bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Physiology and Pharmacology of
HERG
Authors: Kiehn Johann , Lacerda Antonio E. , Wible Barbara , Brown Arthur M.
Published: June 2012

Background
The human ether-a-go-go–related gene (
HERG
) is one locus for the hereditary long-QT syndrome. A hypothesis is that
HERG
produces the repolarizing cardiac potassium current I
Kr
, with the consequence that mutations in
HERG
prolong the QT interval by reducing I
Kr
. The elementary properties of
HERG
are unknown, and as a test of the hypothesis that
HERG
produces I
Kr
, we compared their elementary properties.

Methods and Results
We injected
HERG
cRNA into
Xenopus
oocytes and measured currents from single channels or current variance from the noise produced by ensembles of channels recorded from macro patches. Single-channel conductance was dependent on the extracellular potassium concentration ([K]
o
)
.
At physiological [K]
o
, it was 2 picosiemens (pS), and at 100 mmol/L [K]
o
, it was 10 pS. Openings occurred in bursts with a mean duration of 26 ms at −100 mV. Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches,
HERG
currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC
50
of 35 nmol/L. Dofetilide block was slow and greatly attenuated at positive potentials at which
HERG
rectifies.

Conclusions
The microscopic physiology of
HERG
and I
Kr
is similar, consistent with
HERG
being an important component of I
Kr
. The pharmacology is also similar; dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.
Role of Nitric Oxide and Its Interaction With Superoxide in the Suppression of Cardiac Muscle Mitochondrial Respiration
Authors: Xie Yi-Wu , Wolin Michael S.
Published: June 2012

Background
Nitric oxide (NO); superoxide anion (O
2
.
d
−
); the reaction product of NO with O
2
.
d
−
, peroxynitrite (ONOO
−
); and ischemia/reperfusion have all been reported to inhibit respiration in isolated mitochondria. However, the specific species involved in the inhibition of respiration in intact tissues are poorly understood.

Methods and Results
O
2
consumption in isolated cardiac muscle from bovine calf hearts was quantified by use of a Clark-type electrode. Exogenous and endogenous sources of NO, from
S
-nitroso-
N
-acetylpenicillamine (SNAP) and bradykinin or carbachol, reversibly inhibited respiration, whereas the O
2
.−
releasing agent, pyrogallol (PG), inhibited respiration in a manner that was only partially reversed when examined 15 minutes after the removal of PG. The generation of ONOO
−
with SNAP+PG caused a potentiation of the O
2
.−
-elicited inhibition of respiration when examined 15 minutes after the removal of the ONOO
−
generating system. Tiron (a scavenger of O
2
.−
) did not alter the actions of SNAP, but it attenuated the direct inhibitory effects of PG±SNAP and essentially eliminated the suppression of respiration observed 15 minutes after removal of the O
2
.−
or ONOO
−
generating system. Urate (a scavenger of ONOO
−
) antagonized only the actions of PG+SNAP. After exposure of muscle slices to a model of hypoxia (15 minutes) and reoxygenation (10 minutes), respiratory inhibition was observed. This reoxygenation-induced inhibition was potentiated by
l
-arginine, the substrate for NO biosynthesis, and was markedly blocked by nitro-
l
-arginine (an NO synthase inhibitor), Tiron, or urate.

Conclusions
The potentially physiological reversible regulation of respiration in cardiac muscle by NO is converted to an effect that does not show rapid reversibility under conditions in which ONOO
−
forms, and this could contribute to cardiac dysfunction in situations such as hypoxia/reoxygenation.
Intake of Dietary Fiber and Risk of Coronary Heart Disease in a Cohort of Finnish Men
Authors: Pietinen Pirjo , Rimm Eric B. , Korhonen Pasi , Hartman Anne M. , Willett Walter C. , Albanes Demetrius , Virtamo Jarmo
Published: June 2012

Background
Even though dietary fiber has been hypothesized to reduce the risk of coronary heart disease, few large epidemiological studies have examined this relation with good methodology.

Methods and Results
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was a randomized, double-blind, placebo-controlled trial with daily supplementation of α-tocopherol and/or beta-carotene. Of the participants, 21 930 smoking men aged 50 to 69 years who were free of diagnosed cardiovascular disease and had completed a validated dietary questionnaire at baseline were followed for 6.1 years. We monitored the incidence of major coronary events (a combination of first nonfatal myocardial infarction and coronary heart disease death; n=1399) and mortality from coronary heart disease (n=635). Both entities had a significant inverse association with dietary fiber, but the association was stronger for coronary death. For men in the highest quintile of total dietary fiber intake (median, 34.8 g/d), the relative risk for coronary death was 0.69 (95% confidence interval, 0.54 to 0.88;
P
<.001 for trend) compared with men in the lowest quintile of intake (median, 16.1 g/d). With an adjustment for known cardiovascular risk factors, intake of saturated fatty acids, beta-carotene, vitamin C, and vitamin E did not materially change the result. Water-soluble fiber was slightly more strongly associated with reduced coronary death than water-insoluble fiber, and cereal fiber also had a stronger association than vegetable or fruit fiber.

Conclusions
These findings suggest that independent of other risk factors, greater intake of foods rich in fiber can substantially reduce the risk of coronary heart disease, and particularly coronary death, in middle-aged, smoking men.
Expression of Kunitz Protease Inhibitor–Containing Forms of Amyloid β-Protein Precursor Within Vascular Thrombi
Authors: Lang Irene M. , Moser Kenneth M. , Schleef Raymond R.
Published: June 2012

Background
The presence of patent neovessels within vascular occlusions in chronic thromboembolic pulmonary hypertension suggests that local mechanisms exist to regulate the coagulation system. This study investigated the expression of a potent inhibitor of Factor IXa and Factor XIa (ie, protease nexin-2/amyloid β-protein precursor, AβPP) in the organized vascular occlusions harvested from patients with this disease.

