bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Atrial Repolarization by Site of Pacing in the Isolated Rabbit Heart
Authors: Wood Mark A. , Mangano Robert A. , Schieken Richard M. , Baumgarten Clive M. , Simpson Pippa M. , Ellenbogen Kenneth A.
Published: June 2012

Background
Single-site or multisite atrial pacing may reduce the incidence of atrial fibrillation in humans. The therapeutic mechanisms may include synchronization of atrial repolarization (repolarization “memory”) and/or decreased dispersion of atrial repolarization. These responses have not been well documented in intact atria.

Methods and Results
Monophasic action potential recordings were made from six atrial epicardial sites in 39 isolated perfused rabbit heart preparations during 3 hours of continuous right atrial, left atrial, or biatrial pacing. Action potential recordings obtained at times 0, 45, 90, 135, and 180 minutes were computer analyzed for activation time (AT) and 90% action potential duration (APD) at each site. No consistent relationship could be demonstrated between APD and AT at any time during atrial pacing (all
P
>.05). On average, left atrial APDs were longer than right atrial APDs by up to 6.3 ms at all times, regardless of the site of pacing (
P
≤.05). At all times, dispersion of atrial repolarization was minimized by left atrial pacing compared with right atrial pacing (21.6±9.1 versus 32.4±15.1 ms, respectively, at time 0;
P
<.05). Biatrial pacing provided no further reduction in dispersion of repolarization compared with left atrial pacing (all
P
>.05).

Conclusions
No relationship can be demonstrated between atrial AT and APD in the isolated rabbit heart preparation. This differs from ventricular repolarization “memory,” which is demonstrable under the same conditions. Left atrial APD is, on average, longer than right atrial APD, suggesting spatial heterogeneity in repolarization. Dispersion of atrial repolarization is minimized by left atrial pacing in this preparation with no further advantage to biatrial pacing.
Expression of Angiotensin-Converting Enzyme in Remaining Viable Myocytes of Human Ventricles After Myocardial Infarction
Authors: Hokimoto Seiji , Yasue Hirofumi , Fujimoto Kazuteru , Yamamoto Hideyuki , Nakao Koichi , Kaikita Koichi , Sakata Ryuzo , Miyamoto Eishichi
Published: June 2012

Background
Local ACE in the heart may be important in the pathophysiological state after myocardial infarction (MI). It is unknown, however, whether ACE is expressed in myocytes of the human heart.

Methods and Results
Using a newly generated polyclonal antibody to a synthetic peptide corresponding to part of the human endothelial ACE sequence, we examined the localization of ACE in left ventricles of patients (n=10) with MI obtained at left ventricular aneurysmectomy or autopsy and in the hearts of control subjects at autopsy (n=10). The avidin–biotinylated peroxidase complex method was used for the immunohistochemical staining for ACE. In the left ventricles, positively stained myocytes for ACE were found in 8 of the 10 patients with MI. ACE immunoreactivity was seen in the remaining viable myocytes located near the infarct scar of the aneurysmal left ventricle and in nonmyocytes such as fibroblasts, macrophages, vascular smooth muscle cells, and endothelial cells within the scarred tissue. On the other hand, no immunoreactivity for ACE was detected in the ventricular myocytes of all control hearts obtained at autopsy.

Conclusions
We observe immunohistochemical staining for ACE in the left ventricular myocytes of the region adjacent to the infarct scar and in nonmyocytes. These results indicate that ACE is markedly increased on the edge of the infarct scar and suggest that local ACE may be important in the ventricular remodeling after MI.
Compound Heterozygosity for a Structural Apolipoprotein A-I Variant, Apo A-I(L141R)
Pisa
, and an Apolipoprotein A-I Null Allele in Patients With Absence of HDL Cholesterol, Corneal Opacifications, and Coronary Heart Disease
Authors: Miccoli Roberto , Bertolotto Alessandra , Navalesi Renzo , Odoguardi Leonardo , Boni Andrea , Wessling Johannes , Funke Harald , Wiebusch Heiko , von Eckardstein Arnold , Assmann Gerd
Published: June 2012

Background
The concentration of HDL cholesterol is inversely correlated with the risk of coronary heart disease (CHD). Some rare mutations in the apolipoprotein (apo) A-I gene are associated with low levels of HDL cholesterol. Their association with cardiovascular risk is controversial.

Methods and Results
We studied the molecular defects underlying corneal opacities and absence of HDL cholesterol in three brothers and a sister. In a family study, the importance of these defects for lipid metabolism and manifestation of coronary heart disease was investigated. The frequency of these apo A-I defects was assessed by genotype and phenotype analysis of 477 DNA
−
and plasma samples, respectively, from the population. The four patients were compound heterozygotes for a null allele and a missense mutation in the apo A-I gene that leads to a leucine→arginine substitution at residue 141 [apo A-I(L141R)
Pisa
]. Heterozygotes for either the null allele or the structural variant had half-normal concentrations of HDL cholesterol and apo A-I compared with unaffected family members. Apo A-I(L141R)
Pisa
was detected in one more unrelated subject. Coronary angiography of the four compound heterozygotes revealed the presence of CHD in all male patients, whose ages ranged between 45 and 52 years. They presented with additional risk factors, including elevated LDL cholesterol levels, obesity, and arterial hypertension. Despite complete HDL deficiency and hypercholesterolemia, CHD was absent in the 51-year-old premenopausal sister.

