bluuebunny/crossref_metadata_2025 huggingface dataset:
Relations of Stroke Volume and Cardiac Output to Body Composition
Authors: Collis Tarquin , Devereux Richard B. , Roman Mary J. , de Simone Giovanii , Yeh Jeun-Liang , Howard Barbara V. , Fabsitz Richard R. , Welty Thomas K.
Published: June 2012

Background
—Although cardiac output (CO) plays the vital role of delivering nutrients to body tissues, few data are available concerning the relations of stroke volume (SV) and CO to body composition in large population samples.

Methods and Results
—Doppler and 2D echocardiography and bioelectric impedance in 2744 Strong Heart Study participants were used to calculate SV and CO and to relate them to fat-free body mass (FFM), adipose mass, and demographic variables. Both SV and CO were higher in men than women and in overweight than normal-weight individuals, but these differences were diminished or even reversed by normalization for FFM or body surface area. In both sexes, SV and CO were more strongly related to FFM than adipose mass, other body habitus measures, arterial pressure, diabetes, or age. In multivariate analyses using the average of Doppler and left ventricular SV to minimize measurement variability, FFM was the strongest correlate of SV and CO; other independent correlates were adipose mass, systolic pressure, diabetes, age, and use of digoxin and calcium channel and β-blockers.

Conclusions
—In a population-based sample, SV and CO are more strongly related to FFM than other variables; increased FFM may be the primary determinant of increased SV and CO in obesity.
Vitamin C Augments the Inotropic Response to Dobutamine in Humans With Normal Left Ventricular Function
Authors: Mak Susanna , Newton Gary E.
Published: June 2012

Background
—We studied the effect of an antioxidant, the intracoronary infusion of vitamin C, on basal and dobutamine-stimulated left ventricular (LV) contractility.

Methods and Results
—Nineteen patients with normal ventricular function participated in this study. A micromanometer-tipped catheter was inserted into the LV. In the experimental group (n=10), an infusion catheter was positioned in the left main coronary artery. LV peak +dP/dt (LV +dP/dt) was measured in response to the intravenous infusion of dobutamine before (Dob) and during (Dob+vit C) the intracoronary infusion of vitamin C. The intracoronary infusion of vitamin C had no effect on basal LV +dP/dt or any other hemodynamic parameter. The infusion of vitamin C augmented the LV +dP/dt response to dobutamine by 22±4% (Dob, 1680±76 mm Hg/s; Dob+vit C, 1814±97 mm Hg/s,
P
<0.01). In the control group (n=9), LV +dP/dt was measured in response to sequential infusions of dobutamine (Dob, Dob-2) given at the same time intervals as in the experimental group but without the intracoronary infusion of vitamin C. In contrast to the experimental group, no difference in LV +dP/dt was observed between the 2 infusions of dobutamine (Dob, 1706±131 mm Hg/s; Dob-2, 1709±138 mm Hg/s,
P
=NS).

Conclusions
—The administration of the antioxidant vitamin C augments the inotropic response to dobutamine in humans. This suggests that redox environment contributes to the adrenergic regulation of ventricular contractility.
Gene Transfer of Heat-Shock Protein 70 Reduces Infarct Size In Vivo After Ischemia/Reperfusion in the Rabbit Heart
Authors: Okubo Shinji , Wildner Oliver , Shah Maulik R. , Chelliah Jeya C. , Hess Michael L. , Kukreja Rakesh C.
Published: June 2012

Background
—Heat-shock protein 70 (HSP 70) plays a role in myocardial protection. No studies are available, however, to show that direct gene transfer of HSP 70 reduces myocardial infarction in vivo.

Methods and Results
—Rabbit hearts were injected with vehicle or Ad.HSP70 at 3 sites (1.5×10
9
pfu, 50 μL/site) in the left ventricle (LV). Four days later, hearts were removed, and expression of inducible (HSP 70) and constitutive (HSC 70) proteins was measured in the LV and right ventricle (RV). Subsets of 5 to 7 animals in the vehicle-, Ad.lacZ-, and Ad.HSP70-treated groups were subjected to 30 minutes of ischemia and 3 hours of reperfusion. Infarct size was measured by tetrazolium staining. Increased expression of HSP 70 was observed in LV injected with Ad.HSP70 compared with vehicle-treated hearts. HSP 70 was undetectable in RV, the noninjected region of the heart. The expression of HSC 70 remained unchanged in hearts treated with vehicle or Ad.HSP70. Infarct size (% risk area) decreased to 24.5±2.8 in Ad.HSP70-injected hearts compared with 41.9±2.8 and 42.7±2.5 in the vehicle- and Ad.LacZ-treated hearts (
P
<0.01). The infarct size was not different between the vehicle- and Ad.LacZ-treated hearts (
P
>0.05). The risk areas (% of LV) were not different among the 3 groups, ie, 50.1±5.2, 47.7±3.5, and 53.3±2.9 in vehicle-, Ad.lacZ-, and Ad.HSP70-treated groups (
P
>0.05).