Methods and Results
Immunohistochemical analysis revealed intense immunoreactivity for AβPP in the single layer of cells that line the neovessels. A positive signal was also detected by in situ hybridization analysis with the use of a
35
S-UTP–labeled antisense riboprobe that recognizes the various alternatively spliced mRNA forms of this molecule. To identify the forms of AβPP produced within the thrombi, total RNA was extracted from the thrombi, reverse transcribed, and subjected to amplification with the use of the polymerase chain reaction (PCR) and primers that flank the region encoding the alternatively spliced 56–amino acid Kunitz-type protease inhibitor (KPI) domain. The major PCR products consisted of 255 bp and 312 bp and corresponded to transcripts encoding this domain (ie, AβPP
751
and AβPP
770
). In situ hybridization analysis with the use of a
35
S-UTP–labeled antisense riboprobe complementary to the region encoding the KPI domain confirmed the presence of these mRNA species in nucleated cells lining the neovessels.

Conclusions
The expression of KPI-containing isoforms of AβPP in thrombus endothelial cells may represent one mechanism utilized in this disease to shift the local hemostatic balance and preserve regional vessel patency.
Long-term Angiotensin-Converting Enzyme Inhibition With Fosinopril Improves Depressed Responsiveness to Ca
2+
in Myocytes From Aortic-Banded Rats
Authors: Kagaya Yutaka , Hajjar Roger J. , Gwathmey Judith K. , Barry William H. , Lorell Beverly H.
Published: June 2012

Background
We have previously shown that long-term ACE inhibition with fosinopril prolongs survival and improves ventricular function despite persistent severe left ventricular pressure overload in ascending aortic–banded rats with left ventricular hypertrophy during the transition from compensation to failure.

Methods and Results
To study the cellular mechanism of the effects of long-term ACE inhibition on the modification of the transition to failure in pressure-overload hypertrophy, we measured simultaneous intracellular Ca
2+
transients and myocyte shortening in isolated left ventricular myocytes from fosinopril-treated aortic-banded rats (n=9), untreated aortic-banded rats (n=9), and normal age-matched control rats (n=10). Fosinopril therapy was begun 6 weeks after banding and was continued until week 21 after banding, when the animals were killed. Collagenase-dissociated myocytes loaded with indo 1-AM were paced at 3 Hz at 36°C and superfused at [Ca
2+
]
o
of 0.6, 1.2, and 3.0 mmol/L. In myocytes from untreated aortic-banded rats, peak systolic [Ca
2+
]
i
was higher than in control myocytes, and the relationship between myocyte shortening and [Ca
2+
]
i
was depressed relative to control myocytes, implicating impaired responsiveness to Ca
2+
. Long-term fosinopril treatment improved both myocyte shortening and the relationship of shortening to [Ca
2+
]
i
(
P
<.05 versus myocytes from untreated aortic-banded rats). Maximal Ca
2+
-activated force was depressed in chemically skinned left ventricular fibers from untreated aortic-banded hypertrophied rats relative to age-matched controls but not in the fosinopril-treated aortic-banded rats.

Conclusions
Long-term ACE inhibition improves responsiveness to Ca
2+
in the presence of normalization of maximal Ca
2+
-activated force in aortic-banded rats subjected to persistent pressure overload. This may contribute to the favorable effects whereby ACE inhibition modifies the transition from compensated hypertrophy to failure.
Electrical Remodeling in Atrial Fibrillation
Authors: Goette Andreas , Honeycutt Clegg , Langberg Jonathan J.
Published: June 2012

Background
Atrial fibrillation is self-perpetuating, suggesting that the tachyarrhythmia causes electrophysiological changes that contribute to the progressive nature of the disease. In animal models, pacing-induced rapid atrial rates result in sustained atrial fibrillation. This is mediated by shortening of refractory periods termed electrical remodeling. The purpose of the present study was to characterize the time course of electrical remodeling and to define mechanisms of the phenomenon.

Methods and Results
Closed-chest dogs were anesthetized, pretreated with atropine and propranolol, and subjected to 7 hours of atrial pacing at 800 bpm. The effective and absolute refractory periods (ARP and ERP) were measured during and after rapid pacing, and transvenous endocardial biopsy specimens were examined using electron microscopy. Despite autonomic blockade and the absence of change in right atrial pressure, persistent atrial tachycardia caused ARP and ERP to fall by >10%. Electrical remodeling developed quickly, with more than half of the phenomenon occurring during the first 30 minutes of high-rate pacing. Pretreatment with glibenclamide in doses sufficient to block the ATP-sensitive potassium current had no effect. Atrial electrical remodeling was blocked by verapamil and accentuated by hypercalcemia. Biopsy specimens from controls subjected to rapid pacing showed mitochondrial swelling consistent with calcium overload. Biopsies from verapamil-treated animals were normal.

Conclusions
Atrial electrical remodeling develops quickly, is progressive, and may be persistent. Shifts in autonomic tone, atrial stretch, or depletion of high-energy phosphates do not contribute significantly to the phenomenon. Results of the study suggest that atrial electrical remodeling is mediated by rate-induced intracellular calcium overload.
Immunocytochemical Localization of rH1 Sodium Channel in Adult Rat Heart Atria and Ventricle
Authors: Cohen Sidney A.
Published: June 2012

Background
Of the five sodium channel subtypes expressed in cardiac tissues, the rat (rH1) and human (hH1) isoforms are thought to be the predominant subtypes on the basis of heterologous expression studies. In this study, subtype-specific antibodies and immunocytochemistry were used to confirm protein expression and to localize rH1 protein in cardiac tissues.

