bluuebunny/crossref_metadata_2025 huggingface dataset:
Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina
Authors: Soejima Hirofumi , Irie Atsushi , Miyamoto Shinzo , Kajiwara Ichiro , Kojima Sunao , Hokamaki Jun , Sakamoto Tomohiro , Tanaka Tomoko , Yoshimura Michihiro , Nishimura Yasuharu , Ogawa Hisao
Published: May 2003

Background—

Coronary artery spasm plays an important role in the pathogenesis of ischemic heart diseases such as unstable angina (UA) and acute myocardial infarction. Nitric oxide (NO) plays an important role in coronary artery spasm. We previously reported a deficiency in NO activity in the spasm arteries of patients with coronary spastic angina (CSA). Others have reported that NO influences the immune response. Therefore, we investigated the balance between T-helper type 1 (Th1) and 2 (Th2) responses in patients with CSA by evaluating the frequencies of interferon (IFN)-γ–producing T cells and interleukin (IL)-4–producing T cells in the peripheral blood of such patients.

Methods and Results—

Peripheral blood mononuclear cells were collected from 50 consecutive patients with CSA, 23 consecutive patients with UA, 36 patients with stable angina (SA), and 21 patients with chest pain syndrome (CPS). Cytokine-producing CD4+ T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA and CSA were associated with a significant increase in the frequency of CD4+ T cells that produced IFN-γ, whereas these conditions caused no significant difference in the frequency of CD4+ T cells that produced IL-4. Culturing with an NO donor compound for 24 hours before stimulation inhibited the increase in the frequency of CD4+ T cells that produced IFN-γ.

Conclusions—

We demonstrated that there was a preference toward the Th1-type response in patients with CSA and that T cells showed a reduced Th1-type response after being treated with NO.
Left Atrial Volume
Authors: Møller Jacob E. , Hillis Graham S. , Oh Jae K. , Seward James B. , Reeder Guy S. , Wright R. Scott , Park Seung W. , Bailey Kent R. , Pellikka Patricia A.
Published: May 2003

Background—

After acute myocardial infarction (AMI), diastolic function assessed by Doppler echocardiography provides important prognostic information that is incremental to systolic function. However, Doppler variables are affected by multiple factors and may change rapidly. In contrast, left atrial (LA) volume is less influenced by acute changes and reflects subacute or chronic diastolic function. This may be of importance when one assesses risk in patients with AMI.

Methods and Results—

Three hundred fourteen patients with AMI who had a transthoracic echocardiogram with assessment of left ventricular (LV) systolic and diastolic function and measurement of LA volume during admission were identified. The LA volume was corrected for body surface area, and the population was divided according to LA volume index of 32 mL/m
2
(2 SDs above normal). LA volume index was >32 mL/m
2
in 142 (45%). The primary study end point was all-cause mortality. During follow-up of 15 (range 0 to 33) months, 46 patients (15%) died. LA volume index was a powerful predictor of mortality and remained an independent predictor (hazard ratio 1.05 per 1-mL/m
2
change, 95% CI 1.03 to 1.06,
P
<0.001) after adjustment for clinical factors, LV systolic function, and Doppler-derived parameters of diastolic function.

Conclusions—

Increased LA volume index is a powerful predictor of mortality after AMI and provides prognostic information incremental to clinical data and conventional measures of LV systolic and diastolic function.
Defibrillator Versus β-Blockers for Unexplained Death in Thailand (DEBUT)
Authors: Nademanee Koonlawee , Veerakul Gumpanart , Mower Morton , Likittanasombat Khanchit , Krittayapong Rungroj , Bhuripanyo Kiertijai , Sitthisook Surapun , Chaothawee Lertlak , Lai Mei Ying , Azen Stanley P.
Published: May 2003

Background—

Sudden Unexplained Death Syndrome (SUDS) is the leading cause of death in young, healthy, Southeast Asian men. The role of an implantable cardioverter defibrillator (ICD) for mortality reduction in these patients remains unclear.

Methods and Results—

The Defibrillator Versus β-Blockers for Unexplained Death in Thailand (DEBUT) study is a randomized, clinical trial conducted in 2 phases (pilot study followed by the main trial) to compare the annual all-cause mortality rates among SUDS patients treated with β-blockers versus that among those treated with an ICD. A total of 86 patients who were SUDS survivors and probable SUDS survivors were randomized to receive an ICD or propranolol (20 patients were in the pilot study and 66 were in the main trial). The primary end point was death from all causes. The secondary end point was recurrent ventricular tachycardia/ventricular fibrillation (VF) or cardiac arrest. During the 3-year follow-up period of the main trial, there were 4 deaths; all occurred in the β-blocker group (
P
=0.02). Seven subjects in the ICD arm had recurrent VF, and all were effectively treated by the ICD. On the basis of the main trial results, the Data Safety Monitoring Board stopped the study. In total (both from the Pilot study and the main trial), there were 7 deaths (18%) in the β-blocker group and no deaths in the ICD group, but there were a total of 12 ICD patients receiving ICD discharges due to recurrent VF.