Conclusions
—Direct gene delivery of HSP 70 in vivo reduces the severity of ischemic injury in the heart.
Dynamic Relationship of Cycle Length to Reentrant Circuit Geometry and to the Slow Conduction Zone During Ventricular Tachycardia
Authors: Ciaccio Edward J.
Published: June 2012

Background
—Knowledge of cycle-to-cycle changes in isthmus geometry is of potential importance for radiofrequency catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that isthmus geometry often undergoes continuous evolution throughout reentry and that cycle-length variability measurements could be used to segment reentry into distinct phases and to predict changes in isthmus geometry.

Methods and Results
—A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure 8 pattern of conduction was used for analysis (25 monomorphic reentry episodes, 20 experiments). Tachycardias were segmented, on the basis of cycle-length variations, into 2 to 3 distinct phases corresponding to onset, maintenance, and spontaneous termination, when it occurred (6/25 episodes). Trends of linear cycle-length change occurred throughout the maintenance phase in all tachycardias. For each trend, quantitative geometric parameters of the isthmus were measured, and the following linear relationships were established. During a trend, the slow conduction zone activation interval and tachycardia cycle length increased, while isthmus length decreased. When isthmus length decreased, isthmus width decreased at its narrowed portion. Larger decreases in isthmus length corresponded to higher rates of linear cycle-length prolongation. Also, greater cycle-length variability tended to prolong tachycardia.

Conclusions
—Cycle-length alterations occur throughout reentry in this canine model and are predictive of isthmus geometry changes. Because similar reentry dynamics, which affect catheter ablation efficacy, have been observed clinically, estimation of changes in geometry during electrophysiological study may help target ablation sites.
Healed Plaque Ruptures and Sudden Coronary Death
Authors: Burke Allen P. , Kolodgie Frank D. , Farb Andrew , Weber Deena K. , Malcom Gray T. , Smialek John , Virmani Renu
Published: June 2012

Background
—Subclinical episodes of plaque disruption followed by healing are considered a mechanism of increased plaque burden. Detailed pathological studies of healed ruptures, however, are lacking.

Methods and Results
—We identified acute and healed ruptures from 142 men who died of sudden coronary death and performed morphometric measurements of plaque burden, luminal stenosis, and smooth muscle cell phenotype. Healed ruptures were found in 61% of hearts and were associated with healed myocardial infarction, increased heart weight, dyslipidemia, and diabetes. Multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture; the percent area luminal narrowing increased with increased numbers of healed sites of previous rupture. The underlying percent luminal narrowing for acute ruptures (mean 79±15%) exceeded that for healed ruptures (mean 66±14%,
P
=0.0001), and the area within the internal elastic lamina was significantly less in healed ruptures than in acute ruptures, when segments were grouped by distance from the ostium. Healed ruptures favored the accumulation of immature smooth muscle cells at repair sites, with a cellular proliferation index of 0.40±0.09%, significantly higher than the index at the sites of rupture (
P
=0.008).

Conclusions
—These data provide evidence that silent plaque rupture is a form of wound healing that results in increased percent stenosis. Healed ruptures occur in arteries with less cross-sectional area luminal narrowing than acute ruptures and are a frequent finding in men who die suddenly with severe coronary atherosclerosis.
Anticardiolipin Antibodies From Patients With the Antiphospholipid Antibody Syndrome Recognize Epitopes in Both β
2
-Glycoprotein 1 and Oxidized Low-Density Lipoprotein
Authors: Hörkkö Sohvi , Olee Tsaiwei , Mo Lian , Branch D. Ware , Woods Virgil L. , Palinski Wulf , Chen Pojen P. , Witztum Joseph L.
Published: June 2012

Background
—We recently suggested that many anticardiolipin antibodies bind only to oxidized cardiolipin (OxCL) and/or to OxCL–β
2
-glycoprotein 1 (β
2
GP1) adducts but not to a “reduced” cardiolipin that is unable to undergo oxidation. To test this hypothesis, we investigated 24 sera, 4 protein A–purified IgG fractions, and 3 human monoclonal antibodies that were all isolated from patients with antiphospholipid antibody syndrome (APS); testing was also performed in 7 controls. Two monoclonal antibodies (IS3 and IS4) were selected for binding to CL and one was selected for binding to β
2
GP1 (LJB8).

Methods and Results
—By chemiluminescent immunoassay, all APS sera samples bound only to OxCL and not to reduced CL, and the binding was inhibited >95% by OxCL but not reduced CL. All purified IgG fractions bound to β
2
GP1 but only when the β
2
GP1 was plated on microtiter wells coated with OxCL. All 3 monoclonal antibodies bound only to OxCL. On Western blots, IS4 and LJB8 bound to β
2
GP1 as well as to delipidated apoB of oxidized LDL but not to native apoB. IS3 also bound to oxidized apoB on Western blot. Covalent modification of β
2
GP1 with oxidation products of CL made it more antigenic for APS serum samples, for purified IgG fractions, and for the monoclonal antibodies.