Conclusions
Apo A-I deficiency may lead to premature atherosclerosis if present in conjunction with additional cardiovascular risk factors.
Pericardioscopy in the Etiologic Diagnosis of Pericardial Effusion in 141 Consecutive Patients
Authors: Nugue Olivier , Millaire Alain , Porte Henri , de Groote Pascal , Guimier Philippe , Wurtz Alain , Ducloux Ge´rard
Published: June 2012

Background
Although previous small series have documented the utility of pericardioscopy for accurate etiologic diagnosis of pericardial effusion, this technique remains underused. The aim of our study was to assess the benefits and risks of surgical pericardioscopy in a large prospective series.

Methods and Results
One hundred forty-one consecutive patients with unexplained pericardial effusion underwent 142 pericardioscopies with a rigid mediastinoscope. For each patient, the etiologic data obtained by pericardioscopy (visualization of pericardium, guided biopsies, subxiphoid window biopsy, and fluid analysis) were compared with the results that would have been obtained with only conventional surgical drainage and biopsy (subxiphoid window biopsy and fluid analysis). After complete workup, a specific cause was found in 69 cases (48.6%); the other 73 cases were considered idiopathic effusions (51.4%). Procedural and in-hospital mortality was 8 of 141 patients (5.6%). No death was directly attributable to pericardioscopy. During long-term follow-up (median duration, 24 months; range, 6 to 96), a previously unrecognized cause was discovered in 6 patients (4%). By comparing the areas under the receiver-operating characteristic curves, the diagnostic advantage of pericardioscopy was significant for the whole series (pericardioscopy, 0.98±0.011; conventional surgical drainage, 0.89±0.029;
P
<.001). The increase in sensitivity was more marked for some types such as neoplastic (21%), radiation-induced (100%), or purulent (83%) effusions.

Conclusions
Our data demonstrate that pericardioscopy increases the diagnostic sensitivity of surgical pericardial drainage and biopsy without specific risk.
Pharmacological Stress Thallium Scintigraphy With 2-Cyclohexylmethylidenehydrazinoadenosine (WRC-0470)
Authors: Glover David K. , Ruiz Mirta , Yang Joo Y. , Koplan Bruce A. , Allen Terry R. , Smith William H. , Watson Denny D. , Barrett Richard J. , Beller George A.
Published: June 2012

Background
Pharmacological stress imaging with adenosine or dipyridamole is associated with a high incidence of side effects, including hypotension, chest pain, AV conduction abnormalities, and bronchospasm. Although the desired coronary vasodilatory response is mediated primarily by the adenosine A
2A
receptors, these side effects result from stimulation of the A
1
, A
2B
, or A
3
adenosine receptors. We hypothesized that a selective adenosine A
2A
receptor agonist would induce coronary vasodilatation appropriate for pharmacological stress imaging, without evoking adenosine receptor–mediated side effects.

Methods and Results
Infusions of a potent and selective A
2A
adenosine receptor agonist, WRC-0470 (0.1 to 3 μg · kg
−1
·min
−1
for 10 minutes), to five open-chest dogs produced dose-related left anterior descending (LAD) and left circumflex (LCx) coronary artery vasodilatation without altering mean arterial pressure, heart rate, left atrial pressure, or left ventricular dP/dt. In the same dogs, adenosine (300 μg · kg
−1
· min
−1
for 4 minutes) produced coronary vasodilatation that was limited by significant hypotension. To determine the utility of WRC-0470 for pharmacological stress imaging, the hemodynamic responses to WRC-0470 (0.6 μg · kg
−1
· min
−1
for 10 minutes) and adenosine (250 μg · kg
−1
· min
−1
for 4 minutes) were compared in dogs with critical LAD stenoses.
201
Tl was injected at the peak WRC-0470 stress response. WRC-0470 increased LCx flow nearly fivefold but did not significantly lower mean arterial pressure. Anteroseptal defects were readily apparent in slice images from all dogs. The mean defect ratio (LAD/LCx) was 0.59±0.06.

Conclusions
The potent A
2A
-selective adenosine receptor agonist WRC-0470 is a short-acting coronary vasodilator with potential utility for pharmacological stress perfusion imaging.
Influence of External Stent Size on Early Medial and Neointimal Thickening in a Pig Model of Saphenous Vein Bypass Grafting
Authors: Izzat Mohammad Bashar , Mehta Dheeraj , Bryan Alan J. , Reeves Barnaby , Newby Andrew C. , Angelini Gianni D.
Published: June 2012

Background
Late saphenous vein graft failure results from intimal and medial thickening due to migration and proliferation of vascular smooth muscle cells and superimposed atheroma. These changes may represent an adaptation by the vein to its insertion into the arterial system. Using a porcine model of arteriovenous bypass grafting, we recently demonstrated that supporting the graft with a nonrestrictive external Dacron velour stent significantly reduced intimal hyperplasia and total wall thickness. In the present study, we investigated the influence of different external stent sizes on graft wall dimensions and cell proliferation.