Conclusions—

ICD treatment provides full protection from death related to primary VF in a SUDS population and is superior to β-blockade treatment.
Serum Total Cholesterol Concentrations and Awareness, Treatment, and Control of Hypercholesterolemia Among US Adults
Authors: Ford Earl S. , Mokdad Ali H. , Giles Wayne H. , Mensah George A.
Published: May 2003

Background—

Serum cholesterol concentrations have decreased in the US population. Whether the decline continued during the 1990s is unknown.

Methods and Results—

We used data from 4148 men and women aged ≥20 years who had a total cholesterol determination or reported using cholesterol-lowering medications and who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000 (this is a cross-sectional health examination survey of the US population), and we compared the results with data from 15 719 participants in NHANES III (1988 to 1994). For all adults, the age-adjusted mean total cholesterol concentration decreased from 5.31 mmol/L (205 mg/dL) in NHANES III to 5.27 mmol/L (203 mg/dL) in NHANES 1999 to 2000 (
P
=0.159). The age-adjusted mean total cholesterol concentration decreased by 0.02 mmol/L (0.7 mg/dL) among men (
P
=0.605) and 0.06 mmol/L (2.3 mg/dL) among women (
P
=0.130). Significant decreases were observed among men aged ≥75 years, black men, and Mexican-American women. Among participants who had a total cholesterol concentration ≥5.2 mmol/L (200 mg/dL) or who reported using cholesterol-lowering medications, 69.5% reported having had their cholesterol checked, 35.0% were aware that they had hypercholesterolemia, 12.0% were on treatment, and 5.4% had a total cholesterol concentration <5.2 mmol/L (200 mg/dL) after age adjustment.

Conclusions—

The mean serum total cholesterol concentration of the adult US population in 1999 to 2000 has changed little since 1988 to 1994. The low percentage of adults with controlled blood cholesterol concentration suggests the need for a renewed commitment to the prevention, treatment, and control of hypercholesterolemia.
Is There Functional Collateral Flow During Vascular Occlusion in Angiographically Normal Coronary Arteries?
Authors: Wustmann Kerstin , Zbinden Stephan , Windecker Stephan , Meier Bernhard , Seiler Christian
Published: May 2003

Background—

Thus far, it is unknown whether there is functional collateral flow through preexisting anastomoses in patients with angiographically normal coronary arteries. Such preformed coronary collateral vessels could form the basis for subsequently developing protective natural bypasses in the presence of coronary artery disease.

Methods and Results—

Among 100 patients, the collateral flow index (CFI) was measured in coronary arteries without stenotic lesions. The CFI was determined by simultaneous measurement of mean aortic pressure, central venous pressure, and coronary wedge pressure via a sensor-tipped guidewire at the end of a 1-minute balloon occlusion. Patients were divided in 2 groups according to complete angiographic absence (51 patients) or partial presence (49 patients) of stenotic lesions in coronary arteries other than that undergoing collateral measurement. CFI in all patients (61±10 years; men/women, 69/31) amounted to 0.18±0.08 (range, 0.04 to 0.36). It showed a normal Gaussian frequency distribution; 22 individuals had a CFI ≥0.25, a value that was empirically found to represent well-developed collaterals protective against myocardial ischemia during coronary occlusion. Accordingly, 17 patients did not reveal signs of myocardial ischemia during coronary balloon occlusion, as assessed from an intracoronary ECG, and 26 patients did not experience angina pectoris during occlusion.

Conclusion—

In humans with angiographically normal coronary arteries, there are functional collateral vessels to the extent that one fifth to one quarter of them do not show signs of myocardial ischemia during brief vascular occlusions.
Improved Exercise Tolerance and Quality of Life With Cardiac Rehabilitation of Older Patients After Myocardial Infarction
Authors: Marchionni Niccolò , Fattirolli Francesco , Fumagalli Stefano , Oldridge Neil , Del Lungo Francesco , Morosi Linda , Burgisser Costanza , Masotti Giulio
Published: May 2003

Background—

Whether cardiac rehabilitation (CR) is effective in patients older than 75 years, who have been excluded from most trials, remains unclear. We enrolled patients 46 to 86 years old in a randomized trial and assessed the effects of 2 months of post-myocardial infarction (MI) CR on total work capacity (TWC, in kilograms per meter) and health-related quality of life (HRQL).

Methods and Results—

Of 773 screened patients, 270 without cardiac failure, dementia, disability, or contraindications to exercise were randomized to outpatient, hospital-based CR (Hosp-CR), home-based CR (Home-CR), or no CR within 3 predefined age groups (middle-aged, 45 to 65 years; old, 66 to 75 years; and very old, >75 years) of 90 patients each. TWC and HRQL were determined with cycle ergometry and Sickness Impact Profile at baseline, after CR, and 6 and 12 months later. Within each age group, TWC improved with Hosp-CR and Home-CR and was unchanged with no CR. The improvement was similar in middle-aged and old persons but smaller, although still significant, in very old patients. TWC reverted toward baseline by 12 months with Hosp-CR but not with Home-CR. HRQL improved in middle-aged and old CR and control patients but only with CR in very old patients. Complications were similar across treatment and age groups. Costs were lower for Home-CR than for Hosp-CR.