Conclusions
—These data support the hypothesis that oxidation of CL is needed to generate epitopes for many anticardiolipin antibodies and that some of these epitopes are covalent adducts of OxCL with β
2
GP1 or apoB.
Cardiovascular Disease, Interleukin-6, and Risk of Mortality in Older Women
Authors: Volpato Stefano , Guralnik Jack M. , Ferrucci Luigi , Balfour Jennifer , Chaves Paulo , Fried Linda P. , Harris Tamara B.
Published: June 2012

Background
—Systemic chronic inflammation has been found to be related to all-cause mortality risk in older persons. We investigated whether specific chronic conditions, particularly cardiovascular disease (CVD), affect the association between high interleukin (IL)-6 level and mortality in a sample of disabled older women.

Methods and Results
—IL-6 serum level was measured at baseline in 620 women ≥65 years old. The presence and severity of medical conditions was ascertained by standard criteria that used multiple sources of information. The sample was surveyed over the 3-year follow-up. After adjustment for potential confounders, compared with those in the lowest tertile, women in the highest IL-6 tertile were at higher risk of all-cause mortality. The presence of CVD, however, strongly affected the risk of mortality associated with high IL-6. Among women with prevalent CVD, those with high IL-6 levels had >4-fold risk of death (RR 4.6; 95% CI 2.0 to 10.5) compared with women in the lowest tertile, whereas the relative risk associated with high IL-6 among those without CVD was much lower and not significant (RR 1.8; 95% CI 0.7 to 4.2). Adjustment for all chronic diseases and disease severity measures, including ankle-brachial index, forced expiratory volume, and exercise tolerance, did not change the results.

Conclusions
—IL-6 level is helpful in identifying a subgroup of older CVD patients with high risk of death over a period of 3 years. Systemic inflammation, as measured by IL-6, may be related to the clinical evolution of older patients with CVD.
Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits
Authors: Fukumoto Yoshihiro , Libby Peter , Rabkin Elena , Hill Christopher C. , Enomoto Makoto , Hirouchi Yasuhiko , Shiomi Masashi , Aikawa Masanori
Published: June 2012

Background
—Acute coronary syndromes often result from rupture of vulnerable plaques. The collagen content of plaques probably regulates their stability. This study tested whether HMG-CoA reductase inhibitors (statins) alter interstitial collagen gene expression or matrix metalloproteinase (MMP) levels in rabbit atheroma.

Methods and Results
—We administered equihypocholesterolemic doses of pravastatin (a hydrophilic statin, 50 mg · kg
−1
· d
−1
, n=9), fluvastatin (a cell-permeant lipophilic statin, 20 mg · kg
−1
· d
−1
, n=10), or placebo (n=10) to mature Watanabe heritable hyperlipidemic rabbits for 52 weeks. The fluvastatin group achieved a much higher peak plasma concentration (23.7 μmol/L) than did the pravastatin group (1.3 μmol/L) under these conditions. Immunohistochemistry revealed that MMP-1, MMP-3, and MMP-9 expression by macrophages in the intima was lower in both the pravastatin and fluvastatin groups than in the placebo group, whereas there was no difference in macrophage numbers. Numbers of intimal smooth muscle cells (SMCs) (identified by immunohistochemistry) and expression of type I procollagen mRNA (detected by in situ hybridization), however, were significantly higher in the pravastatin group than in the fluvastatin group. Treatment with pravastatin, but not fluvastatin, preserved interstitial collagen content in vivo (detected by picrosirius red polarization). In vitro, fluvastatin, but not pravastatin, decreased numbers of rabbit and human aortic SMCs without altering procollagen I mRNA expression.

Conclusions
—This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.
Recombinant Soluble P-Selectin Glycoprotein Ligand-1-Ig Reduces Restenosis Through Inhibition of Platelet-Neutrophil Adhesion After Double Angioplasty in Swine
Authors: Bienvenu Jean-Guy , Tanguay Jean-François , Théorêt Jean-François , Kumar Anjali , Schaub Robert G. , Merhi Yahye
Published: June 2012

Background
—P-selectin mediates leukocyte recruitment to activated platelets and endothelium through its high-affinity receptor P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte activation and binding have been reported after coronary angioplasty and were correlated with restenosis. We investigated the effect of a recombinant soluble PSGL-1 (rPSGL-Ig) on the adhesion of platelets and neutrophils and the development of restenosis after double arterial injury.

Methods and Results
—Four weeks after angioplasty of both carotid arteries in pigs, a second angioplasty was performed at the same sites, 15 minutes after a single administration of vehicle or rPSGL-1 (1 mg/kg IV). Animals were euthanized 1 hour, 4 hours, 1 week, or 4 weeks later. Adhesion of autologous
51
Cr-platelets and
111
In-neutrophils was quantified and histological/morphometric analyses were performed. Although rPSGL-Ig did not affect adherence of these cells 1 hour after injury, it significantly reduced the adhesion of platelets (50% at 4 hours and 85% at 1 week) and neutrophils (50% at 4 hours and 78% at 1 week) to deeply injured arteries. At 4 weeks, the residual lumen was 63% larger in rPSGL-Ig–treated arteries as compared with control arteries (6.1±0.6 versus 3.8±0.1 mm
2
;
P
<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm
2
in control). The ratio of the external elastic lamina of injured to uninjured reference segments was >1 in treated arteries and <1 in control arteries.