Methods and Results
Three stent sizes were tested: mildly restrictive, nonrestrictive, and oversized (5, 6, and 8 mm in diameter, respectively). Four weeks after grafting, total wall thickness was decreased 40% by 5-mm stents (
P
=.02), 66% by 6-mm stents (
P
=.0004), and 81% by 8-mm stents (
P
=.02 versus unstented grafts). Neointimal thickness was reduced almost 62% by 6-mm and 72% by 8-mm stents (both
P
=.01) but not by 5-mm stents. As a result, the encroachment of the intima into the lumen was reduced ≈70% by 6- or 8-mm stents (
P
=.02 and
P
=.01 versus unstented grafts, respectively). Both neointimal and medial cell proliferation were significantly reduced by all three stents compared with unstented grafts.

Conclusions
External stenting of saphenous vein bypass grafts reduces early intimal and medial hyperplasia. Oversized stents give equally profound suppression of intimal thickening, obviating the need for precise size matching with the graft and greatly simplifying the surgical procedure.
Age and Outcome With Contemporary Thrombolytic Therapy
Authors: White Harvey D. , Barbash Gabriel I. , Califf Robert M. , Simes R. John , Granger Christopher B. , Weaver W. Douglas , Kleiman Neal S. , Aylward Philip E. , Gore Joel M. , Vahanian Alec , Lee Kerry L. , Ross Allan M. , Topol Eric J.
Published: June 2012

Background
Elderly patients with acute myocardial infarction have much to gain from reperfusion with thrombolytic therapy but are also at increased risk of adverse events. We examined outcomes according to age of patients receiving thrombolysis in an international trial.

Methods and Results
Patients were randomized to streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tissue plasminogen activator (TPA) plus intravenous heparin, or streptokinase and TPA plus intravenous heparin. Clinical outcomes at 30 days (death, stroke, and nonfatal, disabling stroke) and 1-year mortality were summarized descriptively for patients aged <65 (n=24 708), 65 to 74 (n=11 201), 75 to 85 (n=4625), and >85 years (n=412) and assessed as continuous functions of age. Older patients had a higher-risk profile with regard to baseline clinical and angiographic characteristics. Mortality at 30 days increased markedly with age (3.0%, 9.5%, 19.6%, and 30.3% in the four groups, respectively), as did stroke, cardiogenic shock, bleeding, and reinfarction. Combined death or disabling stroke occurred less often with accelerated TPA in all but the oldest patients, who showed a weak trend toward a lower incidence with streptokinase plus subcutaneous heparin: odds ratio 1.13; 95% confidence interval 0.6, 2.1. Similarly, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA versus 40.3% streptokinase).

Conclusions
Lower mortality and greater net clinical benefit were seen with accelerated TPA in patients aged ≤85 years. Because data are limited for patients aged >85 years, the relative superiority of a given thrombolytic regimen cannot be determined. The interactions of stroke and mortality with newer thrombolytic strategies must be examined explicitly in older patients.
Genetic Regulation of Hemodynamic Variables During Dynamic Exercise
Authors: van den Bree M.B.M. , Schieken R.M. , Moskowitz W.B. , Eaves L.J.
Published: June 2012

Background
Both resting and exercise levels of blood pressure in individuals have been used as predictors of adult hypertension. One possible mechanism underlying the relation between childhood resting and exercise blood pressure and future blood pressure is a set of genes expressed in childhood that persists to regulate adult blood pressure.

Methods and Results
To investigate the genetic relation of blood pressure and heart rate during both rest and exercise, we asked: (1) Are the genes that regulate resting hemodynamic variables the same genes that regulate these variables during exercise? (2) How much of the variance in exercise hemodynamic variables is genetic and how much is environmental? (3) Do the genetic and environmental influences on hemodynamic responses change with increasing levels of exercise? To determine how genetic and environmental effects expressed at rest influenced responses during dynamic exercise, a genetic analysis was conducted by fitting a series of models to the covariance matrices with the use of the LISREL VII program.

Conclusions
We found that all the genetic effects expressed at the later stages of exercise can be explained by genetic effects expressed at rest and at the first stage of exercise. The environmental effects appear to be workload specific and include errors of measurement.
Reconstruction of Brachial Artery Pressure From Noninvasive Finger Pressure Measurements
Authors: Bos Willem Jan W. , van Goudoever Jeroen , van Montfrans Gert A. , van den Meiracker Anton H. , Wesseling Karel H.
Published: June 2012

Background
Pulse wave distortions, mainly caused by reflections, and pressure gradients, caused by flow in the resistive vascular tree, may cause differences between finger and brachial artery pressures. These differences may limit the use of finger pressure measurements. We investigated whether brachial artery pressure waves could be reconstructed from finger pressure measurements by correcting for the pressure gradient in addition to correction for pulse wave distortion with a previously described filter.