Conclusions—

Post-MI Hosp-CR and Home-CR are similarly effective in the short term and improve TWC and HRQL in each age group. However, with lower costs and more prolonged positive effects, Home-CR may be the treatment of choice in low-risk older patients.
Hypertrophic Cardiomyopathy
Authors: Richard Pascale , Charron Philippe , Carrier Lucie , Ledeuil Céline , Cheav Theary , Pichereau Claire , Benaiche Abdelaziz , Isnard Richard , Dubourg Olivier , Burban Marc , Gueffet Jean-Pierre , Millaire Alain , Desnos Michel , Schwartz Ketty , Hainque Bernard , Komajda Michel
Published: May 2003

Background—

Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice.

Methods and Results—

The entire coding sequences of 9 genes (
MYH7
,
MYBPC3
,
TNNI3
,
TNNT2
,
MYL2
,
MYL3
,
TPM1
,
ACTC
, and
TNNC1
) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (≈63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (
MYBPC3
) and β-myosin heavy chain (
MYH7
) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (
P
=0.036). Moreover, a mutation was found in 15 of 25 index cases with “sporadic” hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients.

Conclusion—

These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing
MYBPC3
and
MYH7
and then focus on
TNNI3
,
TNNT2
, and
MYL2
. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.
Prospective Investigation of Autonomic Nervous System Function and the Development of Type 2 Diabetes
Authors: Carnethon Mercedes R. , Golden Sherita H. , Folsom Aaron R. , Haskell William , Liao Duanping
Published: May 2003

Background—

Autonomic nervous system (ANS) dysfunction has been correlated with fasting insulin and glucose, independent of clinically diagnosed diabetes. We tested whether men and women (aged 45 to 64 years) from the Atherosclerosis Risk In Communities study (n=8185) with ANS dysfunction, estimated by high heart rate (HR) and low HR variability (HRV), were at increased risk for developing type 2 diabetes.

Methods and Results—

Supine HR and HRV indices were measured for 2 minutes at baseline; indices were divided into quartiles for analyses. From 1987 to 1998 (mean follow-up 8.3 years), there were 1063 cases of incident diabetes. The relative risk (RR) of developing diabetes for participants with low-frequency (LF) power (0.04 to 0.15 Hz) HRV in the lowest quartile (<7.7 ms
2
) compared with the highest quartile (≥38.9 ms
2
) was 1.2 (95% CI 1.0–1.4) after adjustment for age, race, sex, study center, education, alcohol drinking, current smoking, prevalent coronary heart disease, physical activity, and body mass index. Participants in the uppermost (>72.7 bpm) versus the lowest (≤60.1 bpm) quartile of HR had a 60% increased risk (95% CI 33%–92%) of developing diabetes. Results were similar when the sample was restricted to participants with normal fasting glucose (glucose <6.1 mmol/L) at baseline (n=7192) or when adjusted for baseline glucose (HR quartile 4 versus quartile 1, RR=1.4, 95% CI 1.2–1.7).

Conclusions—

These findings suggest that ANS dysfunction may be associated with the development of diabetes in healthy adults.
Chronic Iron Administration Increases Vascular Oxidative Stress and Accelerates Arterial Thrombosis
Authors: Day Sharlene M. , Duquaine Damon , Mundada Lakshmi V. , Menon Rekha G. , Khan Bobby V. , Rajagopalan Sanjay , Fay William P.
Published: May 2003

Background—

Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood.

Methods and Results—

We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4±8.5 minutes; n=10) compared with control mice (54.5±35.5 minutes, n=10,
P
=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of
dl
-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability.

Conclusions—

Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.
Prevention of Chronic Deterioration of Heart Allograft by Recombinant Adeno-Associated Virus-Mediated Heme Oxygenase-1 Gene Transfer
Authors: Tsui Tung-Yu , Wu Xiaobing , Lau Chi-Keung , Ho David W.Y. , Xu Tao , Siu Yeung-Tung , Fan Sheung-Tat
Published: May 2003

Background—

Allograft deterioration is the major obstacle to organ transplantation as a long-term treatment of end-stage heart failure. In this study, we transduced the antioxidant gene, heme oxygenase-1 (HO-1), to heart grafts using a recombinant adeno-associated viral vector (rAAV) in a rat heart transplantation model and investigated its potentiality in prevention of chronic graft deterioration.

