bluuebunny/crossref_metadata_2025 huggingface dataset:
Vagal and Sympathetic Mechanisms in Patients With Orthostatic Vasovagal Syncope
Authors: Morillo Carlos A. , Eckberg Dwain L. , Ellenbogen Kenneth A. , Beightol Larry A. , Hoag Jeffrey B. , Tahvanainen Kari U.O. , Kuusela Tom A. , Diedrich André M.
Published: June 2012

Background
Autonomic and particularly sympathetic mechanisms play a central role in the pathophysiology of vasovagal syncope. We report direct measurements of muscle sympathetic nerve activity in patients with orthostatic vasovagal syncope.

Methods and Results
We studied 53 otherwise healthy patients with orthostatic syncope. We measured RR intervals and finger arterial pressures and in 15 patients, peroneal nerve muscle sympathetic activity before and during passive 60 degree head-up tilt, with low-dose intravenous isoproterenol if presyncope did not develop by 15 minutes. We measured baroreflex gain before tilt with regression of RR intervals or sympathetic bursts on systolic or diastolic pressures after sequential injections of nitroprusside and phenylephrine. Orthostatic vasovagal reactions occurred in 21 patients, including 7 microneurography patients. Presyncopal and nonsyncopal patients had similar baseline RR intervals, arterial pressure, and muscle sympathetic nerve activity. Vagal baroreflex responses were significantly impaired at arterial pressures below (but not above) baseline levels in presyncopal patients. Initial responses to tilt were comparable; however, during the final 200 seconds of tilt, presyncopal patients had lower RR intervals and diastolic pressures than nonsyncopal patients and gradual reduction of arterial pressure and sympathetic activity. Frank presyncope began abruptly with precipitous reduction of arterial pressure, disappearance of muscle sympathetic nerve activity, and RR interval lengthening.

Conclusions
Patients with orthostatic vasovagal reactions have impaired vagal baroreflex responses to arterial pressure changes below resting levels but normal initial responses to upright tilt. Subtle vasovagal physiology begins before overt presyncope. The final trigger of human orthostatic vasovagal reactions appears to be the abrupt disappearance of muscle sympathetic nerve activity.
Effects of Diet and Sexual Maturation on Low-Density Lipoprotein Cholesterol During Puberty
Authors: Kwiterovich Peter O. , Barton Bruce A. , McMahon Robert P. , Obarzanek Eva , Hunsberger Sally , Simons-Morton Denise , Kimm Sue Y. S. , Friedman Lisa Aronson , Lasser Norman , Robson Alan , Lauer Ronald , Stevens Victor , Van Horn Linda , Gidding Samuel , Snetselaar Linda , Hartmuller Virginia W. , Greenlick Merwyn , Franklin Frank
Published: June 2012

Background
The Dietary Intervention Study in Children (DISC) is a multicenter, randomized, controlled clinical trial designed to examine the efficacy and safety of a dietary intervention to reduce serum LDL cholesterol (LDL-C) in children with elevated LDL-C.

Methods and Results
The effects of dietary intake of fat and cholesterol and of sexual maturation and body mass index (BMI) on LDL-C were examined in a 3-year longitudinal study of 663 boys and girls (age 8 to 10 years at baseline) with elevated LDL-C levels. Multiple linear regression was used to predict LDL-C at 3 years. For boys, LDL-C decreased by 0.018 mmol/L for each 10 mg/4.2 MJ decrease in dietary cholesterol (
P
<.05). For girls, no single nutrient was significant in the model, but a treatment group effect was evident (
P
<.05). In both sexes, BMI at 3 years and LDL-C at baseline were significant and positive predictors of LDL-C levels. In boys, the average LDL-C level was 0.603 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (
P
<.01). In girls, the average LDL-C level was 0.274 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (
P
<.05).

Conclusions
In pubertal children, sexual maturation, BMI, dietary intervention (in girls), and dietary cholesterol (in boys) were significant in determining LDL-C. Sexual maturation was the factor associated with the greatest difference in LDL-C. Clinicians screening for dyslipidemia or following dyslipidemic children should be aware of the powerful effects of pubertal change on measurements of lipoproteins.
β-Adrenergic Augmentation of Flecainide-Induced Conduction Slowing in Canine Purkinje Fibers
Authors: Cragun Kevin T. , Johnson Susan B. , Packer Douglas L.
Published: June 2012

Background
This study was undertaken to test the hypothesis that β-adrenergic stimulation in the setting of membrane depolarization will potentiate flecainide-induced conduction slowing.