Methods and Results
Finger artery pressure (with Finapres), intra-arterial brachial artery pressure (BAP), Riva-Rocci/Korotkoff (RRK), oscillometric, and return-to-flow (RTF) measurements were simultaneously performed in 57 healthy elderly subjects and patients with vascular disease and/or hypertension. A generalized waveform filter was used to correct for pulse wave distortions. Correction equations for the pressure gradient, based on finger pressure, RRK, RTF, or oscillometric measurements, were obtained in 28 randomly selected subjects and tested in 29. Before reconstruction, Finapres underestimated mean and diastolic BAP (finger pressure minus BAP: systolic, −3.2±16.9 mm Hg; mean, −13.0±10.5 mm Hg; diastolic, −8.4±9.0 mm Hg [mean±SD]). After filtering, reconstructed BAP waves were similar to actual BAP in shape but not in pressure level. Optimal correction for the pressure gradient with an equation based on RTF measurements reduced the pressure differences to meet American Association for the Advancement of Medical Instrumentation criteria (reconstructed finger pressure minus BAP: systolic, 3.7±7.0 mm Hg; mean, 0.7±4.6 mm Hg; and diastolic, 1.0±4.9 mm Hg).

Conclusions
BAP waves can be reconstructed from noninvasive finger pressure registrations when finger pressure waves are corrected for pulse wave distortion and individual pressure gradients.
Clinical Approach to Genetic Cardiomyopathy in Children
Authors: Schwartz Marcy L. , Cox Gerald F. , Lin Angela E. , Korson Mark S. , Perez-Atayde Antonio , Lacro Ronald V. , Lipshultz Steven E.
Published: June 2012

Background
Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays.

Methods and Results
We present a multidisciplinary diagnostic approach to pediatric CM of genetic etiology. We specify criteria for abnormal left ventricular systolic performance and structure that suggest CM based on established normal echocardiographic measurements and list other indications to consider an evaluation for CM. We provide a differential diagnosis of genetic conditions associated with CM, classified as inborn errors of metabolism, malformation syndromes, neuromuscular diseases, and familial isolated CM disorders. A diagnostic strategy is offered that is based on the clinical presentation: biochemical abnormalities, encephalopathy, dysmorphic features or multiple malformations, neuromuscular disease, apparently isolated CM, and pathological specimen findings. Adjunctive treatment measures are recommended for severely ill patients in whom a metabolic cause of CM is suspected. A protocol is provided for the evaluation of moribund patients.

Conclusions
In summary, we hope to assist pediatric cardiologists and other subspecialists in the evaluation of children with CM for a possible genetic cause using a presentation-based approach. This should increase the percentage of children with CM for whom a diagnosis can be established, with important implications for treatment, prognosis, and genetic counseling.
A Prospective Study of Anger and Coronary Heart Disease
Authors: Kawachi Ichiro , Sparrow David , Spiro Avron , Vokonas Pantel , Weiss Scott T.
Published: June 2012

Background
Recent laboratory and epidemiological studies have suggested that high levels of anger may increase the risk of coronary heart disease (CHD).

Methods and Results
We examined prospectively the relationship of anger to CHD incidence in the Veterans Administration Normative Aging Study, an ongoing cohort of older (mean age, 61 years) community-dwelling men. A total of 1305 men who were free of diagnosed CHD completed the revised Minnesota Multiphasic Personality Inventory (MMPI-2) in 1986. Subjects were categorized according to their responses to the MMPI-2 Anger Content Scale, which measures the degree to which individuals have problems controlling their anger. During an average of 7 years of follow-up, 110 cases of incident CHD occurred, including 30 cases of nonfatal myocardial infarction (MI), 20 cases of fatal CHD, and 60 cases of angina pectoris. Compared with men reporting the lowest levels of anger, the multivariate-adjusted relative risks among men reporting the highest levels of anger were 3.15 (95% confidence interval [CI]: 0.94 to 10.5) for total CHD (nonfatal MI plus fatal CHD) and 2.66 (95% CI: 1.26 to 5.61) for combined incident coronary events including angina pectoris. A dose-response relation was found between level of anger and overall CHD risk (
P
for trend, .008).

Conclusions
These data suggest that high levels of expressed anger may be a risk factor for CHD among older men.
Genetic and Environmental Contributions to Cardiovascular Risk Factors in Mexican Americans
Authors: Mitchell Braxton D. , Kammerer Candace M. , Blangero John , Mahaney Michael C. , Rainwater David L. , Dyke Bennett , Hixson James E. , Henkel Richard D. , Sharp R. Mark , Comuzzie Anthony G. , VandeBerg John L. , Stern Michael P. , MacCluer Jean W.
Published: June 2012

Background
The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes.

Methods and Results
Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for <15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure.

Conclusions
These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.
Effect of Environmental Tobacco Smoke on LDL Accumulation in the Artery Wall
Authors: Roberts K.A. , Rezai A.A. , Pinkerton K.E. , Rutledge J.C.
Published: June 2012

Background
Previous research has shown that exposure to environmental tobacco smoke (ETS) increases the risk of atherosclerosis. To test the hypothesis that exposure to ETS increases LDL accumulation in the artery wall, we developed a model to measure the rate of LDL accumulation in individually perfused rat carotid arteries after the artery had been perfused with plasma taken from rats exposed to ETS (ETS-plasma).