Methods and Results
Subtype-specific antibodies immunolabeled adult rat heart tissue in a manner identical to that obtained with subtype-nonselective antibodies. All antibodies specifically bound to the surface and t-tubular systems of atrial and ventricular muscle cells. Cytoplasmic labeling, reflecting nascent sodium channels or cytoplasmic stores of sodium channel protein, was apparent. Most notably, all antibodies also specifically labeled the subset of intercalated disks located at the ends but not the sides of adjacent ventricular muscle cells.

Conclusions
rH1 is the predominant subtype expressed on rat atrial and ventricular muscle cells. rH1 protein localization in surface and t-tubular membranes is consistent with its proposed role in coordinating membrane depolarization along the length and deep within cardiac muscle cells. rH1 protein localization in terminal intercalated disks suggests that sodium channels may also act as a localized voltage-dependent current amplifier, raising the safety margin for conduction; they also may contribute to anisotropic or saltatory conduction in cardiac tissues. These electrophysiological properties would be particularly important under conditions of altered channel function resulting from ion channel gene defects (eg, long QT syndrome), antiarrhythmic drug therapy, ischemia, or other heart diseases by influencing the electrophysiological substrate for ventricular tachyarrhythmias. (Circulation. 1996;94:3083-3086.)
Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test–Induced Dilations in Coronary Arteries of Hypertensive Patients
Authors: Antony Isabelle , Lerebours Guy , Nitenberg Alain
Published: June 2012

Background
Cold pressor test (CPT)–induced and flow-dependent epicardial coronary artery dilations are impaired in patients with hypertension. ACE inhibition can attenuate sympathetic coronary constriction and potentiate or restore endothelium-dependent relaxations. This study was designed to determine whether the ACE inhibitor perindoprilat can restore normal coronary dilative responses in hypertensive patients.

Methods and Results
Coronary vasomotor responses to CPT and to maximal increase of blood flow induced by papaverine were studied in 10 untreated patients with essential hypertension, no other risk factors, and angiographically normal coronary arteries before and after intravenous ACE inhibition by perindoprilat. Diameters of proximal and distal left anterior descending (LAD) and circumflex coronary arteries were measured by quantitative angiography. Estimates of coronary blood flow and resistance index were calculated with an intracoronary Doppler catheter in the distal LAD. Perindoprilat did not modify the hemodynamic responses to CPT and papaverine. In response to CPT, perindoprilat changed the epicardial coronary constriction (−8.4±5.8%,
P
<.001) into a significant dilation (+12.0±6.4%,
P
<.001). Perindoprilat significantly increased the coronary blood flow (from 33.7±10.0 to 57.9±20.5 mL/min,
P
<.01) and enhanced the decrease in coronary resistance (from 4.28±1.27 to 2.96±0.84 mm Hg·mL
−1
·min
−1
,
P
<.001) caused by CPT. Flow-dependent dilation of the proximal LAD was abolished in the control condition and was restored after perindoprilat (12.6±4.7%,
P
<.001).

Conclusions
ACE inhibition restored CPT-induced and flow-mediated coronary artery dilations in patients with essential hypertension. These results indicate that impaired coronary vasomotor responses may be reversible in recently diagnosed hypertension.
Decline of Coronary Heart Disease Mortality in Finland During 1983 to 1992: Roles of Incidence, Recurrence, and Case-Fatality
Authors: Salomaa V. , Miettinen H. , Kuulasmaa K. , Niemela¨ M. , Ketonen M. , Vuorenmaa T. , Lehto S. , Paloma¨ki P. , Ma¨ho¨nen M. , Immonen-Ra¨iha¨ P. , Arstila M. , Kaarsalo E. , Mustaniemi H. , Torppa J. , Tuomilehto J. , Puska P. , Pyo¨ra¨la¨ K.
Published: June 2012

Background
The rate of coronary heart disease (CHD) mortality in eastern Finland has been the highest in the world. The official mortality statistics suggest, however, that it has declined by 60% during the past 20 years. The aim of the present study was to examine the contributions of incidence, recurrence, and case fatality of coronary events to the trends in CHD mortality in three areas of Finland.

Methods and Results
Population-based myocardial infarction registers have been operating in the provinces of North Karelia and Kuopio in eastern Finland and the Turku/Loimaa area in southwestern Finland from 1983 to 1992. During this 10-year period, each suspected coronary event in persons 35 to 64 years of age was evaluated for registration. Of these, 13 566 fulfilled the criteria of myocardial infarction or coronary death. Almost one fourth (22.4%) of the coronary events were sudden, out-of-hospital deaths. Among men, the average change in mortality was −7.1% per year (95% confidence interval, −8.4% to −5.8%) in North Karelia, −5.0% per year (−7.0% to −3.0%) in Kuopio, and −4.9% per year (−8.2% to −1.6%) in Turku/Loimaa. Among women, the corresponding changes were −5.6% (−11.1% to −0.1%), −4.4% (−8.1% to −0.7%), and −8.1% (−13.0% to −3.2%). In eastern Finland, the decline in CHD mortality was due to a decline in recurrent coronary events but also in the incidence of first coronary events, whereas in southwestern Finland, the decline in case-fatality rate had the major role.

Conclusions
The decline in CHD mortality rate in Finland appears to be the result of a successful combination of primary and secondary prevention measures and improvements in acute coronary care.
Birth Weight and Adult Hypertension, Diabetes Mellitus, and Obesity in US Men
Authors: Curhan Gary C. , Willett Walter C. , Rimm Eric B. , Spiegelman Donna , Ascherio Alberto L. , Stampfer Meir J.
Published: June 2012

Background
Low birth weight has been associated with several chronic diseases in adults, including hypertension, diabetes mellitus, and obesity. Further study of these diseases in a large cohort with information on a wide variety of risk factors is essential to determine more precisely the risks associated with birth weight.