Methods and Results
To elucidate the potential mechanism for the flecainide proarrhythmia observed in CAST, the voltage dependence of β-adrenergic modulation of impulse propagation in eight flecainide-superfused canine Purkinje fibers was examined with a dual-microelectrode technique. At physiological membrane potentials (V
m
) ([K
+
]
o
=5.4 μmol), 1 μmol flecainide decreased V̇
max
from 698±55 to 610±72 V/s (
P
=.003) and squared conduction velocity (θ
2
) from 2.11±1.1 to 1.72±0.9 (m/s)
2
(
P
=.001). With K
+
depolarization to V
m
=−70 mV, flecainide further reduced V̇
max
from 306±101 to 245±65 V/s and θ
2
from 1.12±0.4 to 0.99±0.6 (m/s)
2
, producing a 2.0-mV hyperpolarizing shift of apparent Na
+
channel availability curves derived from θ
2
. The addition of 1 μmol isoproterenol to flecainide-superfused fibers at physiological V
m
increased θ
2
by 8% to 1.84±0.6 (m/s)
2
(
P
<.01) without altering V̇
max
. At −70 mV, the addition of isoproterenol magnified the flecainide-induced reduction of V̇
max
an additional 24% to 185±52 V/s (
P
<.01) and θ
2
by 17% to 0.82±0.5 (m/s)
2
(
P
=.04), producing an additional 1.8-mV (
P
=.002) and 1.9-mV (
P
=.002) hyperpolarizing shift in the apparent Na
+
channel inactivation curves generated from V̇
max
and θ
2
, respectively. At physiological V
m
, the action potential duration (APD
95
) was reduced from 307±35 to 269±27 ms (
P
<.001) by flecainide and subsequently to 217±4 ms (
P
<.001) with isoproterenol addition. With 12 mmol/L K
+
, APD
95
decreased from 198±23 to 182±17 ms (
P
=.005) with flecainide and to 164±10 ms (
P
=.004) with isoproterenol.

Conclusions
At depolarized V
m
, isoproterenol amplified the flecainide-induced reduction of V̇
max
and θ
2
, suggesting a further adrenergic-mediated reduction of Na
+
current. Consequently, the synergy between catecholamines and flecainide at depolarized V
m
and the shortened APD
95
could facilitate arrhythmogenesis in the presence of underlying ischemia.
Circulating Cardiac Troponin I in Severe Congestive Heart Failure
Authors: Missov Emile , Calzolari Charles , Pau Bernard
Published: June 2012

Background
Spontaneous progression of severe congestive heart failure is structurally characterized by cellular degeneration and multiple foci of myocardial cell death. The cardiac muscle isoform of troponin I is uniquely expressed in the adult human myocardium, and an increase in its circulating levels is highly indicative of myocardial injury. Accordingly, we addressed the usefulness of cardiac troponin I as a sensitive and specific molecular marker of congestive heart failure in patients with severely reduced left ventricular performance.

Methods and Results
A new generation single-step immunoenzymoluminometric assay with high analytical sensitivity was used to assess cardiac troponin I in patients with severe congestive heart failure, healthy blood donors, and hospitalized control subjects without known cardiac disease. The cardiac troponin I concentration (mean±SEM) was 72.1±15.8 pg/mL in heart failure patients and 20.4±3.2 and 36.5±5.5 pg/mL in healthy and hospitalized control subjects, respectively (
P
<.01 versus heart failure patients). When both control groups were considered, the mean cardiac troponin I level was 25.4±2.9 pg/mL (
P
<.01 versus heart failure patients). Creatine kinase MB mass and myoglobin concentrations remained within the normal range in all groups.

Conclusions
These data (1) provide the first evidence for ongoing myofibrillar degradation and increased cardiac troponin I levels in patients with advanced heart failure and (2) show potential usefulness of cardiac troponin I as a specific and sensitive new serum marker molecule in severe congestive heart failure.
Effects of Different Atrial Pacing Modes on Atrial Electrophysiology
Authors: Yu Wen-Chung , Chen Shih-Ann , Tai Ching-Tai , Feng An-Ning , Chang Mau-Song
Published: June 2012

Background
Multiple-site atrial pacing has been shown to prevent recurrence of atrial fibrillation. However, information about the mechanisms of different atrial pacing modes in prevention of atrial fibrillation was not clear.

Methods and Results
Forty-two patients without structural heart disease were classified into group 1 and group 2 according to absence or presence of clinical atrial fibrillation, respectively. Atrial conduction time and electrogram width of the right posterior interatrial septum (RPS) were measured during drive-train stimulation (S1) and early extrastimulation (S2). The locations of S1 were the high right atrium (HRA), distal coronary sinus (DCS), or both sites simultaneously. Effective refractory periods (ERPs) of the HRA and DCS were also determined during S1 stimulation at each site and during biatrial pacing. The ERPs were not different between single-site atrial pacing and biatrial pacing. In contrast, early S2 stimulation at the HRA caused greater atrial conduction delay and greater increment of electrogram width of the RPS in patients with a history of atrial fibrillation. Biatrial pacing significantly reduced the conduction delay and electrogram width of the RPS caused by HRA extrastimulation. In addition, in 17 group 2 patients, atrial fibrillation was induced by an early HRA S2 coupled to HRA pacing. However, with the same coupling interval of S2 at HRA, only 6 of them had the arrhythmia induced during biatrial pacing. Furthermore, conduction delay and increase of electrogram width caused by early S2 at the HRA were reduced by biatrial pacing only in patients whose arrhythmia induction was successfully prevented by biatrial pacing.

Conclusions
Biatrial pacing reduced both the atrial conduction delay and increase of electrogram width at the RPS caused by early S2 at HRA, and these effects could prevent induction of atrial fibrillation.
Composition of Human Thrombus Assessed by Quantitative Colorimetric Angioscopic Analysis
Authors: Lehmann Kenneth G. , van Suylen Robert J. , Stibbe Jeane , Slager Cornelis J. , Oomen Jan A. , Maas Arthur , di Mario Carlo , deFeyter Pim , Serruys Patrick W.
Published: June 2012

Background
Angioscopy surpasses other diagnostic tools, such as angiography and intravascular ultrasound, in detecting arterial thrombus. This capability arises in part from the unique ability of angioscopy to assess true color during imaging. In practice, hardware-induced chromatic distortions and the subjectivity of human color perception substantially limit the theoretic potential of angioscopic color. We used a novel application of tristimulus colorimetry to quantify thrombus color to both aid in its detection and assess its composition.