Methods and Results
Rats were exposed to ETS in a chamber in which steady-state sidestream smoke was continuously circulating. After exposure, blood from the animals was collected. Carotid arteries from unexposed rats were perfused first with normal plasma containing fluorescently labeled LDL. Then, the same arteries (10 arteries from five rats) were perfused with ETS-plasma plus fluorescently labeled LDL. Photometric measurements were made during perfusion of the arteries with fluorescently labeled LDL, and rate of LDL accumulation (mV/min) and lumen volume (mV) (volume of fluorescently labeled LDL solution) were determined. Perfusion with ETS-plasma increased the rate of LDL accumulation (mean±SEM, 6.9±1.8 mV/min) compared with control (1.6±0.40 mV/min,
P
≤.02). LDL accumulation was primarily dependent on LDL interaction with ETS-plasma rather than the interaction of ETS-plasma with the artery wall. Also, ETS-plasma significantly increased lumen volume (43.3±5.1 mV) compared with control (35.1±4.4 mV,
P
≤.005).

Conclusions
Exposure to ETS acutely increased LDL accumulation in perfused arteries. Repeated exposure to ETS may represent important early events in atherogenesis.
Different Effects of Calcium Antagonists, Nitrates, and β-Blockers on Platelet Function
Authors: Knight Charles J. , Panesar Manvinder , Wilson Darren J. , Chronos Nicolas A.F. , Patel Deven , Fox Kim , Goodall Alison H.
Published: June 2012

Background
The three major classes of antianginal drug all inhibit platelet aggregation at high concentrations in vitro, but detecting clinically relevant effects has proved to be more difficult. We used whole-blood flow cytometry, a sensitive method that allows direct measurement of activation antigens on the surface of individual platelets in whole unfixed blood, to evaluate the effect of representative antianginal drugs on platelet function in vivo in healthy volunteers.

Methods and Results
The effects of glyceryl trinitrate (GTN), amlodipine, and atenolol were studied in nine normal volunteers. Fibrinogen binding to activated GP IIb/IIIa and expression of P-selectin, GP Ib, and GP IIb/IIIa on the platelet surface were measured. In addition, fibrinogen binding and P-selectin expression were measured in response to ex vivo stimulation with the agonists ADP and thrombin. The three drugs had very different effects on platelets. GTN inhibited platelet fibrinogen binding and expression of P-selectin at rest and in response to agonist stimulation, whereas amlodipine enhanced P-selectin expression and atenolol increased fibrinogen binding in response to agonists. Atenolol did not block the stimulatory effects of epinephrine on ADP-induced platelet activation. GTN neutralized the proactivatory effects of amlodipine, whereas the effects of atenolol and amlodipine were not additive.

Conclusions
The three main classes of antianginal medication have different and possible clinically relevant effects on platelet behavior in vivo, nitrates causing inhibition of aggregation (fibrinogen binding) and degranulation (P-selectin expression), calcium antagonists enhancing degranulation, and β-blockers enhancing aggregation.
Modification of Human Left Ventricular Relaxation by Small-Amplitude, Phase-Controlled Mechanical Vibration on the Chest Wall
Authors: Koiwa Yoshiro , Honda Hideyuki , Takagi Takehiko , Kikuchi Jun-ichi , Hoshi Nobuo , Takishima Tamotsu
Published: June 2012

Background
Direct clinical manipulation to improve an impairment of left ventricular (LV) relaxation has not been reported. We investigated whether the LV relaxation rate in humans could be modulated by phase-controlled mechanical vibration applied to the patient's anterior chest wall and whether there are some quantitative differences in the responses of normal (N), hypertrophied (H), and failing (F) ventricle.

Methods and Results
In 46 patients (N, 10; H, 18 [hypertrophic cardiomyopathy]; F, 18 [heart failure]), the vibrator was attached to the precordium and a 50-Hz, 2-mm sinusoidal mechanical vibration was applied, with the timing restricted from the onset of isovolumic relaxation to end-diastole during cardiac catheterization. Heart rate and peak LV pressure showed no difference with vibration. However, in all patients, precordial vibration caused an acceleration of the LV pressure fall. The magnitude of the induced reduction of the time constant of LV pressure decay (ΔT) was larger (
P
<.01) in H and F than in N (4.6±2.3, 4.0±1.6, and 0.6±1.5 ms for H, F, and N, respectively). ΔT correlated strongly with the magnitude of impaired relaxation and the magnitude of transmitted vibration to the ventricle.

Conclusions
Phase-controlled, small-amplitude vibration on the chest wall can directly modulate LV relaxation rate, especially in those with hypertrophy or failing ventricle.
Angiotensin II Inhibits Protein Kinase A–Dependent Chloride Conductance in Heart via Pertussis Toxin–Sensitive G Proteins
Authors: Obayashi Kazuhiko , Horie Minoru , Xie Lai-Hua , Tsuchiya Kunihiko , Kubota Akira , Ishida Hitoshi , Sasayama Shigetake
Published: June 2012

Background
Angiotensin II receptors are reported to be abundant in the guinea pig ventricle; their coupling to adenylate cyclase in the heart, however, remains controversial. Therefore, we investigated the effect of angiotensin II on Cl
−
conductance activated by cAMP-dependent protein kinase.