Methods and Results—

rAAV/HO-1 was administered to heart grafts through the coronary arteries during cold preservation. We investigated the expression patterns and activities of transgene, graft survival, graft histomorphology, and relevance of HO-1 expression on graft survival and chronic graft deterioration by itself. Long-term allograft survival can be achieved by rAAV/HO-1-mediated stable transgene expression. The development of graft arteriosclerosis and interstitial fibrosis was prevented in rAAV/HO-1–transduced allografts on day 100. rAAV/HO-1–mediated long-term graft protection was accompanied by remarkable downregulation of the intragraft mRNA level of macrophage migration inhibitory factor, tumor necrosis factor-α, and transforming growth factor-β
1
. Blockage of HO activities by zinc protoporphyrin IX at different posttransplant phases showed that the stable expression of HO-1 is a prerequisite for both survival of grafts and prevention of graft arteriosclerosis.

Conclusions—

rAAV/HO-1 gene transfer represents a novel therapeutic approach to prevent chronic allograft deterioration in clinical heart transplantation.
Alterations in Atrial Electrophysiology and Tissue Structure in a Canine Model of Chronic Atrial Dilatation Due to Mitral Regurgitation
Authors: Verheule Sander , Wilson Emily , Everett Thomas , Shanbhag Sujata , Golden Catherine , Olgin Jeffrey
Published: May 2003

Background—

Clinically, chronic atrial dilatation is associated with an increased incidence of atrial fibrillation (AF), but the underlying mechanism is not clear. We have investigated atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation (MR).

Methods and Results—

Thirteen control and 19 MR dogs (1 month after partial mitral valve avulsion) were studied. Dogs in the MR group were monitored using echocardiography and Holter recording. In open-chest follow-up experiments, electrode arrays were placed on the atria to investigate conduction patterns, effective refractory periods, and inducibility of AF. Alterations in tissue structure and ultrastructure were assessed in atrial tissue samples. At follow-up, left atrial length in MR dogs was 4.09±0.45 cm, compared with 3.25±0.28 at baseline (
P
<0.01), corresponding to a volume of 205±61% of baseline. At follow-up, no differences in atrial conduction pattern and conduction velocities were noted between control and MR dogs. Effective refractory periods were increased homogeneously throughout the left and right atrium. Sustained AF (>1 hour) was inducible in 10 of 19 MR dogs and none of 13 control dogs (
P
<0.01). In the dilated MR left atrium, areas of increased interstitial fibrosis and chronic inflammation were accompanied by increased glycogen ultrastructurally.

Conclusions—

Chronic atrial dilatation in the absence of overt heart failure leads to an increased vulnerability to AF that is not based on a decrease in wavelength.
Immediate Administration of Mineralocorticoid Receptor Antagonist Spironolactone Prevents Post-Infarct Left Ventricular Remodeling Associated With Suppression of a Marker of Myocardial Collagen Synthesis in Patients With First Anterior Acute Myocardial Infarction
Authors: Hayashi Masaru , Tsutamoto Takayoshi , Wada Atsuyuki , Tsutsui Takashi , Ishii Chitose , Ohno Keijin , Fujii Masanori , Taniguchi Atsushi , Hamatani Tomokazu , Nozato Yoshitaka , Kataoka Ken , Morigami Naoki , Ohnishi Masato , Kinoshita Masahiko , Horie Minoru
Published: May 2003

Background—

Aldosterone (ALD) has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that ALD was extracted through the infarct heart and extracting ALD-stimulated post-infarct left ventricular (LV) remodeling.

Methods and Results—

To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. However, LV ejection fraction was significantly improved in the MRA group compared with that in the non-MRA group (46.0±0.6% to 53.2±0.8% versus 46.5±0.8% to 51.0±0.8%,
P
interaction
=0.012). LV end-diastolic volume index was significantly suppressed in the MRA group compared with that in non-MRA group (86.5±1.0 to 90.6±2.4 versus 87.5±1.3 to 106.8±3.5 mL/m
2
,
P
interaction
=0.002). Transcardiac extraction of ALD through the heart was significantly suppressed in the MRA group (
P
interaction
=0.001), and plasma procollagen type III aminoterminal peptide level, a biochemical marker of fibrosis, was significant lower in the MRA group compared with the non-MRA group (
P
interaction
=0.002).

Conclusions—

These findings indicate that MRA combined with ACE inhibitor can prevent post-infarct LV remodeling better than ACE inhibitor alone in association with the suppression of a marker of collagen synthesis.
Non-Equilibrium Gating in Cardiac Na
+
Channels
Authors: Clancy Colleen E. , Tateyama Michihiro , Liu Huajun , Wehrens Xander H.T. , Kass Robert S.
Published: May 2003

Background—

Many long-QT syndrome (LQTS) mutations in the cardiac Na
+
channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (I
sus
) during depolarization. However, some Na
+
channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase I
sus
(<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype.

Methods and Results—

We developed new experimental approaches based on theoretical analyses to investigate Na
+
channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation.

Conclusions—

Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.
Left Ventricular Remodeling and Ventricular Arrhythmias After Myocardial Infarction
Authors: St John Sutton Martin , Lee Douglas , Rouleau Jean Lucien , Goldman Steven , Plappert Ted , Braunwald Eugene , Pfeffer Marc A.
Published: May 2003

Background—

The relation between left ventricular (LV) remodeling and ventricular arrhythmias after myocardial infarction is poorly documented. We investigated the relations between LV size, hypertrophy, and function and ventricular arrhythmias in 263 patients from the Survival and Ventricular Enlargement (SAVE) study, using quantitative 2D echocardiography and ambulatory ECG monitoring after myocardial infarction.