Methods and Results
A series of human thrombus models were constructed in vitro. Spatial homogeneity was ensured by light and electron microscopy. Quantitative colorimetric angioscopic analysis demonstrated excellent measurement reproducibility (mean difference, 0.07% to 0.17%), unaffected by illuminating light intensity (coefficient of variation, 0.21% to 3.67%). Colorimetric parameters C
1
and C
2
were strongly correlated (
r
=.99,
P
<.0001) with thrombus erythrocyte concentration. Principal components analysis transformed these parameters into a single value, the thrombus erythrocyte index, with little (0.06%) loss of content. Measured and predicted concentrations were similar (mean difference, 0.16 erythrocytes per 1 ng). Randomly ordered images were also subjected to visual analysis by three experienced angioscopists, with suboptimal levels of both intraobserver (mean κ=0.63) and interobserver (mean κ=0.48) agreement. In addition, visual ranking resulted in a Kendall rank coefficient of 0.72 to 0.76 versus a perfect 1.00 from quantitative measurement.

Conclusions
Quantitative colorimetric angioscopic analysis provides a new, objective, and reproducible analytic tool for assessing angioscopic images of human thrombus. Even under ideal circumstances, experienced angioscopists do a poor job of assessing color (and therefore composition) of human thrombi. This technique can, for the first time, provide quantitative information of thrombus composition during routine diagnostic imaging.
Vasculoprotective Role of Inducible Nitric Oxide Synthase at Inflammatory Coronary Lesions Induced by Chronic Treatment With Interleukin-1β in Pigs in Vivo
Authors: Fukumoto Yoshihiro , Shimokawa Hiroaki , Kozai Toshiyuki , Kadokami Toshiaki , Kuwata Kouichi , Yonemitsu Yoshikazu , Kuga Takeshi , Egashira Kensuke , Sueishi Katsuo , Takeshita Akira
Published: June 2012

Background
We recently developed a porcine model in which chronic, local treatment with interleukin-1β (IL-1β) causes coronary arteriosclerotic changes and hyperconstrictive responses. Inflammatory cytokines are known to induce inducible NO synthase (iNOS) in the vascular smooth muscle. This study was designed to examine whether or not the production of NO by iNOS has a protective or deleterious effect on the coronary artery in vivo.

Methods and Results
A segment of the porcine coronary artery was aseptically wrapped with cotton mesh absorbing IL-1β suspension. We inhibited both eNOS and iNOS activity by cotreatment with L-NAME (a nonspecific inhibitor of NOS) and iNOS activity alone by aminoguanidine (a selective inhibitor of iNOS). Immunostaining showed that iNOS was absent in the normal coronary artery, whereas it was highly expressed 1 day after the application of IL-1β and thereafter downregulated until 14 days. In contrast, eNOS was well maintained throughout the study period. Two weeks after the operation, hyperconstrictive responses to intracoronary serotonin and neointimal formation were noted at the IL-1β–treated site, and both responses were significantly greater at the site cotreated with either L-NAME or aminoguanidine.

Conclusions
These results indicate that iNOS is transiently induced in vivo in response to local inflammation and that NO produced by iNOS exerts an inhibitory effect against the cytokine-induced proliferative/vasospastic changes of the coronary artery in vivo.
Long-term ACE Inhibition Doubles Lifespan of Hypertensive Rats
Authors: Linz Wolfgang , Jessen Timm , Becker Reinhard H. A. , Schölkens Bernward A. , Wiemer Gabriele
Published: June 2012

Background
We compared the outcome of lifelong treatment with the ACE inhibitor ramipril in young prehypertensive stroke-prone spontaneously hypertensive rats (SHR-SP) and age-matched normotensive Wistar-Kyoto (WKY) rats. Ramipril was given in an antihypertensive and subantihypertensive dose. In addition to the primary end point, lifespan, surrogate parameters such as cardiac left ventricular hypertrophy, cardiac function and metabolism, and endothelial function were studied.

Methods and Results
One-month-old SHR-SP and WKY rats, 135 of each, were randomized into 3 groups. Each group was treated via drinking water with an antihypertensive high dose of ramipril (HRA, 1 mg · kg
−1
· d
−1
), a nonantihypertensive low dose of ramipril (LRA, 10 μg · kg
−1
· d
−1
), or placebo. Body weight and blood pressure were determined every 3 months. Molecular, biochemical, and functional data were assessed in SHR-SP and WKY rats after 15 and 30 months, respectively. These were the times when ≈80% of the corresponding placebo group had died. Early-onset long-term ACE inhibition with HRA doubled lifespan to 30 months in SHR-SP, which was identical to the lifespan of placebo-treated normotensive WKY rats. LRA treatment prolonged lifespan from 15 to 18 months. In SHR-SP, left ventricular hypertrophy was completely prevented by HRA but not by LRA treatment. Cardiac function and metabolism as well as endothelial function were significantly improved by both doses of ramipril. Carotid expression of endothelial NO synthase was moderately enhanced, whereas cardiac ACE expression and activity were decreased to values of placebo-treated WKY rats.