Conclusions
—P-selectin antagonism with rPSGL-Ig inhibits early platelet/leukocyte adhesion on injured arteries and reduces restenosis through a positive impact on vascular remodeling. Hence, rPSGL-Ig may have potential in the prevention of restenosis.
Patency of Percutaneous Transluminal Coronary Angioplasty Sites at 6-Month Angiographic Follow-Up
Authors: Van Belle Eric , Ketelers Régis , Bauters Christophe , Périé Marc , Abolmaali Kaveh , Richard Florence , Lablanche Jean-Marc , McFadden Eugène P. , Bertrand Michel E.
Published: June 2012

Background
—Several reports have demonstrated a high mortality rate in diabetic patients treated by standard coronary balloon angioplasty. No clear explanation has been provided for this finding.

Methods and Results
—Consecutive diabetic patients successfully treated by standard coronary balloon angioplasty (n=604) were enrolled in a follow-up program including repeated angiography at 6 months and long-term clinical follow-up. Clinical follow-up was available in 603 patients (99.8%). Twelve patients died, 2 underwent bypass surgery before scheduled repeated angiography, and 76 declined angiography. Determinants of long-term mortality were analyzed in the 513 patients with angiography at 6 months and long-term clinical follow-up (mean follow-up, 6.5±2.4 years). On the basis of the results of repeated angiography, 3 groups of patients were defined: group 1, 162 patients without restenosis (32%); group 2, 257 patients with nonocclusive restenosis (50%); and group 3, 94 patients with coronary occlusion (18%). Overall actuarial 10-year mortality rate was 36%. Actuarial 10-year mortality was 24% in group 1, 35% in group 2, and 59% in group 3 (
P
<0.0001). Multivariate analysis demonstrated that coronary occlusion was a strong and independent correlate of long-term total mortality (hazard ratio, 2.16; 95% CI, 1.43 to 3.26;
P
=0.0003) and cardiac mortality (hazard ratio, 2.38; 95% CI, 1.48 to 3.85;
P
=0.0004).

Conclusions
—This study demonstrates that restenosis, especially in its occlusive form, is a major determinant of long-term mortality in diabetic patients after coronary balloon angioplasty.
Does the Relation of Blood Pressure to Coronary Heart Disease Risk Change With Aging?
Authors: Franklin Stanley S. , Larson Martin G. , Khan Shehzad A. , Wong Nathan D. , Leip Eric P. , Kannel William B. , Levy Daniel
Published: June 2012

Background
—We examined the relative importance of diastolic (DBP), systolic (SBP) and pulse pressure (PP) as predictors of coronary heart disease (CHD) risk in different age groups of Framingham Heart Study participants.

Methods and Results
—We studied 3060 men and 3479 women between 20 and 79 years of age who were free of CHD and were not on antihypertensive drug therapy at baseline. Cox regression adjusted for age, sex, and other risk factors was used to assess the relations of BP indexes to CHD risk over a 20-year follow-up. In the group <50 years of age, DBP was the strongest predictor of CHD risk (hazard ratio [HR] per 10 mm Hg increment, 1.34; 95% CI, 1.18 to 1.51) rather than SBP (HR, 1.14; 95% CI, 1.06 to 1.24) or PP (HR, 1.02; 95% CI, 0.89 to 1.17). In the group 50 to 59 years of age, risks were comparable for all 3 BP indexes. In the older age group, the strongest predictor of CHD risk was PP (HR, 1.24; 95% CI, 1.16 to 1.33). When both SBP and DBP were considered jointly, the former was directly and the latter was inversely related to CHD risk in the oldest age group

Conclusions
—With increasing age, there was a gradual shift from DBP to SBP and then to PP as predictors of CHD risk. In patients <50 years of age, DBP was the strongest predictor. Age 50 to 59 years was a transition period when all 3 BP indexes were comparable predictors, and from 60 years of age on, DBP was negatively related to CHD risk so that PP became superior to SBP.
Positive and Negative Feedback Mechanisms in the Neural Regulation of Cardiovascular Function in Healthy and Spinal Cord–Injured Humans
Authors: Legramante J. M. , Raimondi G. , Massaro M. , Iellamo F.
Published: June 2012

Background
—We tested the hypothesis that in humans, hypertension/tachycardia and hypotension/bradycardia nonbaroreflex sequences that occur within spontaneous arterial pressure (AP) and R-R interval fluctuations are an expression of positive feedback mechanisms neurally regulating the cardiovascular system.