Methods and Results—

Transthoracic 2D echocardiograms and arrhythmia monitoring were performed at baseline (mean, 11 days) and 1 and 2 years after infarction. LV size, short-axis muscle (mass) area (LVMA), and function were quantified from 2D echocardiograms. The prevalence of ventricular tachycardia (VT) and frequent ventricular ectopy (premature ventricular contractions [PVCs] >10/h) was assessed from ambulatory ECG. VT and PVCs >10/h occurred in 20% and 29% of patients at baseline, in 22% and 35% at 1 year and 23% and 39% at 2 years, respectively. VT and PVCs >10/h at baseline and 1 and 2 years were significantly related to LV size, LVMA, and function. Furthermore, changes in LV size and function from baseline to 2 years predicted both VT and PVCs >10/h. The study was underpowered to detect treatment effect of ACE inhibitors and β-adrenergic receptor blockers but did not alter the relations between ventricular arrhythmias, LV size, and function.

Conclusions—

Quantitative echocardiographic assessment of LV size, LVMA, and function and changes in these measurements over time predict ventricular arrhythmias after infarction. Altered LV architecture and function during postinfarction LV remodeling provide an important substrate for triggering high-grade ventricular arrhythmias.
Human Aortic Valve Calcification Is Associated With an Osteoblast Phenotype
Authors: Rajamannan Nalini M. , Subramaniam Malayannan , Rickard David , Stock Stuart R. , Donovan Janis , Springett Margaret , Orszulak Thomas , Fullerton David A. , Tajik A.J. , Bonow Robert O. , Spelsberg Thomas
Published: May 2003

Background—

Calcific aortic stenosis is the third most common cardiovascular disease in the United States. We hypothesized that the mechanism for aortic valve calcification is similar to skeletal bone formation and that this process is mediated by an osteoblast-like phenotype.

Methods and Results—

To test this hypothesis, we examined calcified human aortic valves replaced at surgery (n=22) and normal human valves (n=20) removed at time of cardiac transplantation. Contact microradiography and micro-computerized tomography were used to assess the 2-dimensional and 3-dimensional extent of mineralization. Mineralization borders were identified with von Kossa and Goldner’s stains. Electron microscopy and energy-dispersive spectroscopy were performed for identification of bone ultrastructure and CaPO
4
composition. To analyze for the osteoblast and bone markers, reverse transcriptase–polymerase chain reaction was performed on calcified versus normal human valves for osteopontin, bone sialoprotein, osteocalcin, alkaline phosphatase, and the osteoblast-specific transcription factor Cbfa1. Microradiography and micro-computerized tomography confirmed the presence of calcification in the valve. Special stains for hydroxyapatite and CaPO
4
were positive in calcification margins. Electron microscopy identified mineralization, whereas energy-dispersive spectroscopy confirmed the presence of elemental CaPO
4
. Reverse transcriptase–polymerase chain reaction revealed increased mRNA levels of osteopontin, bone sialoprotein, osteocalcin, and Cbfa1 in the calcified valves. There was no change in alkaline phosphatase mRNA level but an increase in the protein expression in the diseased valves.

Conclusions—

These findings support the concept that aortic valve calcification is not a random degenerative process but an active regulated process associated with an osteoblast-like phenotype.
Preliminary Observations Regarding Angiographic Pattern of Restenosis After Rapamycin-Eluting Stent Implantation
Authors: Colombo Antonio , Orlic Dejan , Stankovic Goran , Corvaja Nicola , Spanos Vassilis , Montorfano Matteo , Liistro Francesco , Carlino Mauro , Airoldi Flavio , Chieffo Alaide , Di Mario Carlo
Published: May 2003

Background—

Restenosis after implantation of drug-eluting stents (DES) is a rare phenomenon, occurring more frequently peri-stent.

Methods and Results—

We evaluated the pattern of restenosis occurring after implantation of DES in unselected lesions. From April 15 to December 6, 2002, we treated 368 patients with 735 lesions by using 841 rapamycin-eluting stents (Cypher, Cordis, a Johnson & Johnson Company). Mean baseline lesion length was 17.48±12.19 mm, and mean stent length was 27.59±14.02 mm. Follow-up ischemia-driven angiography was performed in 24 patients. Eleven patients had angiographic restenosis (≥50% diameter stenosis) in 14 stented segments (stent and 5 mm proximal and distal to the stent). The pattern of restenosis in all 14 stented segments was focal, and in 6 of them it was multifocal, occurring inside the stents. Mean length of restenotic lesions was 5.62±1.90 mm, with a range from 2.54 to 8.44 mm. One multifocal restenosis involved also the distal stent margin. Intravascular ultrasound evaluation at follow-up, performed in 2 patients, showed significant lumen obstruction attributable to in-stent hyperplasia in both cases. Individual cases can be viewed in the Data Supplement.