Conclusions
Lifelong ACE inhibition doubles lifespan in SHR-SP, matching that of normotensive WKY rats. This effect correlated with preservation of endothelial function, cardiac function/size, and metabolism. Thus, these data predict a beneficial outcome on survival in high-risk patients with hypertension and associated cardiovascular diseases by ACE inhibition.
Prognostic Significance of Serial Changes in Left Ventricular Mass in Essential Hypertension
Authors: Verdecchia Paolo , Schillaci Giuseppe , Borgioni Claudia , Ciucci Antonella , Gattobigio Roberto , Zampi Ivano , Reboldi Gianpaolo , Porcellati Carlo
Published: June 2012

Background
—Increased left ventricular (LV) mass predicts an adverse outcome in patients with essential hypertension. The purpose of this study was to determine the relation between changes in LV mass during antihypertensive treatment and subsequent prognosis.

Methods and Results
—Procedures including echocardiography and 24-hour ambulatory blood pressure (BP) monitoring were performed in 430 patients with essential hypertension before therapy and after 1217 patient-years. Months or years after the follow-up visit, 31 patients suffered a first cardiovascular morbid event. The patients with a decrease in LV mass from the baseline to follow-up visit were compared with those with an increase in LV mass. There were 15 events (1.78 per 100 person-years) in the group with a decrease in LV mass and 16 events (3.03 per 100 person-years) in the group with an increase in LV mass (
P
=.029). In a Cox model, the lesser cardiovascular risk in the group with a decrease in LV mass (hazard ratio [HR], 0.46; 95% CI, 0.22 to 0.99) remained significant (
P
=.04) after adjustment for age (HR, 1.06; 95% CI, 1.03 to 1.10;
P
=.0008) and baseline LVH at ECG (HR, 3.85; 95% CI, 1.52 to 9.78;
P
=.012). In that model, baseline LV mass bordered on statistical significance (HR, 1.01; 95% CI, 1.00 to 1.03;
P
=.06). In the subset with LV mass >125 g/m

2

at the baseline visit (26% of subjects), the event rate was lower among the subjects who achieved regression of LVH than in those who did not (1.58 versus 6.27 events per 100 person-years;
P
=.002). This difference held in the multivariate analysis (HR, 0.18; 95% CI, 0.05 to 0.68).

Conclusions
—In essential hypertension, a reduction in LV mass during treatment is a favorable prognostic marker that predicts a lesser risk for subsequent cardiovascular morbid events. Such an association is independent of baseline LV mass, baseline clinic and ambulatory BP, and degree of BP reduction.
Increased Expression of Membrane-Type Matrix Metalloproteinase and Preferential Localization of Matrix Metalloproteinase-2 to the Neointima of Balloon-Injured Rat Carotid Arteries
Authors: Jenkins G. Mark , Crow Michael T. , Bilato Claudio , Gluzband Yehezkiel , Ryu Wang-Seong , Li Zhihe , Stetler-Stevenson William , Nater Cynthia , Froehlich Jeffrey P. , Lakatta Edward G. , Cheng Linda
Published: June 2012

Background
—Remodeling of the injured vascular wall is dependent on the action of several extracellular proteases. Previous studies have shown that expression of matrix metalloproteinases (MMP-2 and MMP-9) is upregulated after vascular injury and that MMP-2 is required for the migration of cultured vascular smooth muscle cells across complex extracellular matrix barriers. The present study examined changes in the expression of membrane-type metalloproteinase (MT–MMP-1), a putative regulator of MMP-2, in the tissue localization of MMP-2, and in the expression of activated and latent forms of MMP-2 and the tissue inhibitor of metalloproteinases, TIMP-2, in rat carotid arteries subjected to balloon catheter injury.

Methods and Results
—MT–MMP-1 mRNA levels increased sixfold after 3 days of injury, coinciding with an increase in MMP-2 activation assessed by gelatin zymography. Western blotting and gelatin zymography showed an increase in MMP-2 protein levels beginning 5 to 7 days after injury; immunocytochemistry and Western blotting showed that the increase occurred preferentially in the developing neointima.

Conclusions
—These results show that increased expression of MT–MMP-1 and activation of MMP-2 occurs early after injury to the rat carotid artery and that at later times MMP-2 is preferentially localized to the developing neointima.
Regulation of Arterial Thrombolysis by Plasminogen Activator Inhibitor-1 in Mice
Authors: Farrehi Peter M. , Ozaki C. Keith , Carmeliet Peter , Fay William P.
Published: June 2012

Background
—Platelet-rich arterial thrombi are resistant to lysis by plasminogen activators. However, the mechanisms underlying thrombolysis resistance are poorly defined. Plasminogen activator inhibitor-1 (PAI-1), which is present in plasma, platelets, and vascular endothelium, may be an important determinant of the resistance of arterial thrombi to lysis. However, in vitro studies examining the regulation of platelet-rich clot lysis by PAI-1 have yielded inconsistent results.