Methods and Results
—We studied 15 spinal cord–injured (SCI) subjects (8 tetraplegics and 7 paraplegics) and 8 healthy subjects. The occurrence of nonbaroreflex (NBseq) and baroreflex (Bseq) sequences, ie, hypertension-bradycardia and hypotension-tachycardia sequences, was assessed during rest and head-up tilt (HUT). The ratio between Bseq and NBseq (B/NB ratio) was also calculated. In resting conditions, the occurrence of NBseq was significantly lower (
P
<0.05) in tetraplegics (7.9±1.5) than in paraplegics (16.2±3.2) and normal subjects (19.0±3.5), whereas the occurrence of Bseq was not significantly different between the 3 groups (38.6±11.9 versus 45.4±6.0 versus 47.0±11.9). In tetraplegics, the B/NB ratio showed a marked, significant decrease (from 8.4±4.2 to 1.9±0.8,
P
<0.05) in response to HUT, whereas in normal subjects, it showed a significant increase (from 3.5±0.7 to 9.4±2.7,
P
<0.05). In paraplegics, the B/NB ratio did not change significantly in response to HUT (from 4.5±1.6 to 4.8±1.1).

Conclusions
—Our data suggest that nonbaroreflex sequences occur in humans and might represent the expression of an integrated, neurally mediated, feed-forward type of short-term cardiovascular regulation that is able to interact dynamically with feedback mechanisms of baroreflex origin.
Endothelial Regulation of Vasomotion in ApoE-Deficient Mice
Authors: Laursen Jørn Bech , Somers Mark , Kurz Sabine , McCann Louise , Warnholtz Ascan , Freeman Bruce A. , Tarpey Margaret , Fukai Tohru , Harrison David G.
Published: June 2012

Background
—Altered endothelial cell nitric oxide (NO
·
) production in atherosclerosis may be due to a reduction of intracellular tetrahydrobiopterin, which is a critical cofactor for NO synthase (NOS). In addition, previous literature suggests that inactivation of NO
·
by increased vascular production superoxide (O
2
·−
) also reduces NO
·
bioactivity in several disease states. We sought to determine whether these 2 seemingly disparate mechanisms were related.

Methods and Results
—Endothelium-dependent vasodilation was abnormal in aortas of apoE-deficient (apoE
−/−
) mice, whereas vascular superoxide production (assessed by 5 μmol/L lucigenin) was markedly increased. Treatment with either liposome-entrapped superoxide dismutase or sepiapterin, a precursor to tetrahydrobiopterin, improved endothelium-dependent vasodilation in aortas from apoE
−/−
mice. Hydrogen peroxide had no effect on the decay of tetrahydrobiopterin, as monitored spectrophotometrically. In contrast, superoxide modestly and peroxynitrite strikingly increased the decay of tetrahydrobiopterin over 500 seconds. Luminol chemiluminescence, inhibitable by the peroxynitrite scavengers ebselen and uric acid, was markedly increased in apoE
−/−
aortic rings. In vessels from apoE
−/−
mice, uric acid improved endothelium-dependent relaxation while having no effect in vessels from control mice. Treatment of normal aortas with exogenous peroxynitrite dramatically increased vascular O
2
·−
production, seemingly from eNOS, because this effect was absent in vessels lacking endothelium, was blocked by NOS inhibition, and did not occur in vessels from mice lacking eNOS.

Conclusions
—Reactive oxygen species may alter endothelium-dependent vascular relaxation not only by the interaction of O
2
·−
with NO
·
but also through interactions between peroxynitrite and tetrahydrobiopterin. Peroxynitrite oxidation of tetrahydrobiopterin may represent a pathogenic cause of “uncoupling” of NO synthase.
Long-Term Efficacy of Intracoronary Irradiation in Inhibiting In-Stent Restenosis
Authors: Brenner David J. , Miller Richard C.
Published: June 2012

Background
—Intracoronary irradiation is a promising modality for inhibition of in-stent restenosis. Results of randomized clinical trials at 6 months after gamma ray irradiation are highly encouraging. The first results at 3 years after irradiation, while still showing benefit, have shown significant late loss. The probable mechanism of the radiation is to inactivate (prevent from dividing) most cells that otherwise could proliferate to produce neointimal formation. We measured the proportion of cells that survive with their clonogenic potential intact after the doses and dose rates used in the randomized trials, and we then modeled the subsequent repopulation of the surviving cells that might cause late restenosis.

Methods and Results
—Human aortic smooth muscle cells were irradiated with gamma rays, including the doses and dose rates used in current trials, and clonogenic surviving fractions were measured. The subsequent repopulation of the surviving cells was modeled with the assumption that the repopulation kinetics were similar to those in unirradiated cells. The radiation is expected to delay the time to restenosis by factors of ≈6 to 8, depending on the dose, shifting the delay from a median of 6 months (for no irradiation) to median values from 36 months (for a nominal 13 Gy) to 43 months (for a nominal 15 Gy).

Conclusions
—These results and predictions are quantitatively consistent with clinical results and suggest that clonogenic inactivation (prevention of cellular division) is the dominant mechanism of radiation action in the delay of restenosis. Intracoronary radiotherapy is a very promising modality for significantly delaying, although probably not preventing, in-stent restenosis.
Aldosterone Induces Angiotensin-Converting-Enzyme Gene Expression in Cultured Neonatal Rat Cardiocytes
Authors: Harada Eisaku , Yoshimura Michihiro , Yasue Hirofumi , Nakagawa Osamu , Nakagawa Masayo , Harada Masaki , Mizuno Yuji , Nakayama Masafumi , Shimasaki Yukio , Ito Teruhiko , Nakamura Shota , Kuwahara Koichiro , Saito Yoshihiko , Nakao Kazuwa , Ogawa Hisao
Published: June 2012

Background

—

The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure.