Conclusions—

The pattern of restenotic lesions after rapamycin-eluting stent implantation was focal and mostly inside the stent.
Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na
+
/H
+
Exchanger Inhibition
Authors: Ennis Irene L. , Escudero Eduardo M. , Console Gloria M. , Camihort Gisela , Dumm César Gomez , Seidler Randolph W. , Camilión de Hurtado María C. , Cingolani Horacio E.
Published: May 2003

Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either α- or β-adrenergic stimulation. Because an association between the Na
+
/H
+
exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na
+
/H
+
exchanger activity (3 mg · kg
−1
· d
−1
BIIB723) was given to male Wistar rats for 30 days. Sex- and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenol+BIIB723-treated group. Heart weight–to–body weight ratio at necropsy was 2.44±0.11 in controls and increased to 3.35±0.10 (
P
<0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82±0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na
+
/H
+
exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45±0.11 vs 0.91±0.05 arbitrary units,
P
<0.05). This effect was significantly reduced by BIIB723 (1.17±0.02,
P
<0.05). In conclusion, our results show that Na
+
/H
+
exchanger inhibition prevented the development of isoproterenol-induced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy.
Baroreflex Buffering in Sedentary and Endurance Exercise–Trained Healthy Men
Authors: Christou Demetra D. , Jones Pamela Parker , Seals Douglas R.
Published: May 2003

Baroreflex buffering plays an important role in arterial blood pressure control. Previous reports suggest that baroreflex sensitivity may be altered in endurance exercise–trained compared with untrained subjects. It is unknown, however, if in vivo baroreflex buffering is altered in the endurance exercise–trained state in humans. Baroreflex buffering was determined in 36 healthy normotensive men (18 endurance exercise–trained, 41±5 [SEM] years; 18 untrained, 41±4 years) by measuring the potentiation of the systolic blood pressure responses to a phenylephrine bolus and to incremental phenylephrine infusion during compared with before ganglionic blockade with trimethaphan. The exercise-trained men had a lower resting heart rate and higher maximal oxygen consumption and heart rate variability than the sedentary control subjects (all
P
=0.01). Mean levels and variability of blood pressure, cardiovagal baroreflex sensitivity (change in heart rate/change in systolic blood pressure), and basal muscle sympathetic nerve activity were not different in the two groups. The systolic blood pressure responses to phenylephrine were not different in the endurance-trained and untrained men before or during ganglionic blockade (
P
>0.6). Measures of baroreflex buffering with the use of a phenylephrine bolus (3.9±0.8 versus 4.0±0.7, trained versus untrained,
P
=0.85) and incremental infusion (2.8±0.4 versus 2.5±0.6,
P
=0.67) were similar in the two groups. Baroreflex buffering does not differ in endurance exercise–trained compared with untrained healthy men. These results support the concept that habitual vigorous endurance exercise does not modulate in vivo baroreflex buffering in healthy humans.
Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients
Authors: Hermida Ramón C. , Ayala Diana E. , Calvo Carlos , López José E. , Fernández José R. , Mojón Artemio , Domínguez María J. , Covelo Manuel
Published: May 2003

Previous studies on the potential influence of aspirin on blood pressure have not taken into consideration the chronopharmacological effects of nonsteroidal anti-inflammatory drugs. This pilot study investigates the effects of aspirin on blood pressure in untreated hypertensive patients who received aspirin at different times of the day according to their rest-activity cycle. We studied 100 untreated patients with mild hypertension (34 men and 66 women), 42.5±11.6 (mean±SD) years of age, randomly divided into 3 groups: nonpharmacological hygienic-dietary recommendations; the same recommendations and aspirin (100 mg/d) on awakening; or the same recommendations and aspirin before bedtime. Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of intervention. The circadian pattern of blood pressure in each group was established by population multiple-component analysis. After 3 months of nonpharmacological intervention, there was a small, nonsignificant reduction of blood pressure (<1.1 mm Hg;
P
>0.341). There was no change in blood pressure when aspirin was given on awakening (
P
=0.229). A highly significant blood pressure reduction was, however, observed in the patients who received aspirin before bedtime (decrease of 6 and 4 mm Hg in systolic and diastolic blood pressure, respectively;
P
<0.001). Results indicate a statistically significant administration time–dependent effect of low-dose aspirin on blood pressure in untreated patients with mild hypertension. The influence of aspirin on blood pressure demonstrated in this study indicates the need to quantify and control for aspirin effects in patients using this drug in combination with antihypertensive medication.
Subcellular Redistribution of Focal Adhesion Kinase and Its Related Nonkinase in Hypertrophic Myocardium
Authors: Yi Xian Ping , Wang Xuejun , Gerdes A. Martin , Li Faqian
Published: May 2003