Methods and Results
—We developed a murine arterial injury model and applied it to wild-type (
PAI-1
+/+) and PAI-1–deficient (
PAI-1
−/−) animals. FeCl
3
was used to induce carotid artery thrombosis. Thrombi consisted predominantly of dense platelet aggregates, consistent with the histology of thrombi in large-animal arterial injury models and human acute coronary syndromes. To examine the role of PAI-1 in regulating endogenous clearance of platelet-rich arterial thrombi, thrombi were induced in 22
PAI-1
+/+ mice 14
PAI-1
−/− mice. Twenty-four hours later, the amount of residual thrombus was determined by histological analysis of multiple transverse sections of each artery. Residual thrombus was detected in 55 of 85 sections (64.7%) obtained from
PAI-1
+/+ mice compared with 19 of 56 sections (33.9%) from
PAI-1
−/− mice (
P
=.009). Computer-assisted planimetry analysis revealed that mean thrombus cross-sectional area was 0.033±0.027 mm
2
in
PAI-1
+/+ mice versus 0.016±0.015 mm
2
in
PAI-1
−/− mice (
P
=.048).

Conclusions
—PAI-1 is an important determinant of thrombolysis at sites of arterial injury. Application of this model to other genetically altered mice should prove useful for studying the molecular determinants of arterial thrombosis and thrombolysis.
Effects of Intranasal Administration of Recombinant Murine Interferon-γ on Murine Acute Myocarditis Caused by Encephalomyocarditis Virus
Authors: Yamamoto Norimi , Shibamori Masafumi , Ogura Motohiro , Seko Yoshinori , Kikuchi Mikio
Published: June 2012

Background
—Viral myocarditis has been strongly implicated in the pathogenesis of dilated cardiomyopathy as well as acute myocarditis. Among the antiviral therapies, interferons (IFNs) have been widely studied and become very important in clinical practice.

Methods and Results
—To investigate the possibilities of IFN therapy in viral myocarditis, we analyzed the effects of recombinant murine interferon (mIFN)-γ and natural mIFN-α/β by the intranasal and intramuscular routes on the development of acute murine myocarditis caused by encephalomyocarditis virus. Both mIFN-γ and mIFN-α/β treatment by either route significantly increased the survival rate; none of the mIFN-γ–treated mice died. The effect of mIFN-γ was significantly greater than that of mIFN-α/β. Furthermore, intranasal administration of mIFN-γ significantly suppressed virus replication and inflammation in the heart.

Conclusions
—Our data demonstrate that IFN therapy, especially intranasal administration of IFN-γ, dramatically improved the prognosis of acute murine viral myocarditis by suppressing virus replication and raises the possibility of antiviral therapy with IFN-γ in patients with acute myocarditis.
Insulin and Risk of Cardiovascular Disease
Authors: Ruige J. B. , Assendelft W. J. J. , Dekker J. M. , Kostense P. J. , Heine R. J. , Bouter L. M.
Published: June 2012

Background
—Our purposes were to estimate the strength of the longitudinal relationship between hyperinsulinemia and cardiovascular diseases (CVD) from the available literature and to identify study characteristics that modify this relationship.

Methods and Results
—Articles were identified by means of a MEDLINE and Embase search and citation tracking. Eligible studies were prospective population-based cohort studies and nested case-control studies on the relationship between, on the one hand, fasting or nonfasting insulin levels and, on the other hand, myocardial infarction, death from coronary heart disease, and/or ECG abnormalities. Data were extracted pertaining to insulin measurements, type of outcome studied, adjustment for confounding, sex, mean age of the study population, follow-up period, insulin assay, and ethnic background (white or nonwhite). Associations of insulin and CVD were reexpressed in a uniform manner, an estimate of relative risk (RR) and 95% CI, to be used in meta–regression analyses. Twelve of 17 potentially eligible articles provided sufficient information. Overall, a weak positive association was found. The meta-analysis resulted in an estimated summary RR (95% CI) of 1.18 (1.08 to 1.29) for differences in insulin level, equivalent to the difference between the 75th and the 25th percentiles of the general population in the Netherlands. Ethnic background and type of insulin assay modified the relationship between insulin and CVD with borderline significance.

Conclusions
—Hyperinsulinemia is a weak risk indicator for the occurrence of CVD. The relationship between hyperinsulinemia and CVD was modified by ethnic background and by the type of insulin assay involved.
Constitutive Expression of phVEGF
165
After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia
Authors: Baumgartner Iris , Pieczek Ann , Manor Orit , Blair Richard , Kearney Marianne , Walsh Kenneth , Isner Jeffrey M.
Published: June 2012

Background
—Preclinical studies have indicated that angiogenic growth factors can stimulate the development of collateral arteries, a concept called “therapeutic angiogenesis.” The objectives of this phase 1 clinical trial were (1) to document the safety and feasibility of intramuscular gene transfer by use of naked plasmid DNA encoding an endothelial cell mitogen and (2) to analyze potential therapeutic benefits in patients with critical limb ischemia.