Methods and Results
After minimizing the contribution of other ionic currents, exposure of single guinea pig ventricular cells to isoproterenol (40 to 50 nmol/L; 36°C) elicited a typical protein kinase A–dependent Cl
−
conductance. Subsequent application of angiotensin II reduced the isoproterenol-induced conductance with an IC
50
of 0.24±0.08 nmol/L. Angiotensin II also inhibited the Cl
−
currents, which were activated through stimulation of adenylate cyclase by forskolin and histamine receptors. CV-11974 (1 μmol/L), an antagonist selective for the angiotensin type 1 receptor, prevented the effect of angiotensin II. Angiotensin II did not inhibit the current that had been persistently activated by intracellular GTPγS (100 μmol/L), a nonhydrolyzable guanine nucleotide, plus isoproterenol. In addition, prior incubation of myocytes with pertussis toxin prevented the angiotensin II inhibitory action. Cl
−
conductance, when activated directly by intracellular dialysis with cAMP (1 mmol/L), was not affected by angiotensin II. Radioimmunologic measurement of cellular cAMP in the dissociated myocytes showed that angiotensin II inhibited the isoproterenol-induced increase of cAMP.

Conclusions
Angiotensin II receptors negatively couple to adenylate cyclase via pertussis toxin–sensitive G proteins, thereby inhibiting cardiac protein kinase A–dependent Cl
−
conductance.
Cost-Effectiveness of Populationwide Educational Approaches to Reduce Serum Cholesterol Levels
Authors: Tosteson Anna N.A. , Weinstein Milton C. , Hunink Maria G.M. , Mittleman Murray A. , Williams Lawrence W. , Goldman Paula A. , Goldman Lee
Published: June 2012

Background
The aim of the present study was to estimate the cost-effectiveness of populationwide approaches to reduce serum cholesterol levels in the US adult population.

Methods and Results
This cost-effectiveness analysis was made from data from the literature and the Coronary Heart Disease Policy Model and was based on the US population age 35 to 84 years. Study interventions were populationwide programs to reduce serum cholesterol levels with costs and cholesterol-lowering effects similar to those reported from the Stanford Three-Community Study, the Stanford Five-City Project, and in North Karelia, Finland. The main outcome measures were cost-effectiveness ratios, defined as the change in projected cost divided by the change in projected life-years when the population receives the intervention compared with the population without the intervention. A populationwide program with the costs ($4.95 per person per year) and cholesterol-lowering effects (an average 2% reduction in serum cholesterol levels) of the Stanford Five-City Project would prolong life at an estimated cost of only $3200 per year of life saved. Under a wide variety of assumptions, a populationwide program would achieve health benefits at a cost equivalent to that of many currently accepted medical interventions. Such programs would also lengthen life and save resources under many scenarios, especially if the program affected persons with preexisting heart disease or altered other coronary risk factors.

Conclusions
Populationwide programs should be part of any national health strategy to reduce coronary heart disease.
Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator
Authors: Biessen Erik A.L. , van Teijlingen Marco , Vietsch Helene , Barrett-Bergshoeff Marrie M. , Bijsterbosch Martin K. , Rijken Dingeman C. , van Berkel Theo J.C. , Kuiper Johan
Published: June 2012

Background
Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake.

Methods and Results
In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster mannoside carrying six mannose groups (M
6
L
5
) displayed a subnanomolar affinity for the mannose receptor (
K
i
=0.41±0.09 nmol/L). Preinjection of M
6
L
5
(1.2 mg/kg) reduced the clearance of
125
I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M
6
L
5
, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent to improve the pharmacokinetics of TPA. Blockade of LRP by 39-kD receptor-associated protein (GST-RAP) also inhibited TPA clearance by 60%. Finally, combined preinjection of M
6
L
5
and GST-RAP almost completely abolished reduced liver uptake of TPA and delayed its clearance by a factor of 10.

Conclusions
It can be concluded that (1) the mannose receptor and LRP appear to be the sole major receptors responsible for TPA clearance and (2) therapeutic levels of TPA can be maintained for a prolonged time span by coadministration of the aforementioned receptor antagonists.
Transballoon Intravascular Ultrasound Imaging During Balloon Angioplasty in Animal Models With Coarctation and Branch Pulmonary Stenosis
Authors: Stock John H. , Reller Mark D. , Sharma Sanjeev , Pavcnik Dusan , Shiota Takahiro , Sahn David J.
Published: June 2012

Background
Intravascular ultrasound (IVUS) studies performed after balloon dilation provide a method for evaluating the adequacy of angioplasty and the nature of associated changes in vessel walls. Previously, IVUS studies required the use of separate scanning catheters inserted independently before and after balloon angioplasty. We tested a 0.035-in, 30-MHz IVUS transducer wire that images from within commercially available 5F balloon dilation catheters.