Methods and Results

—

To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10
−5
mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7±0.5-fold versus control,
P
=NS), but similar treatment with aldosterone (10
−5
mol/L) induced a 23.3±7.9-fold increase (
P
<0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC
50
, 4×10
−7
mol/L), and it was significantly (
P
<0.01) inhibited by spironolactone, a specific mineralocorticoid receptor antagonist.

Conclusions

—

Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. Thus, spironolactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II.
Platelet Glycoprotein IIIa

Pl

A
Polymorphism, Fibrinogen, and Platelet Aggregability
Authors: Feng DaLi , Lindpaintner Klaus , Larson Martin G. , O’Donnell Christopher J. , Lipinska Izabella , Sutherland Patrice A. , Mittleman Murray , Muller James E. , D’Agostino Ralph B. , Levy Daniel , Tofler Geoffrey H.
Published: June 2012

Background

—

Recent data suggest that the
Pl
A2
allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the
Pl
A2
allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that
Pl
A2
-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with
Pl
A
genotype in modulating platelet aggregability.

Methods and Results

—

Glycoprotein IIIa
Pl
A
genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (
P
=0.002) and a trend for ADP-induced aggregation (
P
=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the
Pl
A1/A1
genotype (
P
=0.0005 and
P
=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the
Pl
A2
-positive genotype (
P
>0.90).

Conclusion

—

Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding
Pl
A
genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.
Short- and Long-Term Black Tea Consumption Reverses Endothelial Dysfunction in Patients With Coronary Artery Disease
Authors: Duffy Stephen J. , Keaney Jr John F. , Holbrook Monika , Gokce Noyan , Swerdloff Peter L. , Frei Balz , Vita Joseph A.
Published: June 2012

Background

—

Epidemiological studies suggest that tea consumption decreases cardiovascular risk, but the mechanisms of benefit remain undefined. Endothelial dysfunction has been associated with coronary artery disease and increased oxidative stress. Some antioxidants have been shown to reverse endothelial dysfunction, and tea contains antioxidant flavonoids.

Methods and Results

—

To test the hypothesis that tea consumption will reverse endothelial dysfunction, we randomized 66 patients with proven coronary artery disease to consume black tea and water in a crossover design. Short-term effects were examined 2 hours after consumption of 450 mL tea or water. Long-term effects were examined after consumption of 900 mL tea or water daily for 4 weeks. Vasomotor function of the brachial artery was examined at baseline and after each intervention with vascular ultrasound. Fifty patients completed the protocol and had technically suitable ultrasound measurements. Both short- and long-term tea consumption improved endothelium- dependent flow-mediated dilation of the brachial artery, whereas consumption of water had no effect (
P
<0.001 by repeated-measures ANOVA). Tea consumption had no effect on endothelium-independent nitroglycerin-induced dilation. An equivalent oral dose of caffeine (200 mg) had no short-term effect on flow-mediated dilation. Plasma flavonoids increased after short- and long-term tea consumption.

Conclusions

—

Short- and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.
Abciximab Suppresses the Rise in Levels of Circulating Inflammatory Markers After Percutaneous Coronary Revascularization
Authors: Lincoff A.Michael , Kereiakes Dean J. , Mascelli Mary A. , Deckelbaum Lawrence I. , Barnathan Elliot S. , Patel Kamlesh K. , Frederick Bart , Nakada Marian T. , Topol Eric J.
Published: June 2012

Background

—

Previous investigators have shown that systemic markers of inflammation may be increased in patients with acute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, avβ3, and αMβ2 receptors, abciximab may reduce inflammatory processes.

Methods and Results

—

Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-α were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo (
P
=0.025); the rise in interleukin-6 levels was 76% less in the abciximab group (
P
<0.001); and the rise in tumor necrosis factor-α levels was 100% less with abciximab therapy (
P
=0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups.

Conclusions

—

Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect.
Platelet Reactivity Characterized Prospectively
Authors: Kabbani Samer S. , Watkins Matthew W. , Ashikaga Taka , Terrien Edward F. , Holoch Peter A. , Sobel Burton E. , Schneider David J.
Published: June 2012

Background

—

Platelet activation is pivotal in the pathogenesis of complications after percutaneous coronary interventions (PCI). We previously reported substantial interindividual variability in activation of glycoprotein (GP) IIb/IIIa in response to a low concentration of ADP. We assessed GP IIb/IIIa activation prospectively to determine whether this could differentiate patients at low risk from those at high risk for complications early and late after PCI.