Methods and Results
—Gene transfer was performed in 10 limbs of 9 patients with nonhealing ischemic ulcers (n=7/10) and/or rest pain (n=10/10) due to peripheral arterial disease. A total dose of 4000 μg of naked plasmid DNA encoding the 165-amino-acid isoform of human vascular endothelial growth factor (phVEGF
165
) was injected directly into the muscles of the ischemic limb. Gene expression was documented by a transient increase in serum levels of VEGF monitored by ELISA. The ankle-brachial index improved significantly (0.33±0.05 to 0.48±0.03,
P
=.02); newly visible collateral blood vessels were directly documented by contrast angiography in 7 limbs; and magnetic resonance angiography showed qualitative evidence of improved distal flow in 8 limbs. Ischemic ulcers healed or markedly improved in 4 of 7 limbs, including successful limb salvage in 3 patients recommended for below-knee amputation. Tissue specimens obtained from an amputee 10 weeks after gene therapy showed foci of proliferating endothelial cells by immunohistochemistry. PCR and Southern blot analyses indicated persistence of small amounts of plasmid DNA. Complications were limited to transient lower-extremity edema in 6 patients, consistent with VEGF enhancement of vascular permeability.

Conclusions
—These findings may be cautiously interpreted to indicate that intramuscular injection of naked plasmid DNA achieves constitutive overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with critical limb ischemia.
Return Cycle Mapping After Entrainment of Ventricular Tachycardia
Authors: Nitta Takashi , Schuessler Richard B. , Mitsuno Masataka , Rokkas Chris K. , Isobe Fumitaka , Cronin Christopher S. , Cox James L. , Boineau John P.
Published: June 2012

Background
—The central common pathway, which is the target for ablation in reentrant ventricular tachycardia, can be localized by entrainment mapping techniques. However, localization of the pathway is not always possible because of the elevated pacing threshold and the low voltage and fractionated potentials at the pathway. We examined whether return cycle mapping after entrainment localizes the pathway without pacing at the pathway or recording the potentials from the pathway and determined the required electrode resolution to localize the pathway.

Methods and Results
—Epicardial mapping was performed with 253 unipolar electrodes during and after entrainment of 13 morphologies of ventricular tachycardia that were induced in dogs 4 days after infarction. The return cycle was calculated by subtracting the first activation time from the second activation time after the last stimulus and the return cycle distribution map was constructed for each stimulation site. The return cycle isochrones equal to the ventricular tachycardia cycle length converged on the lines of conduction block irrespective of the stimulation site, and the central common pathway was localized at the region between the intersections of the return cycle isochrones after entrainment from different stimulation sites. The potentials from the central common pathway were not required to localize the pathway, and the mapping accuracy did not change with or without analysis of the potentials from the pathway. According to the correlation between the electrode resolution and the mapping accuracy, an interelectrode distance of 8.5 mm was estimated as sufficient resolution for successful tachycardia termination during radiofrequency ablation guided by return cycle mapping.

Conclusions
—Return cycle mapping after entrainment localizes the central common pathway without pacing at the pathway or recording the potentials from the pathway. This new mapping technique could improve the success rate of the ablative procedures.
Role of Dobutamine Stress Echocardiography in Predicting Outcome in 860 Patients With Known or Suspected Coronary Artery Disease
Authors: Chuah Seng-Chye , Pellikka Patricia A. , Roger Veronique L. , McCully Robert B. , Seward James B.
Published: June 2012

Background
—Increasingly, dobutamine stress echocardiography has been used for detection of coronary artery disease. Less information exists regarding the incremental prognostic value of the test, including semiquantitative wall scoring, compared with clinical and rest echocardiographic variables.

Methods and Results
—Follow-up information was obtained from 860 patients who underwent dobutamine stress echocardiography over a 2-year period. To determine the value of dobutamine stress echocardiography in predicting cardiac events, including cardiac death and myocardial infarction, clinical and rest and stress echocardiographic data were considered in a stepwise Cox multivariate regression model. During follow-up of up to 52 months, 72 patients underwent coronary revascularization before any cardiac event and were censored. Eighty-six patients had cardiac events, including nonfatal myocardial infarction in 36 and cardiac death in 50. In a multivariate model, a history of congestive heart failure, the percentage of abnormal segments at peak stress, and an abnormal left ventricular end-systolic volume response to stress were independent predictors of cardiac events. The model that best predicted subsequent cardiac events included clinical and stress echocardiographic data.

Conclusions
—Dobutamine stress echocardiography with semiquantitative segmental wall scoring provides important incremental information in predicting subsequent cardiac events.
Electrocardiographic Imaging
Authors: Oster Howard S. , Taccardi Bruno , Lux Robert L. , Ershler Philip R. , Rudy Yoram
Published: June 2012

Background
—A recent study demonstrated the ability of electrocardiographic imaging (ECGI) to reconstruct, noninvasively, epicardial potentials, electrograms, and activation sequences (isochrones) generated by epicardial activation. The current study expands the earlier work to the three-dimensional myocardium and investigates the ability of ECGI to characterize intramural myocardial activation noninvasively and to relate it to the underlying fiber structure of the myocardium. This objective is motivated by the fact that cardiac excitation and arrhythmogenesis involve the three-dimensional ventricular wall and its anisotropic structure.

Methods and Results
—Intramural activation was initiated by pacing a dog heart in a human torso tank. Body surface potentials (384 electrodes) were used to compute epicardial potentials noninvasively. Accuracy of reconstructed epicardial potentials was evaluated by direct comparison to measured ones (134 electrodes). Protocols included pacing from five intramural depths. Epicardial potentials showed characteristic patterns (1) early in activation, central negative region with two flanking maxima aligned with the orientation of fibers at the depth of pacing; (2) counterclockwise rotation of positive potentials with time for epicardial pacing, clockwise rotation for subendocardial pacing, and dual rotation for midmyocardial pacing; and (3) central positive region for endocardial pacing. Noninvasively reconstructed potentials closely approximated these patterns. Reconstructed epicardial electrograms and epicardial breakthrough times closely resembled measured ones, demonstrating progressively later epicardial activation with deeper pacing.