Methods and Results
We examined the relation between birth weight and cumulative incidence of adult hypertension, incidence of non–insulin-dependent diabetes mellitus, and prevalence of obesity in a cohort of 22 846 US men (Health Professionals Follow-up Study). Birth weights, medical histories, family histories, and other factors were collected by biennial mailed questionnaires. Logistic regression was used to examine the association between birth weight and these chronic adult diseases. Low birth weight was associated with an increased risk of hypertension and diabetes; high birth weight was associated with an increased risk of obesity. Compared with men in the referent birth weight category (7.0 to 8.4 lb), men who weighed <5.5 lb had an age-adjusted odds ratio for hypertension of 1.26 (95% confidence interval [CI], 1.11 to 1.44) and for diabetes mellitus of 1.75 (95% CI, 1.21 to 2.54). There was no material change after controlling for adult body mass index and parental histories of hypertension and diabetes mellitus. Compared with men in the referent group, the age-adjusted odds ratio of being in the highest versus the lowest quintile of adult body mass index for men with birth weight ≥10.0 lb was 2.08 (95% CI, 1.73 to 2.50).

Conclusions
These findings support the hypothesis that early life exposures, for which birth weight is a marker, are associated with several chronic diseases in adulthood.
Direct Intramuscular Gene Transfer of Naked DNA Encoding Vascular Endothelial Growth Factor Augments Collateral Development and Tissue Perfusion
Authors: Tsurumi Yukio , Takeshita Satoshi , Chen Dongfen , Kearney Marianne , Rossow Susan T. , Passeri Jonathan , Horowitz Jeffrey R. , Symes James F. , Isner Jeffrey M.
Published: June 2012

Background
Striated muscle has been shown to be capable of taking up and expressing foreign genes transferred in the form of naked plasmid DNA, although typically with a low level of gene expression. In the case of genes that encode secreted proteins, however, low transfection efficiency may not preclude bioactivity of the secreted gene product. Accordingly, we investigated the hypothesis that intramuscular (IM) gene therapy with naked plasmid DNA encoding vascular endothelial growth factor (VEGF) could augment collateral development and tissue perfusion in an animal model of hindlimb ischemia.

Methods and Results
Ten days after ischemia was induced in one rabbit hindlimb, 500 μg of phVEGF
165
, or the reporter gene
LacZ
, was injected IM into the ischemic hindlimb muscles. Thirty days later, angiographically recognizable collateral vessels and histologically identifiable capillaries were increased in VEGF transfectants compared with controls. This augmented vascularity improved perfusion to the ischemic limb, documented by a superior calf blood pressure ratio for phVEGF
165
(0.85±0.05) versus controls (0.64±0.05,
P
<.01), improved blood flow in the ischemic limb (measured with an intra-arterial Doppler wire) at rest (phVEGF
165
=21.3±3.9 mL/min, control=14.6±1.6 mL/min,
P
<.01) and after a vasodilator (phVEGF
165
=54.2±12.0 mL/min, control=37.3±8.9 mL/min,
P
<.01) and increased microspheres in the adductor (phVEGF
165
=4.3±1.6 mL·min
−1
·100 g of tissue
−1
, control=2.9±1.2 mL·min
−1
·100 g of tissue
−1
,
P
<.05) and gastrocnemius (phVEGF
165
=3.9±1.0 mL·min
−1
·100 g of tissue
−1
, control=2.8±1.4 mL·min
−1
·100 g of tissue
−1
,
P
<.05) muscles of the ischemic limb.

Conclusions
Ischemic skeletal muscle represents a promising target for gene therapy with naked plasmid DNA. IM transfection of genes encoding angiogenic cytokines, particularly those that are naturally secreted by intact cells, may constitute an alternative treatment strategy for patients with extensive peripheral vascular disease in whom the use of intravascular catheter–based gene transfer is compromised and/or prohibited.
Chronic Hypoxia Increases β
1
-Adrenergic Receptor mRNA and Density but Not Signaling in Neonatal Rat Cardiac Myocytes
Authors: Li Hong-Tai , Honbo Norman Y. , Karliner Joel S.
Published: June 2012

Background
It is well recognized that the β-adrenergic receptor–adenylylcyclase system is altered during myocardial ischemia/hypoxia. However, there are no data regarding either regulation of β-adrenergic receptors, particularly at the mRNA level, or adenylylcyclase activity in isolated cardiac myocytes exposed to chronic hypoxia.

Methods and Results
In a chronic hypoxia model in which neonatal rat ventricular myocytes were exposed to a 1% O
2
environment for 72 hours, we investigated (1) β
1
-mRNA and receptor expression and adenylylcyclase activity and (2) β
1
-mRNA and receptor downregulation and adenylylcyclase desensitization induced by prolonged norepinephrine incubation. We found that hypoxia for 72 hours increased myocardial membrane β
1
-adrenergic receptor density by 44%. This increase was not associated with a corresponding decrease in cytosolic β
1
-adrenergic receptors. RNase protection assays demonstrated that hypoxia increased the steady-state levels of β
1
-mRNA by 109%. Adenylylcyclase activity stimulated by isoproterenol, sodium fluoride, guanyl-5′-imidodiphosphate, and forskolin in hypoxic membranes was not altered compared with normoxic controls. Hypoxia for 72 hours also did not affect norepinephrine-induced β
1
-mRNA and receptor downregulation and adenylylcyclase desensitization in response to isoproterenol, guanyl-5′-imidodiphosphate, or forskolin.