Methods and Results

—

A total of 112 patients undergoing PCI were studied. Platelet reactivity was determined with the use of flow cytometry. Patients were classified into high and low platelet reactivity groups on the basis of extent of activation of GP IIb/IIIa in response to 0.2 μmol/L ADP. The median value was used for differentiation. The incidence during 90-day follow-up interval of a composite end point (myocardial infarction, urgent revascularization, or repeat revascularization) was determined in each group. Follow up was completed in all 112 patients. The 2 groups were similar with respect to diverse clinical characteristics. Nevertheless, the incidence of the composite end point occurred in 26.8% of the high and 7.1% in the low platelet reactivity group (
P
=0.01). The difference in the composite end point was most striking during the 30- to 90-day interval after PCI (16.7% versus 1.9%;
P
=0.02). Repeat revascularization was more frequent in those with increased platelet reactivity (17.9% versus with 3.6%,
P
=0.029).

Conclusions

—

Prospective assessment of platelet GP IIb/IIIa activation permits stratification of patients into low- and high-risk groups with respect to adverse events after PCI.
Use of Human Immunodeficiency Virus-1 Protease Inhibitors Is Associated With Atherogenic Lipoprotein Changes and Endothelial Dysfunction
Authors: Stein James H. , Klein Melissa A. , Bellehumeur Jennifer L. , McBride Patrick E. , Wiebe Donald A. , Otvos James D. , Sosman James M.
Published: June 2012

Background

Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction.

Methods and Results

This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count. Group 1 subjects had higher total cholesterol (5.68 versus 4.42 mmol/L,
P
=0.007) and triglyceride (4.43 versus 1.98 mmol/L,
P
=0.009) levels, characterized by elevated levels of IDL and VLDL. Subjects in group 1 had impaired FMD (2.6±4.6%), indicative of significant endothelial dysfunction. Group 2 subjects had normal FMD (8.1±6.7%,
P
=0.005). In group 1, chylomicron, VLDL, IDL, and HDL cholesterol levels predicted FMD.

Conclusions

Use of HIV PIs is associated with atherogenic lipoprotein changes and endothelial dysfunction. Because these metabolic and vascular changes predispose to atherosclerosis, monitoring and treatment of dyslipidemia in patients taking these medications is warranted.
Stroke in Relation to Cardiac Procedures in Patients With Non–ST-Elevation Acute Coronary Syndrome
Authors: Cronin Lisa , Mehta Shamir R. , Zhao Feng , Pogue Janice , Budaj Andrzej , Hunt David , Yusuf Salim
Published: June 2012

Background

There are few published data on risk factors for stroke in patients with non–ST-elevation acute coronary syndrome (ACS). We investigated prognostic factors for stroke in 2 large cohorts of patients from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry (8010) and the OASIS-2 trial (10 141)

Methods and Results

A total of 18 151 patients with non–ST-elevation ACS were enrolled in the OASIS program. Data from these 2 studies were pooled (a test for heterogeneity was nonsignificant,
P
=0.34). Overall, 238 patients (1.3%) had a stroke over a 6-month follow-up. Those who experienced stroke had a 4-fold increase in 6-month mortality (27.0% versus 6.3%,
P
<0.001). A Cox multivariate regression analysis identified CABG surgery as the most important predictor of stroke (hazard ratio [HR], 4.6), followed by history of stroke (HR, 2.3), diabetes mellitus (HR, 1.7), older age (HR, 1.6 per 10-year increase), higher heart rate (HR, 1.1 per 10-bpm increase), and on-site catheterization facility (HR, 1.4). There was no significant excess in stroke in patients undergoing percutaneous coronary intervention (
P
=0.21). Patients who underwent early CABG surgery were at a substantially increased risk compared with those who had later CABG (3.3% versus 1.6%; HR, 2.1;
P
=0.003) or who had no surgery (3.3% versus 1.1%; HR, 3.95;
P
=0.0001).

Conclusions

In this large cohort of patients with ACS, stroke was an uncommon but serious event associated with high mortality. The performance of early CABG surgery was a powerful independent predictor of stroke.
Human Coxsackie-Adenovirus Receptor Is Colocalized With Integrins α
v
β
3
and α
v
β
5
on the Cardiomyocyte Sarcolemma and Upregulated in Dilated Cardiomyopathy
Authors: Noutsias Michel , Fechner Henry , de Jonge Henriëtte , Wang Xiaomin , Dekkers Dick , Houtsmuller A.B. , Pauschinger Matthias , Bergelson Jeffrey , Warraich Rahat , Yacoub Magdi , Hetzer Roland , Lamers Jos , Schultheiss Heinz-Peter , Poller Wolfgang
Published: June 2012

Background

The coxsackievirus and adenovirus receptor (CAR) was identified as a common cellular receptor for both viruses, but its biological and pathogenic relevance is uncertain. Knowledge of CAR localization in the human cardiovascular system is limited but important with respect to CAR-dependent viral infections and gene transfer using CAR-dependent viral vectors.