Conclusions
—ECGI can noninvasively estimate the depth of intramyocardial electrophysiological events and provides information on the spread of excitation in the three-dimensional anisotropic myocardium on a beat-by-beat basis.
Prospective Study of Calcium Channel Blocker Use, Cardiovascular Disease, and Total Mortality Among Hypertensive Women
Authors: Michels Karin B. , Rosner Bernard A. , Manson JoAnn E. , Stampfer Meir J. , Walker Alexander M. , Willett Walter C. , Hennekens Charles H.
Published: June 2012

Background
—In several observational studies, patients prescribed calcium channel blockers had higher risks of cardiovascular diseases and mortality than those prescribed other antihypertensive medications. We explored these associations in the Nurses’ Health Study.

Methods and Results
—A total of 14 617 women who reported hypertension and regular use of diuretics, β-blockers, calcium channel blockers, ACE inhibitors, or a combination in 1988 were included in the analyses. Cardiovascular events and deaths were ascertained through May 1, 1994. We documented 234 cases of myocardial infarction. Calcium channel blocker monodrug users had an age-adjusted relative risk (RR) of myocardial infarction of 2.36 (95% CI, 1.43 to 3.91) compared with those prescribed thiazide diuretics. Women prescribed calcium channel blockers had a higher prevalence of ischemic heart disease. After adjustment for these and other coronary risk factors, the RR was 1.64 (95% CI, 0.97 to 2.77). Comparing the use of any calcium channel blocker (monodrug and multidrug users) with that of any other antihypertensive agent, the adjusted RR was 1.42 (95% CI, 1.01 to 2.01). An association between calcium channel blocker use and myocardial infarction was apparent among women who had ever smoked cigarettes (covariate-adjusted RR, 1.81; 95% CI, 1.20 to 2.72) but not among never-smokers (RR, 0.94; 95% CI, 0.48 to 1.84).

Conclusions
—In analyses adjusted only for age, we found a significant elevation in RR of total myocardial infarction among women who used calcium channel blockers compared with those who did not. After adjustment for comorbidity and other covariates, the RR was reduced. Whether the remaining observed elevated risk is real, or a result of residual confounding by indication, or chance, or a combination of the above cannot be evaluated with certainty on the basis of these observational data.
Improvement of Repolarization Abnormalities by a K
+
Channel Opener in the LQT1 Form of Congenital Long-QT Syndrome
Authors: Shimizu Wataru , Kurita Takashi , Matsuo Kiyotaka , Suyama Kazuhiro , Aihara Naohiko , Kamakura Shiro , Towbin Jeffrey A. , Shimomura Katsuro
Published: June 2012

Background
—This study used monophasic action potential (MAP) to examine the effect of nicorandil, a K
+
channel opener, on repolarization abnormalities induced by epinephrine in the LQT1 form of congenital long-QT syndrome in which the
KvLQT1
mutation underlies the defect in the channel responsible for the slowly activating component of the delayed rectifier potassium current.

Methods and Results
—MAPs were recorded simultaneously from two or three sites on the right ventricular and left ventricular endocardium in 6 patients with a congenital form of LQT1 syndrome with
KvLQT1
defect (17 sites) and 8 control patients (24 sites). In LQT1 patients, epinephrine infusion prolonged the QT interval and 90% MAP duration (MAPD
90
) and increased the dispersion of MAPD
90
. Epinephrine also induced early afterdepolarizations (EADs) as well as ventricular premature complexes (VPCs) in 2 of the 6 patients. Nicorandil during epinephrine infusion abbreviated the QT interval and MAPD
90
, decreased the dispersion of MAPD
90
, and abolished the EADs as well as the VPCs in 1 patient. Addition of propranolol completely reversed the effect of epinephrine in prolonging the QT interval and MAPD
90
and increasing the dispersion and eliminated the EADs and VPCs in another patient. In control patients, the effect of epinephrine and that of additional nicorandil and propranolol on repolarization parameters were much less than in the LQT1 patients.

Conclusions
—Our results suggest that nicorandil, a K
+
channel opener, improves repolarization abnormalities in the LQT1 form of congenital long-QT syndrome with
KvLQT1
defect.
Myocardial Discontinuities
Authors: White James B. , Walcott Gregory P. , Pollard Andrew E. , Ideker Raymond E.
Published: June 2012

Background
—Theoretical models suggest that an electrical stimulus causes regions of depolarization and hyperpolarization on either side of a myocardial discontinuity. This study determined experimentally whether an artificial discontinuity gives rise to an activation front in response to an electrical stimulus, consistent with the creation of such polarized regions.