Focal adhesion kinase (FAK) and focal adhesion kinase-related nonkinase (FRNK) are likely involved in mechanical signaling during hypertension. We investigated expression, subcellular distribution, and phosphorylation of FAK, as well as FRNK in left ventricles of spontaneously hypertensive heart failure rats. Compared with normotensive controls, FAK and FRNK increased in left ventricles of hypertensive rats. Increased FAK and FRNK were mainly present in membrane cytoskeleton and nuclear fractions. Confocal microscopy demonstrated that FAK and FRNK translocated to nuclei and intercalated disks in cardiac myocytes from hypertensive rats. Serine and tyrosine phosphorylation of FAK increased dramatically in hypertensive rats. FAK phosphorylated at tyrosine 397 was present in membranes and intercalated disks, but not in nuclei. FAK was also phosphorylated on serine 722 but not on serine 910. In contrast, FRNK was phosphorylated on serine 217, the equivalent site of FAK serine 910, but not serine on 30, the homologous site of FAK serine 722. Serine phosphorylated FAK and FRNK accumulated in membranes and nuclei but not in intercalated disks. Nuclear translocation of FAK and FRNK may play important roles in regulating mechanical signal transduction in cardiac myocytes.
Ca
2+
Mobilization Induced by Ouabain in Thymocytes Involves Intracellular and Extracellular Ca
2+
Pools
Authors: Echevarria-Lima Juliana , de Araújo Elizabeth Giestal , de Meis Leopoldo , Rumjanek Vivian M.
Published: May 2003

Immune dysfunction has been reported in hypertensive rats, and circulating levels of ouabain are increased in some experimental models of hypertension. Ouabain is an inhibitor of the Na
+
/K
+
-ATPase capable of diverse effects on cells of the immune system, but its mode of action on these cells is still unknown. The levels of cytoplasmic calcium ions play an important role in cell signaling, and ouabain may induce an increase in intracellular calcium indirectly through the Na
+
/Ca
2+
exchanger. The current work examined the possibility that this drug could be exerting its effects on thymocytes through calcium mobilization and an increase in the cytosolic calcium concentration. Intracellular calcium was evaluated by using Balb-c mouse thymocytes loaded with FURA-2. Both intracellular and extracellular calcium pools were mobilized by ouabain (3 to 1000 nmol). The influx of extracellular calcium depended on the Na
+
/Ca
2+
exchanger and on voltage-dependent calcium channels, as it was inhibited by amiloride and benzamil, consistent with the inhibition of the Na
+
/K
+
pump. In addition, the increase of calcium from intracellular stores was extremely rapid. Furthermore, an increase in cytosolic calcium levels was obtained with the combination of ouabain and thapsigargin, which was greater than that seen with either drug alone. Our data suggest that low concentrations of ouabain may be acting on thymocytes through a mechanism different from the traditional inhibition of the Na
+
/K
+
-ATPase, as the cytosolic calcium rise was partly dependent on the release from intracellular stores.
Adolescent Pain Sensitivity Is Associated With Cardiac Autonomic Function and Blood Pressure Over 8 Years
Authors: Campbell Tavis S. , Ditto Blaine , Séguin Jean R. , Sinray Sarah , Tremblay Richard E.
Published: May 2003

Low pain sensitivity has been reported in hypertensive subjects as well in groups deemed to be at increased risk of development of the disorder. However, it is uncertain whether individual differences in pain sensitivity are associated prospectively with increases in blood pressure. In the current study, 24-hour blood pressure and heart rate variability were recorded in 110, 22-year-old men previously assessed at age 14 years for casual blood pressure and pain sensitivity (mechanical finger pressure). Significant correlations were observed between pain tolerance in 14-year-olds and current 24-hour systolic blood pressure (
r
=0.37,
P
<0.01) and diastolic blood pressure (
r
=0.36,
P
<0.01). Hierarchical multiple regression analyses indicated that information regarding pain tolerance improved prediction of systolic and diastolic blood pressure at age 22 years beyond that afforded by differences in blood pressure, parental history of hypertension, and body mass index at age 14 years. Similar analyses revealed that average pain sensitivity at age 14 was also associated with 24-hour high-frequency heart rate variability (
r
=0.28,
P
<0.01) and low-frequency/high-frequency heart rate variability at age 22 (
r
=−0.35,
P
<0.01), suggesting increased sympathetic and reduced parasympathetic tone among individuals less sensitive to pain. These results provide further evidence that blood pressure related hypoalgesia might be related to processes involved in blood pressure regulation as well as in the development of sustained high blood pressure.
Phosphatidylinositol 3-Kinase and Calcium-Activated Transcription Pathways Are Required for VLDL-Induced Smooth Muscle Cell Proliferation
Authors: Lipskaia Larissa , Pourci Marie-Luce , Deloménie Claudine , Combettes Laurent , Goudounèche Dominique , Paul Jean-Louis , Capiod Thierry , Lompré Anne-Marie
Published: May 2003