Methods and Results

Explanted failing hearts from 13 patients (8 with dilated cardiomyopathy [DCM] and 5 with other heart diseases [non-DCM]) and normal donor hearts (n=7) were investigated for the expression levels and subcellular localization of CAR and the adenovirus coreceptors α
v
β
3
and α
v
β
5
integrins. CAR immunoreactivity was very low in normal and non-DCM hearts, whereas strong CAR signals occurred at the intercalated discs and sarcolemma in 5 of the 8 DCM hearts (62.5%); these strong signals colocalized with both integrins. In all hearts, CAR was detectable in subendothelial layers of the vessel wall, but not on the luminal endothelial surface, and on interstitial cells. Human CAR (hCAR) expressed in rat cardiomyocytes was targeted to cell-cell contacts, which resembled CAR localization in DCM hearts and resulted in 15-fold increased adenovirus uptake.

Conclusions

Low hCAR abundance may render normal human myocardium resistant to CAR-dependent viruses, whereas re-expression of hCAR, such as that observed in DCM, may be a key determinant of cardiac susceptibility to viral infections. Asymmetric expression of hCAR in the vessel wall may be an important determinant of adenovirus tropism in humans. hCAR subcellular localization in human myocardium and hCAR targeting to cell-cell contacts in cardiomyocyte cultures suggest that hCAR may play a role in cell-cell contact formation.
Usefulness of Serum Carboxy-Terminal Propeptide of Procollagen Type I in Assessment of the Cardioreparative Ability of Antihypertensive Treatment in Hypertensive Patients
Authors: López Begoña , Querejeta Ramón , Varo Nerea , González Arantxa , Larman Mariano , Martínez Ubago José L. , Díez Javier
Published: June 2012

Background

We investigated whether serum concentration of carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, can be used to assess the ability of antihypertensive treatment to regress myocardial fibrosis in hypertensive patients.

Methods and Results

The study was performed in 37 patients with essential hypertension and hypertensive heart disease. After randomization, 21 patients were assigned to losartan and 16 patients to amlodipine treatment. At baseline and after 12 months, right septal endomyocardial biopsies were performed to quantify collagen volume fraction (CVF) on picrosirius red–stained sections with an automated image-analysis system. Serum PIP was measured by specific radioimmunoassay. Nineteen patients in the losartan group and 11 in the amlodipine group finished the study. Time-course changes in blood pressure during treatment were similar in the 2 groups of patients. In losartan-treated patients, CVF decreased from 5.65±2.03% to 3.96±1.46% (
P
<0.01) and PIP from 127±30 to 99±26 μg/L (
P
<0.01). Neither CVF or PIP changed significantly in amlodipine-treated patients. CVF was directly correlated with PIP (
r
=0.44,
P
<0.001) in all hypertensives before and after treatment.

Conclusions

These findings suggest that the ability of antihypertensive treatment to regress fibrosis in hypertensives with biopsy-proven myocardial fibrosis is independent of its antihypertensive efficacy. Our data also suggest that blockade of the angiotensin II type 1 receptor is associated with inhibition of collagen type I synthesis and regression of myocardial fibrosis in hypertensives. Thus, determination of serum PIP may be useful to assess the cardioreparative properties of antihypertensive treatment in hypertensives.
Transmural Distribution of Three-Dimensional Systolic Strains in Stunned Myocardium
Authors: Mazhari Reza , Omens Jeffrey H. , Pavelec Richard S. , Covell James W. , McCulloch Andrew D.
Published: June 2012

Background

Regional function in stunned myocardium is usually thought to be more depressed in the endocardium than the epicardium. This has been attributed to the greater loss of blood flow at the endocardium during ischemia.

Methods and Results

We measured transmural distributions of 3D systolic strains relative to local myofiber axes in open-chest anesthetized dogs before 15 minutes of left anterior descending coronary artery occlusion and during 2 hours of reperfusion. During ischemia, regional myocardial blood flow was reduced 84% at the endocardium and 32% at the epicardium (
P
<0.005, n=7), but changes in end-systolic fiber length from baseline were transmurally uniform. Relative to baseline, radial segments in stunned tissue were significantly thinner at the endocardium than the epicardium at end systole (24±5% versus 16±3%;
P
<0.05, n=8), consistent with previous reports. Unlike radial and cross-fiber segments, however, the increase of end-systolic fiber lengths in stunned myocardium had no significant transmural gradient (23±8% epicardium versus 21±4% endocardium). We also observed significant 3D diastolic dysfunction in the ischemic-reperfused region transmurally.

Conclusions

Myocardial ischemia/reperfusion in the dog results in a significant transmural gradient of dysfunction between epicardial and endocardial layers in radial and cross-fiber segments, but not for fiber segments, despite a gradient in blood flow reduction during ischemia. Perhaps systolic fiber dysfunction rather than the degree of perfusion deficit during the preceding ischemic period may be the main determinant of myocardial dysfunction during reperfusion.
Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase
Authors: Duplain Hervé , Burcelin Rémy , Sartori Claudio , Cook Stéphane , Egli Marc , Lepori Mattia , Vollenweider Peter , Pedrazzini Thierry , Nicod Pascal , Thorens Bernard , Scherrer Urs
Published: June 2012

Background

Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure.

Methods and Results

To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS
−/−
mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS
−/−
mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal.

Conclusions

These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.