Methods and Results
Seven stenoses were created in the left pulmonary artery (n=3) and in the aortic isthmus (n=4) in six lambs (weight, 3.4 to 12.5 kg). The balloon catheter selected was advanced across the stenotic area and the IVUS wire advanced in the guide lumen to the center of the balloon. Continuous IVUS images were obtained through balloons before, during, and after dilation. Transballoon imaging confirmed balloon location within the stenotic segment. Luminal diameters of stenotic and adjacent vessel segments before and after angioplasty by IVUS showed good correlation with angiographic measurements (
r
=.93,
P
≤.001). After successful dilation, imaging during deflation allowed the assessment of vascular elastic recoil, mural dissection, and luminal size without requiring changes in balloon position. Repeat dilation could be undertaken and the inflation pressure and technique modified on the basis of the observed results.

Conclusions
This transballoon IVUS system provides important on-line information about lumen diameter and wall structure for evaluation of angioplasty without the need for catheter changes, providing a method to possibly reduce the likelihood of excessive wall damage and to potentially reduce the number of angiograms required to accomplish and confirm results.
Intravenous Immune Globulin in the Therapy of Myocarditis and Acute Cardiomyopathy
Authors: McNamara Dennis M. , Rosenblum Warren D. , Janosko Karen M. , Trost Mary K. , Villaneuva Flordeliza S. , Demetris A.J. , Murali Srinivas , Feldman Arthur M.
Published: June 2012

Background
Although an autoimmune pathogenesis has been postulated for dilated cardiomyopathy, immunosuppressive therapy has not been shown to be effective in clinical trials. Immune modulatory therapy with immune globulin is an effective therapy for Kawasaki disease in children, and recent data suggest that it improves ventricular function in children with new-onset dilated cardiomyopathies. The role of immune globulin therapy in adults with this disorder has not previously been evaluated.

Methods and Results
Ten patients were treated with high-dose intravenous immune globulin infusions (2 g/kg). All were hospitalized with NYHA class III to IV heart failure, left ventricular ejection fraction (LVEF) <0.40, and symptoms for <6 months at the time of presentation. One patient died before the completion of therapy. The remaining 9 were discharged, and LVEF was reassessed 12 months after therapy. LVEF improved from 0.24±0.02 (mean±SEM) at baseline to 0.41±0.04 at follow-up (
P
=.003). All 9 patients improved functionally to NYHA class I to II, and there have been no subsequent hospitalizations for heart failure during the course of follow-up.

Conclusions
In this series of patients with new-onset dilated cardiomyopathy treated with high-dose immune globulin, LVEF improved 17 EF units. The effectiveness of intravenous immune globulin therapy in this disorder should be evaluated in a randomized, multicenter trial.
Extracellular Mg
2+
Inhibits Capacitative Ca
2+
Entry in Vascular Smooth Muscle Cells
Authors: Yoshimura Mitsuisa , Oshima Tetsuya , Matsuura Hideo , Ishida Takafumi , Kambe Masayuki , Kajiyama Goro
Published: June 2012

Background
Agonist-induced Ca
2+
entry is thought to be mediated by capacitative Ca
2+
entry other than L-type Ca
2+
channels in vascular smooth muscle cells (VSMCs). The mechanism for capacitative Ca
2+
entry has not been fully elucidated. Our objective was to examine the effect of external Mg
2+
on capacitative Ca
2+
entry in cultured rat aortic VSMCs.

Methods and Results
Three doses of external Mg
2+
concentration (nominally 0, 1, and 5 mmol/L) were used. After exposure to 1 μmol/L angiotensin II (Ang II) in Ca
2+
-free medium, addition of Ca
2+
to the medium caused an increase in cytosolic free Ca
2+
concentration ([Ca
2+
]
i
), indicating Ang II–induced Ca
2+
influx. This Ca
2+
influx was attenuated in cells preincubated with high external Mg
2+
concentrations or with 1 μmol/L nifedipine. After VSMCs in Ca
2+
-free medium were exposed to 1 μmol/L thapsigargin, which inhibits the sarcoplasmic reticulum Ca
2+
-ATPase and depletes Ca
2+
stores, addition of Ca
2+
to the medium induced an increase in [Ca
2+
]
i
, indicating capacitative Ca
2+
entry. This entry pathway was found to be independent of dihydropyridine-sensitive Ca
2+
channels and inhibited by increased external Mg
2+
concentration. External Mg
2+
concentration did not influence Ca
2+
efflux across the plasma membrane after stimulation with Ang II plus thapsigargin.

Conclusions
Results suggest that in VSMCs, capacitative Ca
2+
entry is reduced by external Mg
2+
. This mechanism may explain in part the inhibitory effect of external Mg
2+
on Ca
2+
handling.
Plasma Angiotensin-Converting Enzyme Activity and Left Ventricular Dilation After Myocardial Infarction
Authors: Oosterga Margreeth , Voors Adriaan A. , de Kam Pieter-Jan , Schunkert Heribert , Pinto Yigal M. , Kingma J. Herre , van Gilst Wiek H.
Published: June 2012

Background
Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the
ACE DD
genotype. The
ACE DD
genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance for subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI.

Methods and Results
Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7±0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided into a group having low ACE activity (≤12 IU/L, n=15) and a group having high ACE activity (>12 IU/L, n=49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (
P
=.0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (
P
=.0006 and
P
=.02, respectively) 1 year after MI.