Little is known regarding the molecular mechanisms of atherogenicity of triglyceride-rich lipoproteins such as very low-density lipoproteins (VLDLs). We examined the effect of VLDL on proliferation of rat aortic smooth muscle cells, intracellular Ca
2+
handling, and activity of cAMP-responsive element binding protein (CREB) and nuclear factor of activated T cells (NFAT) transcription factors. VLDL, isolated from human serum, dose- and time-dependently promoted proliferation. After 4 hours of exposure to VLDL (0.15 g/L proteins), the caffeine-induced Ca
2+
release was inhibited and the IP3-sensitive Ca
2+
release induced by ATP (10 μmol/L) was markedly prolonged. In quiescent cells, CREB was phosphorylated (pCREB) and NFAT was present in the cytosol, whereas in cells exposed to VLDL for 4 to 24 hours, pCREB disappeared and NFAT was translocated to the nucleus. VLDL-induced NFAT translocation and proliferation were blocked by cyclosporin A and LY294002 involving calcineurin and phosphatidylinositol 3-kinase (PI3K) pathways. Indeed, VLDLs rapidly phosphorylate protein kinase B and glycogen synthase kinase-3β in a PI3K-dependent way. These results provide the first evidence that VLDLs induce smooth muscle cell proliferation by activating the PI3K pathway and nuclear NFAT translocation. Blockade of the Ca
2+
-induced Ca
2+
release mechanism and dephosphorylation of pCREB contribute but were not sufficient to induce a proliferating phenotype.
Receptor Tyrosine Kinase Axl Modulates the Osteogenic Differentiation of Pericytes
Authors: Collett Georgina , Wood Alan , Alexander M. Yvonne , Varnum Brian C. , Boot-Handford Raymond P. , Ohanian Vasken , Ohanian Jacqueline , Fridell Yih-Woei , Canfield Ann E.
Published: May 2003

Vascular pericytes undergo osteogenic differentiation in vivo and in vitro and may, therefore, be involved in diseases involving ectopic calcification and osteogenesis. The purpose of this study was to identify factors that inhibit the entry of pericytes into this differentiation pathway. RNA was prepared from pericytes at confluence and after their osteogenic differentiation (mineralized nodules). Subtractive hybridization was conducted on polyA PCR-amplified RNA to isolate genes expressed by confluent pericytes that were downregulated in the mineralized nodules. The subtraction product was used to screen a pericyte cDNA library and one of the positive genes identified was Axl, the receptor tyrosine kinase. Northern and Western blotting confirmed that Axl was expressed by confluent cells and was downregulated in mineralized nodules. Western blot analysis demonstrated that confluent pericytes also secrete the Axl ligand, Gas6. Immunoprecipitation of confluent cell lysates with an anti-phosphotyrosine antibody followed by Western blotting using an anti-Axl antibody, demonstrated that Axl was active in confluent pericytes and that its activity could not be further enhanced by incubating the cells with recombinant Gas6. The addition of recombinant Axl-extracellular domain (ECD) to pericyte cultures inhibited the phosphorylation of Axl by endogenous Gas6 and enhanced the rate of nodule mineralization. These effects were inhibited by coincubation of pericytes with Axl-ECD and recombinant Gas6. Together these results demonstrate that activation of Axl inhibits the osteogenic differentiation of vascular pericytes.
Mechanisms of Delayed Electrical Uncoupling Induced by Ischemic Preconditioning
Authors: Jain Sandeep K. , Schuessler Richard B. , Saffitz Jeffrey E.
Published: May 2003

Electrical uncoupling of cardiac myocytes during ischemia is delayed by ischemic preconditioning. This presumably adaptive response may limit development of arrhythmia substrates. To elucidate responsible mechanisms, we studied isolated, perfused rat hearts subjected to a standard preconditioning protocol of 3 cycles of 3 minutes of global no-flow ischemia each followed by 5 minutes of reperfusion before a 30-minute interval of ischemia. Changes in coupling were monitored by measuring whole-tissue resistance. Changes in phosphorylation and subcellular distribution of connexin43 (Cx43) were defined by quantitative immunoblotting and confocal microscopy. Preconditioning caused a 34% decrease in the maximal rate of uncoupling and delayed the time to plateau in uncoupling. Dephosphorylation of Cx43, known to occur during uncoupling induced by ischemia, was dramatically decreased in preconditioned hearts. Translocation of Cx43 from gap junctions to the cytosol, also known to occur during ischemia, was reduced by >5-fold in preconditioned hearts. The K
ATP
channel blockers glybenclamide and 5-hydroxydecanoate prevented these effects in preconditioned hearts, whereas the K
ATP
channel agonist diazoxide mimicked these effects in nonpreconditioned hearts. Intracellular translocation of Cx43 was blocked, but Cx43 dephosphorylation was not blocked during ischemia in preconditioned hearts treated with the PKC inhibitors chelerythrine and calphostin C. Uncoupling during ischemia was accelerated by PKC and K
ATP
channel inhibition. Thus, delayed uncoupling in preconditioned hearts is likely related to diminished dephosphorylation and intracellular redistribution of Cx43 during prolonged ischemia. Both of these effects are regulated by activation of K
ATP
channels, whereas PKC plays a role in internalization of Cx43.