Conclusions
In neonatal rat cardiac myocytes, chronic hypoxia (1) increases β
1
-mRNA and receptor expression but does not alter adenylylcyclase activity stimulated at either the receptor or the postreceptor level and (2) does not affect agonist-induced β
1
-mRNA and receptor downregulation and desensitization of the adenylylcyclase response.
Influence of HLA Matching on Thoracic Transplant Outcomes
Authors: Hosenpud Jeffrey D. , Edwards Erick B. , Lin Hung-Mo , Daily O. Patrick
Published: June 2012

Background
The benefit of matching donor organs and recipients for HLAs has been well established in renal transplantation and has been suggested for thoracic organ transplantation. To determine the effect of HLA matching in cardiac and single-lung transplantation, the following study was performed.

Methods and Results
Using the joint Thoracic Transplant Registry of the United Network for Organ Sharing and the International Society for Heart and Lung Transplantation, all adult primary heart and single-lung transplant procedures performed in the United States from October 1987 through December 1993 were analyzed to determine the effects of HLA matching on transplant mortality. Both total HLA matches and matches at individual HLA loci were considered. Including HLA matching, 16 potential risk factors for heart transplant outcome and 16 potential risk factors for lung transplant outcome were subjected to multivariate analysis. A total of 10 752 heart transplants and 1239 lung transplants were included in the independent analyses for each organ. For heart transplantation, there was a progressive reduction in risk for greater matching (1 or 2 matches: risk ratio, 0.83; 3 matches: risk ratio, 0.67; 4 to 6 matches: risk ratio, 0.59; all
P
≤.01). The primary benefit of matching appeared to be at the A and DR loci (risk ratios, 0.87 and 0.79, respectively;
P
<.001). For lung transplantation, any matching had an independent positive effect on outcome; however, the relationship between numbers of HLA matches and relative risk was not present and ranged from risk ratios of 0.71 to 0.87 (
P
=.01 and
P
=.47, respectively). In this analysis, only matching at the A locus appeared to statistically influence outcome (risk ratio, 0.76;
P
=.01).

Conclusions
These data demonstrate that HLA matching independently impacts survival in both heart and single-lung transplantation.
Nitric Oxide Activity Is Deficient in Spasm Arteries of Patients With Coronary Spastic Angina
Authors: Kugiyama Kiyotaka , Yasue Hirofumi , Okumura Ken , Ogawa Hisao , Fujimoto Kazuteru , Nakao Koichi , Yoshimura Michihiro , Motoyama Takeshi , Inobe Yoshito , Kawano Hiroaki
Published: June 2012

Background
Coronary spasm can be induced by acetylcholine, serotonin, ergonovine, or histamine, all of which cause vasodilation when the endothelium is intact by releasing nitric oxide (NO). Coronary spasm is promptly relieved by nitroglycerin, which vasodilates through its conversion to NO. It is thus possible that NO release may be deficient in the spasm arteries in patients with coronary spastic angina (CSA). The aim of this study was to determine whether NO release is deficient in coronary arteries of patients with CSA.

Methods and Results
N
G
-monomethyl-
l
-arginine (L-NMMA), an inhibitor of NO synthase, was infused into coronary arteries in 21 patients with coronary spastic angina (CSA) and in 28 control patients. Coronary spasm was induced by intracoronary injection of acetylcholine and was documented angiographically in all patients with CSA. L-NMMA dose-dependently decreased basal luminal diameter of coronary arteries in control patients, whereas it had no effect on basal diameter of the spasm arteries in patients with CSA. L-NMMA abolished the dilator response to acetylcholine and enhanced the constrictor response to acetylcholine in control arteries, whereas it had no effect on the constrictor response to acetylcholine in spasm arteries. Intracoronary infusion of
l
-arginine did not affect the diameter of spasm or control arteries. The dilator response to nitroglycerin was increased markedly in spasm arteries compared with control ar-teries, whereas response to diltiazem did not differ between them.

Conclusions
There is a deficiency in endothelial NO activity in spasm arteries, which leads to the supersensitivity of the artery to the vasodilator effect of nitroglycerin and to the vasoconstrictor effect of acetylcholine in patients with CSA. This deficient endothelial NO activity plays an important role in the pathogenesis of coronary spasm.
Apolipoprotein A-I and B Levels and the Risk of Ischemic Heart Disease During a Five-Year Follow-up of Men in the Que´bec Cardiovascular Study
Authors: Lamarche Benoiˆt , Moorjani Sital , Lupien Paul J. , Cantin Bernard , Bernard Paul-Marie , Dagenais Gilles R. , Despre´s Jean-Pierre
Published: June 2012

Background
Results obtained largely from case-control studies have suggested that an elevated plasma concentration of apolipoprotein (apo) B may be considered an important risk factor for ischemic heart disease (IHD). Prospective data on the relevance of measuring apo A-I and apo B levels in the assessment of IHD risk, however, remain sparse as well as controversial.

Methods and Results
Plasma lipid, apo B, and apo A-I levels as well as other risk factors were evaluated at baseline in 1985 in a sample of 2155 men (45 to 76 years old) who were followed for a period of 5 years for clinical signs of IHD. Proportional-hazards analyses indicated that plasma apo B concentrations measured at entry were strongly associated with onset of IHD (relative rate, 1.4; 95% confidence interval [CI], 1.2 to 1.7), independent of covariables such as age, smoking, diabetes mellitus, and systolic blood pressure. Controlling for triglycerides, HDL cholesterol, and total/HDL cholesterol ratio did not eliminate the relationship between plasma apo B levels and IHD. The association between apo A-I and IHD was of lower magnitude (relative rate, 0.85; 95% CI, 0.7 to 1.0), and adjustment for selected plasma lipid and lipoprotein levels eliminated this association. Stepwise logistic regression analysis revealed that, among metabolic variables, apo B was the strongest correlate of IHD.

