , Yamauchi-Takihara Keiko , Hirano Toshio , Kawase Ichiro , Hirota Hisao
Published: July 2003

Grb2-associated binder-1 (Gab1) is a scaffolding/docking protein and contains a Pleckstrin homology domain and potential binding sites for Src homology (SH) 2 and SH3 domains. Gab1 is tyrosine phosphorylated and associates with protein tyrosine phosphatase SHP2 and p85 phosphatidylinositol 3-kinase on stimulation with various cytokines and growth factors, including interleukin-6. We previously demonstrated that interleukin-6–related cytokine, leukemia inhibitory factor (LIF), induced cardiac hypertrophy through gp130. In this study, we report the role of Gab1 in gp130-mediated cardiac hypertrophy. Stimulation with LIF induced tyrosine phosphorylation of Gab1, and phosphorylated Gab1 interacted with SHP2 and p85 in cultured cardiomyocytes. We constructed three kinds of adenovirus vectors, those carrying wild-type Gab1 (AdGab1
WT
), mutated Gab1 lacking SHP2 binding site (AdGab1
F627/659
), and β-galactosidase (Adβ-gal). Compared with cardiomyocytes infected with Adβ-gal, longitudinal elongation of cardiomyocytes induced by LIF was enhanced in cardiomyocytes infected with AdGab1
WT
but inhibited in cardiomyocytes infected with AdGab1
F627/659
. Upregulation of BNP mRNA expression by LIF was evoked in cardiomyocytes infected with Adβ-gal and AdGab1
WT
but not in cardiomyocytes infected with AdGab1
F627/659
. In contrast, Gab1 repressed skeletal α-actin mRNA expression through interaction with SHP2. Furthermore, activation of extracellular signal–regulated kinase 5 (ERK5) was enhanced in cardiomyocytes infected with AdGab1
WT
compared with cardiomyocytes infected with Adβ-gal but repressed in cardiomyocytes infected with AdGab1
F627/659
. Coinfection of AdGab1
WT
with adenovirus vector carrying dominant-negative ERK5 abrogated longitudinal elongation of cardiomyocytes induced by LIF. Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5.