Methods and Results
—After a thoracotomy in six dogs, a 504-unipolar-electrode plaque was sutured to the right ventricular epicardium to map activations. From a line electrode parallel to one side of the plaque, 10 S
1
stimuli were delivered, followed by S
2
and S
3
stimuli (S
1
S
1
, S
1
S
2
, S
2
S
3
interval=300 ms). S
1
and S
3
stimuli were 25 mA; 5-ms S
2
stimuli of both polarities were initially 25 mA and increased in 25 mA increments. The plaque was removed, and a transmural incision was made through the ventricular wall in the middle of the mapped region and sutured closed. The plaque was replaced and the stimulation protocol repeated. Before the incision, S
2
stimuli directly activated tissue only near the stimulation site. An activation front arose at the border of the directly activated region and propagated across the plaque. As the S
2
stimulus strength was increased, the size of the directly activated region increased. After the incision, sufficiently large S
2
stimuli caused direct activation of tissue adjacent to the transmural incision as well as at the stimulation site. Activation fronts that arose adjacent to the transmural incision either propagated proximally toward the stimulation site and collided with the activation front originating from the stimulation wire or propagated distally away from the incision. Minimum S
2
stimulus strengths activating areas adjacent to the incision were only 45±14% (cathode) and 39±18% (anode) of the strengths required to directly activate the same area before the incision was formed (
P
<.05).

Conclusions
—Myocardial discontinuities can give rise to activation fronts after a stimulus, suggesting the presence of polarized regions adjacent to the discontinuity.
Evidence for Association and Genetic Linkage of the Angiotensin-Converting Enzyme Locus With Hypertension and Blood Pressure in Men but Not Women in the Framingham Heart Study
Authors: O’Donnell Christopher J. , Lindpaintner Klaus , Larson Martin G. , Rao Valluri S. , Ordovas Jose M. , Schaefer Ernst J. , Myers Richard H. , Levy Daniel
Published: June 2012

Background
—There is controversy regarding the association of the angiotensin-converting enzyme deletion-insertion (
ACE D/I
) polymorphism with systemic hypertension and with blood pressure. We investigated these relations in a large population-based sample of men and women by using association and linkage analyses.

Methods and Results
—The study sample consisted of 3095 participants in the Framingham Heart Study. Blood pressure measurements were obtained at regular examinations. The
ACE D/I
polymorphism was identified by using a polymerase chain reaction assay. In logistic regression analysis, the adjusted odds ratios for hypertension among men for the
DD
and
DI
genotypes were 1.59 (95% confidence interval [CI], 1.13 to 2.23) and 1.18 (95% CI, 0.87 to 1.62), respectively, versus
II
(χ
2
P
=.02). In women, adjusted odds ratios for the
DD
and
DI
genotypes were 1.00 (95% CI, 0.70 to 1.44) and 0.78 (95% CI, 0.56 to 1.09), respectively (
P
=.14). In linear regression analysis, there was an association of the
ACE DD
genotype with increased diastolic blood pressure in men (age-adjusted
P
=.03, multivariate-adjusted
P
=.14) but not women. Quantitative trait linkage analyses in 1044 pairs of siblings, by using both
ACE D/I
and a nearby microsatellite polymorphism of the human growth hormone gene, supported a role of the
ACE
locus in influencing blood pressure in men but not in women.

Conclusions
—In our large, population-based sample, there is evidence for association and genetic linkage of the
ACE
locus with hypertension and with diastolic blood pressure in men but not women. Our data support the hypothesis that
ACE
, or a nearby gene, is a sex-specific candidate gene for hypertension. Confirmatory studies in other large population-based samples are warranted.
Effects of Lowering Average or Below-Average Cholesterol Levels on the Progression of Carotid Atherosclerosis
Authors: MacMahon Stephen , Sharpe Norman , Gamble Greg , Hart Hamish , Scott John , Simes John , White Harvey
Published: June 2012

Background
—Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels.

Methods and Results
—In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all
2P
<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both
2P
<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (
2P
for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (
2P
for interaction >.8).

Conclusions
—Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up.
Evolution and Resolution of Long-term Cardiac Memory
Authors: Shvilkin Alexei , Danilo Peter , Wang Jie , Burkhoff Daniel , Anyukhovsky Evgeny P. , Sosunov Eugene A. , Hara Motoki , Rosen Michael R.
Published: June 2012

Background
—Cardiac memory (CM) refers to T-wave changes induced by ventricular pacing or arrhythmia that accumulate in magnitude and duration with repeated episodes of abnormal activation. We report herein the kinetics of long-term CM and its association with the ventricular action potential.

Methods and Results
—Dogs were paced from the ventricles at rates of 110 to 120 bpm for ≈3 weeks. CM characterized by gradual sinus rhythm T vector rotation toward the paced QRS vector evolved in all dogs regardless of pacing site (left ventricular [LV] anterior apex or base, posterior LV, or right ventricular free wall). Cardiac hemodynamics and myocardial flow (microsphere studies) were unaltered by the pacing. Recovery time for the memory T wave to return to control increased with duration of the previous pacing. The protein synthesis inhibitor cycloheximide markedly (
P
<.05) and reproducibly attenuated evolution of CM. When pacing was performed from the atrium, CM did not occur. Standard microelectrode techniques were used to study action potential from the LV free wall of control and CM dogs. CM was associated with increased action potential duration in epicardial and endocardial but not midmyocardial cells, significantly altering the transmyocardial gradient for repolarization.

Conclusions
—CM is a dynamic process for which the final T vector is predicted by the paced QRS vector and which is associated with significant changes in epicardial and endocardial but not midmyocardial cell action potential duration, such that the transmural gradient of repolarization is altered. It is unaccompanied by evidence of altered hemodynamics or flow, requires a change in pathway of activation, and appears to require new protein synthesis.