Conclusions
These prospective results emphasize the importance of apo B as a risk factor for IHD. Apo B may be regarded as a relevant tool in the assessment of IHD risk in men, because it may provide information that would not be obtained from the conventional lipid-lipoprotein profile.
Only Hibernating Myocardium Invariably Shows Early Recovery After Coronary Revascularization
Authors: Shivalkar Bharati , Maes Alex , Borgers Marcel , Ausma Jannie , Scheys Ilse , Nuyts Johan , Mortelmans Luc , Flameng Willem
Published: June 2012

Background
The aims of this study were to identify hibernating myocardium (hypocontractile, hypoperfused viable myocardium that regains contractility after revascularization) in the clinical setting and to predict functional outcome in patients with coronary artery disease after coronary revascularization.

Methods and Results
Preoperative data related to the anterior free wall of the left ventricle were collected in 50 coronary bypass surgery candidates (positron emission tomography [PET], [
13
N]NH
3
for flow, and [
18
F]FDG for metabolism [MET]; equilibrium-gated nuclear angiography [EGNA] for regional ejection fraction [REF]; and histological data from myocardial biopsies for percentage fibrosis and viable myocytes). Three months after surgery, the patients had follow-up PET and EGNA investigations. A principal-components analysis identified four patient clusters. Cluster 1 (n=9) had normal viable myocardium. Cluster 2 (n=18) had viable hypocontractile myocardium (REF, 39±12%) showing a PET mismatch pattern. Cluster 3 (n=16) had viable hypocontractile myocardium associated with morphological myocyte injury showing a matched moderate decrease in flow (66±11%) and MET (70±11%). Cluster 4 (n=7) had hypocontractile myocardium with mainly scar tissue (fibro-sis, 74±12%). After surgery, only cluster 2, with hibernating myocardium, showed significant improvement in REF (from 39±12% to 50±13%,
P
<.05). Cluster 3, with sites of morphological myocyte injury, showed no recovery. The stepwise logistic regression showed a combination of low preoperative REF and high MET to be the best predictor of functional recovery (
P
<.008).

Conclusions
Multivariate analysis identifies hibernating myocardium showing early postrevascularization recovery, as opposed to viable but myolytic myocardium with no early recovery. Postrevascularization recovery can be predicted (combination of low REF and high MET) by noninvasive techniques.
Endothelin and Calcium Antagonists in the Skin Microcirculation of Patients With Coronary Artery Disease
Authors: Wenzel Rene´ R. , Duthiers Nadine , Noll Georg , Bucher Julia , Kaufmann Urs , Lu¨scher Thomas F.
Published: June 2012

Background
Endothelin, a potent endothelium-derived vasoconstrictor peptide, is elevated in coronary artery disease (CAD); however, its pathophysiological role is uncertain. Calcium antagonists are widely used in patients with CAD. Using laser Doppler flowmetry, we investigated the influence of two endothelin antagonists and the calcium antagonist diltiazem on endogenous and exogenous endothelin in the skin microcirculation of CAD patients and healthy control subjects.

Methods and Results
Both endothelin antagonists and diltiazem applied intradermally induced vasodilation in CAD patients, which was more pronounced with the ET
A
/ET
B
antagonist than with the ET
A
antagonist or diltiazem. Exogenous endothelin led to profound vasoconstriction in CAD patients and healthy volunteers. Both endothelin antagonists and diltiazem blunted the vasoconstriction to exogenous endothelin in CAD patients and young healthy volunteers and less so in old healthy volunteers. However, compared with both endothelin antagonists, a 10-times-higher dose of diltiazem was required. Systemic diltiazem (240 mg, slow release) attenuated endothelin-induced vasoconstriction in CAD patients. Neurogenic vasodilation to exogenous endothelin was inhibited by both endothelin antagonists.

Conclusions
This study demonstrates that endogenous endothelin of CAD patients contributes to the regulation of vascular tone in the skin microcirculation not only through ET
A
receptors but also possibly through ET
B
receptors. Diltiazem inhibited endothelin-induced vasoconstriction, but endothelin antagonists were slightly more effective. Thus, endothelin antagonists represent potent new tools to interfere with the vascular effects of endothelin in CAD patients. Future studies must confirm these findings in other areas of the circulation.
Predictors of Atrial Fibrillation After Coronary Artery Surgery
Authors: Aranki Sary F. , Shaw David P. , Adams David H. , Rizzo Robert J. , Couper Gregory S. , VanderVliet Martha , Collins John J. , Cohn Lawrence H. , Burstin Helen R.
Published: June 2012

Background
Atrial fibrillation (AF) after coronary artery bypass surgery (CABG) is the most common sustained arrhythmia. Its pathophysiology is unclear, and its prevention and management remain suboptimal. The aim of this prospective study was to determine the current incidence of AF, identify its clinical predictors, and examine its impact on resource utilization.