Conclusions
Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.
Vitamin C Improves Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans With Hypercholesterolemia
Authors: Ting Henry H. , Timimi Farris K. , Haley Elizabeth A. , Roddy Mary-Anne , Ganz Peter , Creager Mark A.
Published: June 2012

Background
Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia. Oxidative degradation of endothelium-derived nitric oxide plays a major role in endothelial dysfunction in animal models of hypercholesterolemia. To assess whether this mechanism is relevant to humans, we studied the effect of vitamin C, an antioxidant, on vasodilator function in forearm resistance vessels of patients with hypercholesterolemia.

Methods and Results
We studied 11 hypercholesterolemic and 12 healthy control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of methacholine (0.3 to 10 μg/min). Endothelium-independent vasodilation was measured by intra-arterial infusion of nitroprusside (0.3 to 10 μg/min) and verapamil (10 to 300 μg/min). Forearm blood flow dose-response curves were determined for each drug before and during coadministration of vitamin C (24 mg/min). In hypercholesterolemic subjects, endothelium-dependent vasodilation to methacholine was augmented by coinfusion of vitamin C (
P
=.001); in contrast, endothelium-independent vasodilation to nitroprusside and verapamil were not affected by coinfusion of vitamin C (
P
=.8 and
P
=.3, respectively). In control subjects, vitamin C administration did not alter endothelium-dependent vasodilation (
P
=.2).

Conclusions
We conclude that vitamin C improves endothelium-dependent vasodilation in the forearm resistance vessels of patients with hypercholesterolemia. These findings suggest that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in hypercholesterolemic humans.
Tissue Plasminogen Activator and Risk of Myocardial Infarction
Authors: van der Bom Johanna G. , de Knijff Peter , Haverkate Frits , Bots Michiel L. , Meijer Piet , de Jong Paulus T. V. M. , Hofman Albert , Kluft Cornelis , Grobbee Diederick E.
Published: June 2012

Background
Impaired fibrinolytic capacity, as assessed by euglobulin clot lysis time or plasma concentration of fibrinolytic parameters, has been associated with an increased risk of myocardial infarction (MI). We studied the association of a polymorphism in the gene for TPA and of plasma concentrations of TPA (antigen and activity) with the prevalence of MI.

Methods and Results
A case-control study was performed. Subjects with a history of MI (n=121) and controls (n=250) were drawn from the Rotterdam Study, a population-based cohort study of 7983 subjects ≥55 years old. We determined TPA antigen and activity in plasma and genotyped all subjects for the
Alu
repeat insertion/deletion polymorphism in intron h in the TPA gene. Homozygosity for the insertion was associated with twice as many cases of MI as was homozygosity for the deletion (odds ratio, 2.24; 95% CI, 1.11-4.50). TPA antigen was positively associated with the risk of MI; compared with that in the lowest quartile, the relative risks (odds ratio) in the second, third, and upper quartiles were 1.7 (CI, 0.9-3.3), 2.3 (1.2-4.4), and 2.0 (1.0-3.8), respectively. When adjusted for body mass index, HDL and total cholesterol, systolic and diastolic blood pressures, and current smoking, the risk associated with TPA antigen concentration was attenuated. Increased concentrations of TPA activity tended to be associated with an increased risk of MI.

Conclusions
This study provides evidence for an independent association of the insertion allele of the insertion/deletion polymorphism in the TPA gene with nonfatal MI. Increased TPA antigen is associated with an increased risk of MI; however, this association was not independent of cardiovascular disease risk factors.
Mechanical Pressure and Stretch Release Endothelin-1 From Human Atherosclerotic Coronary Arteries In Vivo
Authors: Hasdai David , Holmes David R. , Garratt Kirk N. , Edwards William D. , Lerman Amir
Published: June 2012

Background
Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogenic properties. In vitro, vascular release of ET-1 is increased in response to mechanical stress. The goal of the present study was to examine whether ET-1 is released from human atherosclerotic coronary arteries in vivo in response to mechanical pressure and stretch and to characterize immunoreactivity for ET-1 and its precursor, big ET-1, within the atheromatous plaque.

Methods and Results
Circulating ET-1 levels were measured in 20 patients before and after coronary angioplasty for stable angina at three sampling sites: the femoral artery and the coronary artery segments proximal and distal to the lesion dilated. In addition, atheromatous tissue obtained from 20 patients undergoing directional coronary atherectomy for stable angina were analyzed for immunoreactivity for ET-1 and big ET-1. In patients undergoing angioplasty, ET-1 levels in the distal coronary artery increased after balloon dilatation (8.4±0.9 to 16.4±2 pg/mL,
P
<.05); proximal coronary artery and systemic ET-1 levels were unchanged. The degree of mechanical stress applied (product of duration and pressure of balloon inflation) correlated with the change in distal coronary artery ET-1 levels (
r
=.71,
P
<.01). Immunoreactivity for big ET-1 and ET-1 was ubiquitous in the extracellular space and the intracellular compartment (macrophages, myointimal cells, myofibroblasts, and endothelial cells) of human coronary atheromatous tissue.

Conclusions
Big ET-1 and ET-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of coronary atherosclerotic tissue. ET-1 is released from these sites in response to mechanical stress. These findings support a role for endothelins in the evolution and progression of coronary atherosclerosis in humans.