Methods and Results
Over a 12-month period ending July 31, 1994, a CABG procedure was performed on 570 consecutive patients (age range, 32 to 87 years; median age, 67 years; 232 [41%] were ≥70 years; 175 [31%] were women; 173 [30%] were diabetics; 364 [65%] required nonelective surgery; 86 [15%] had had a prior CABG; and 86 [15%] had had prior percutaneous transluminal coronary angioplasty). AF occurred in 189 patients (33%). The median age for patients with AF was 71 years compared with 66 for patients without (
P
=.0001). Multivariate logistic regression analysis (odds ratio, ±95% CI,
P
value) was used to identify the following independent predictors of postoperative AF: increasing age (age 70 to 80 years [OR=2; CI, 1.3 to 3;
P
=.002], age >80 years [OR=3; CI, 1.6 to 5.8;
P
=.0007]), male gender (OR=1.7; CI, 1.1 to 2.7;
P
=.01), hypertension (OR=1.6; CI, 1.0 to 2.3;
P
=.03), need for an intraoperative intra-aortic balloon pump (OR=3.5; CI, 1.2 to 10.9;
P
=.03), postoperative pneumonia (OR=3.9; CI, 1.3 to 11.5;
P
=.01), ventilation for >24 hours (OR=2; CI, 1.3 to 3.2;
P
=.003), and return to the intensive care unit (OR=3.2; CI, 1.1 to 8.8;
P
=.03). The mean length of hospital stay after surgery was 15.3±28.6 days for patients with AF compared with 9.3±19.6 days for patients without AF (
P
=.001). The adjusted length of hospital stay attributable to AF was 4.9 days, corresponding to ≥$10 055 in hospital charges.

Conclusions
AF remains the most common complication after CABG and consequently is a drain on hospital resources. Concerted efforts to reduce the incidence of AF and the associated increased length of stay would result in substantial cost savings and decrease patient morbidity.
Extent of Clinical Improvement After Surgical Treatment of Hypertrophic Obstructive Cardiomyopathy
Authors: McCully Robert B. , Nishimura Rick A. , Tajik A. Jamil , Schaff Hartzell V. , Danielson Gordon K.
Published: June 2012

Background
A subgroup of patients with hypertrophic obstructive cardiomyopathy remain severely symptomatic despite optimal medical therapy. Septal myectomy reduces or eliminates left ventricular outflow obstruction and produces marked symptomatic improvement. With the recent advent of alternative methods for treatment of this disorder, such as dual-chamber pacing, it is necessary to establish the risks and benefits of septal myectomy in the modern surgical era.

Methods and Results
The clinical, ECG, echocardiographic, cardiac catheterization, and surgical data were analyzed for 65 patients 20 to 70 years old with hypertrophic obstructive cardiomyopathy who had surgical treatment between 1986 and 1992. Specific symptoms and overall functional status were evaluated before surgery and at the end of the first postoperative year. Subsequent long-term clinical postoperative follow-up was also obtained. The extent of postoperative improvement was measured by the presence and severity of persistent symptoms, overall New York Heart Association (NYHA) functional class, and patients' self-perceptions of overall improvement. Of the patients, 95% were in NYHA functional class III or IV before surgery: 95% had dyspnea, 62% had angina, 63% had near-syncope, and 23% had syncope. The overall early mortality rate was 4.6%; there was no mortality among the 45 patients who underwent isolated septal myectomy. At the 1-year postoperative evaluation, 89% of survivors were in NYHA functional class I or II, and 47% believed that they had 100% improvement. Significant improvement (as defined) was seen in 67% of patients with dyspnea, 90% with angina, 86% with near-syncope, and 100% with syncope. The 5-year survival rate was 92%.

Conclusions
The results of the present study reaffirm the efficacy of surgical treatment of hypertrophic obstructive cardiomyopathy in patients who are severely symptomatic despite optimal medical therapy and serve as a useful reference by which the surgical approach can be compared with new and potentially promising treatment alternatives.
Prospective Study of Oral Contraceptives and Hypertension Among Women in the United States
Authors: Chasan-Taber Lisa , Willett Walter C. , Manson JoAnn E. , Spiegelman Donna , Hunter David J. , Curhan Gary , Colditz Graham A. , Stampfer Meir J.
Published: June 2012

Background
Oral contraceptives induce hypertension in approximately 5% of users of high-dose pills that contain at least 50 μg estrogen and 1 to 4 mg progestin, and small increases in blood pressure have been reported even among users of modern low-dose formulations. However, neither the responsible hormone in the oral contraceptive nor particular subgroups of women who might be susceptible to the hypertensive effect of oral contraceptives have been identified.

Methods and Results
In a prospective cohort study in the United States, 68 297 female nurses aged 25 to 42 years and free of diagnosed hypertension, diabetes, coronary heart disease, stroke, and cancer at baseline were followed up for 4 years. During 231 006 person-years of follow-up, 1567 incident cases of hypertension were diagnosed. Compared with women who had never used oral contraceptives, the age-adjusted relative risk was 1.5 (95% CI=1.2 to 1.8) for current use and 1.1 (95% CI=0.9 to 1.2) for past use. After adjustment for age, body mass index, cigarette smoking, family history of hypertension, parity, physical activity, alcohol intake, and ethnicity, current users of oral contraceptives had an increased risk of development of hypertension (RR=1.8; 95% CI=1.5 to 2.3) compared with women who had never used them. The multivariate relative risk for past users was 1.2 (95% CI=1.0 to 1.4). There were no important modifying effects of age, family history of hypertension, ethnicity, or body mass index.

Conclusions
Current users of oral contraceptives had a significant, moderately increased risk of hypertension. However, among this group, only 41.5 cases per 10 000 person-years could be attributed to oral contraceptive use. Risk decreased quickly with cessation of oral contraceptives, and past users appeared to have only a slightly increased risk.
Local Venous Responses to Endotoxin in Humans
Authors: Bhagat Kiran , Collier Joe , Vallance Patrick
Published: June 2012

Background
Septic shock is characterized by arterial and venous dilatation and decreased responsiveness to vasoconstrictors. We have developed a method to explore the effects and mechanisms of action of administration of endotoxin into a blood vessel in vivo.

Methods and Results
Endotoxin was instilled into a dorsal hand vein for 1 hour and then removed. A dose-response curve to norepinephrine was constructed before and 1, 2, 3, and 4 hours after endotoxin. In a separate study, dose-response curves to norepinephrine were constructed in two separate veins on the same hand, only one of which received endotoxin. Sympathetic-mediated venoconstrictor responses were also studied. Cyclooxygenase inhibitors, nitric oxide synthase inhibitors, and hydrocortisone were used to explore the mechanisms of the effects seen. Endotoxin caused a rightward shift in the dose-response curve to norepinephrine. The effect was greatest at 1 hour (maximal constriction: before endotoxin, 87±4%; after endotoxin, 52±8%; n=4;
P
<.05) and returned to normal by 4 hours. In addition, deep-breath venoconstrictor responses were abolished in the endotoxin-treated vein. Instillation of endotoxin daily for 3 days resulted in the development of tolerance (maximal constriction to norepinephrine after endotoxin: day 1, 39±6%; day 2, 67±7%; day 3, 85±7%). Cyclooxygenase and/or nitric oxide synthase inhibitors did not alter the response to endotoxin, whereas prior administration of hydrocortisone abolished the effects.

Conclusions
Instillation of endotoxin caused a glucocorticoid-inhibitable hyporesponsiveness to the constrictor effects of norepinephrine and abolished sympathetically induced and drug-induced venoconstriction. This acute response does not appear to be mediated by nitric oxide or prostanoids. Direct vascular tolerance to endotoxin occurs on repeated administration.
Atrioventricular Junctional Tissue
Authors: McGuire Mark A. , de Bakker Jacques M.T. , Vermeulen Jessica T. , Moorman Antoon F.M. , Loh Peter , Thibault Bernard , Vermeulen Jacqueline L.M. , Becker Anton E. , Janse Michiel J.
Published: June 2012

Background
Previous work has demonstrated that cells with AV nodal-type action potentials are not confined to Koch's triangle but may extend along the AV orifices. The aim of this study was to examine the histological and electrophysiological characteristics of this tissue.

Methods and Results
Studies were performed in isolated, blood-perfused dog and pig hearts. Microelectrode recordings revealed cells with nodal-type action potentials around the tricuspid and mitral valve rings. These cells were found within 1 to 2 mm of the valve annuli. A zone of cells with intermediate action potentials, ≈1 cm wide, separated cells with nodal-type action potentials from cells with atrial-type action potentials in the body of the atria. In cells with nodal-type action potentials, adenosine caused a reduction in action potential amplitude (49±2 versus 33±2 mV, mean±SE;
P
<.001), upstroke velocity (2.5±0.2 versus 2.0±0.2 V/s,
P
<.05), and duration (150±4 versus 96±8 ms,
P
<.001). The light microscopic appearance of AV junctional cells was similar to that of myocytes in the body of the atrium. A polyclonal antibody raised against connexin-43 bound to atrial and ventricular tissue but not to the AV junctional tissue or AV nodal region. The absence of connexin-43 correlated with the sites of cells with nodal-like action potentials. With pacing techniques, the AV junctional tissue in the region of the posterior AV nodal approaches could be electrically dissociated from atrial, AV nodal, and ventricular tissue. AV nodal echoes were induced with ventricular pacing in three dog hearts. In each case, retrograde conduction was through the slow pathway, and anterograde conduction was through the fast pathway. During echoes, activation of AV junctional cells preceded atrial activation during retrograde slow pathway conduction, but these cells were not activated during anterograde fast pathway conduction.

Conclusions
AV junctional cells around both annuli are histologically similar to atrial cells but resemble nodal cells in their cellular electrophysiology, response to adenosine, and lack of connexin-43. The light microscopic appearance of AV junctional cells is a poor guide to their action potential characteristics. The AV junctional cells in the posterior AV nodal approaches appear to participate in slow pathway conduction. These cells may be the substrate of the slow “AV nodal” pathway.
Economic Assessment of Platelet Glycoprotein IIb/IIIa Inhibition for Prevention of Ischemic Complications of High-Risk Coronary Angioplasty
Authors: Mark Daniel B. , Talley J. David , Topol Eric J. , Bowman Lee , Lam Lai Choi , Anderson Keaven M. , Jollis James G. , Cleman Michael W. , Lee Kerry L. , Aversano Thomas , Untereker William J. , Davidson-Ray Linda , Califf Robert M.
Published: June 2012

Background
In the EPIC trial, c7E3 Fab, an antiplatelet IIb/IIIa receptor antibody, reduced 30-day ischemic end points after high-risk coronary angioplasty by 35% and 6-month ischemic events by 23% but increased in-hospital bleeding episodes.

Methods and Results
Of the 2099 patients randomized in EPIC, data were collected on 2038 (97%) for prospective hospital cost and major resources. Physician fees were estimated from the Medicare Fee Schedule. Regression analysis was used to examine the economic tradeoff between reduced ischemic events and increased major bleeding during the initial hospitalization. A potential cost savings of $622 per patient during the initial hospitalization from reduced acute ischemic events with c7E3 Fab was offset by an equivalent rise ($521) in costs as the result of an increase in bleeding episodes. Baseline medical costs for the bolus and infusion c7E3 Fab arm averaged $13 577 (exclusive of drug cost) compared with $13 434 for placebo (
P
=.42). During the 6-month follow-up, c7E3 Fab decreased repeat hospitalization rates by 23% (
P
=.004) and repeat revascularization by 22% (
P
=.04), producing a mean $1270 savings per patient (exclusive of drug cost) (
P
=.018). With a cost of $1407 for the bolus and infusion c7E3 Fab regimen, the cumulative net 6-month cost to switch from standard care to routine c7E3 Fab averaged $293 per patient.

Conclusions
In high-risk coronary angioplasty, aggressive platelet inhibition with c7E3 Fab, by significantly reducing ischemic events and repeat revascularization, recoups most of the cost of therapy and has the potential to pay for itself.