bluuebunny/crossref_metadata_2025 huggingface dataset:
Monoamine- and Histamine-Synthesizing Enzymes and Neurotransmitters Within Neurons of Adult Human Cardiac Ganglia
Authors: Singh Sanjay , Johnson Patricia I. , Javed Adil , Gray Thackery S. , Lonchyna Vassyl A. , Wurster Robert D.
Published: June 2012

Background
—Cardiac ganglia were originally thought to contain only cholinergic neurons relaying parasympathetic information from preganglionic brain stem neurons to the heart. Accumulating evidence, however, suggests that cardiac ganglia contain a heterogeneous population of neurons that synthesize or respond to several different neurotransmitters and neuropeptides. Reports regarding monoamine and histamine synthesis and neurotransmission within cardiac ganglia, however, present conflicting information or are limited in number. Furthermore, very few studies have examined the neurochemistry of adult human cardiac ganglia. The purpose of this study was, therefore, to determine whether monoamine- and histamine-synthesizing enzymes and neurotransmitters exist within neurons of adult human cardiac ganglia.

Methods and Results
—Human heart tissue containing cardiac ganglia was obtained during autopsies of patients without cardiovascular pathology. Avidin-biotin complex immunohistochemistry was used to demonstrate tyrosine hydroxylase,
l
-dopa decarboxylase, dopamine β-hydroxylase, phenylethanolamine-
N
-methyltransferase, tryptophan hydroxylase, and histidine decarboxylase immunoreactivity within neurons of cardiac ganglia. Dopamine, norepinephrine, serotonin, and histamine immunoreactivity was also found in ganglionic neurons. Omission or preadsorption of primary antibodies from the antisera and subsequent incubation with cardiac ganglia abolished specific staining in all cases examined.

Conclusions
—Our results suggest that neurons within cardiac ganglia contain enzymes involved in the synthesis of monoamines and histamine and that they contain dopamine, norepinephrine, serotonin, and histamine immunoreactivity. Our findings suggest a putative role for monoamine and histamine neurotransmission within adult human cardiac ganglia. Additional, functional evidence will be necessary to evaluate what the physiological role of monoamines and histamine may be in neural control of the adult human heart.
Coronary Arteriolar Dilation to Acidosis
Authors: Ishizaka Hiroshi , Gudi Siva R. , Frangos John A. , Kuo Lih
Published: June 2012

Background
—We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (K
ATP
) channels. However, the signal transduction involved in the K
ATP
-channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)–sensitive G proteins may be involved in the signal transduction for K
ATP
-channel activation. However, it remains unclear whether this transduction process also occurs in the vascular tissue and, in particular, whether it exerts functional dilation in response to acidosis.

Methods and Results
—To examine the signaling pathway for acidosis-induced dilation, porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. The GTPase activity in reconstituted G proteins was examined at different levels of pH. Extravascular acidosis (pH 7.3 to 7.0) produced a graded dilation of coronary arterioles. This dilation was not affected by removal of endothelium but was significantly attenuated after inhibition of K
ATP
channels and G proteins by glibenclamide and PTX, respectively. Glibenclamide and PTX attenuated the acidosis-induced arteriolar dilation to the same extent, and combined administration of both inhibitors did not further inhibit the vasodilation. These results indicated that both inhibitors act on the same vasodilatory pathway. Furthermore, vasodilation of coronary arterioles to the K
ATP
-channel opener pinacidil and to the endothelium-independent vasodilator sodium nitroprusside was not affected by PTX. Because PTX inhibited acidosis-induced vasodilation without inhibiting K
ATP
-channel function, it is suggested that PTX inhibits the vasodilatory pathway upstream from K
ATP
channels. GTPase activity in reconstituted G proteins was significantly enhanced by a reduction in pH, indicating that G proteins were directly activated by acidosis.

Conclusions
—On the basis of these findings, we conclude that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle K
ATP
channels through the activation of PTX-sensitive G proteins.
Dynamic Holographic Imaging of the Beating Human Heart
Authors: Hunziker Patrick R. , Smith Steven , Scherrer-Crosbie Marielle , Liel-Cohen Noah , Levine Robert A. , Nesbitt Ryder , Benton Stephen A. , Picard Michael H.
Published: June 2012

Background
—Currently, the reporting and archiving of echocardiographic data suffer from the difficulty of representing heart motion on printable 2-dimensional (2D) media.

Methods and Results
—We studied the capability of holography to integrate motion into 2D echocardiographic prints. Images of normal human hearts and of a variety of mitral valve function abnormalities (mitral valve prolapse, systolic anterior motion of the mitral leaflets, and obstruction of the mitral valve by a myxoma) were acquired digitally on standard echocardiographic machines. Images were processed into a data format suitable for holographic printing. Angularly multiplexed holograms were then printed on a prototype holographic “laser” printer, with integration of time in vertical parallax, so that heart motion became visible when the hologram was tilted up and down. The resulting holograms displayed the anatomy with the same resolution as the original acquisition and allowed detailed study of valve motion with side-by-side comparison of normal and abnormal findings. Comparison of standard echocardiographic measurements in original echo frames and corresponding hologram views showed an excellent correlation of both methods (
P
<0.0001,
r
2
=0.979, mean bias=2.76 mm). In this feasibility study, both 2D and 3D holographic images were produced. The equipment needed to view these holograms consists of only a simple point-light source.

Conclusions
—Holographic representation of myocardial and valve motion from echocardiographic data is feasible and allows the printing on a 2D medium of the complete heart cycle. Combined with the recent development of online holographic printing, this novel technique has the potential to improve reporting, visualization, and archiving of echocardiographic imaging.
Enhanced Shear-Induced Platelet Aggregation in Acute Myocardial Infarction
Authors: Goto Shinya , Sakai Hiroyuki , Goto Mami , Ono Miyuki , Ikeda Yasuo , Handa Shunnosuke , Ruggeri Zaverio M.
Published: June 2012

Background
—Experiments under controlled flow conditions indicate that the binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ibα and integrin α
IIb
β
3
(GP IIb/IIIa complex) is crucial for aggregation at elevated shear rates. We have tested how the plasma of patients with acute myocardial infarction affects this process.

Methods and Results
—Citrated plasma was obtained from 18 patients with acute myocardial infarction within 6 hours from the onset of symptoms and from 26 control subjects with chest pain syndrome without evidence of ischemia. Aggregation of normal platelets at high shear rates was significantly greater in the presence of patient than control plasma and was inhibited by both anti-GP Ibα and anti-α
IIb
β
3
monoclonal antibodies. The observed values (mean±SD) were 47.6±17.8% versus 30.1±9.9% at 10 800 s
−1
(
P
<0.01) and 32.9±14.1% versus 17.5±9.5% at 7200 s
−1
(
P
<0.01), respectively, and were positively correlated with plasma vWF antigen levels and ristocetin cofactor activities. In contrast, at the lower shear rate of 1200 s
−1
, aggregation was similar in the presence of control or patient plasma and was not inhibited by the anti-GP Ibα antibody. Both vWF antigen and platelet aggregation decreased 2 weeks after the onset of myocardial infarction.

Conclusions
—Shear-induced platelet aggregation is enhanced in plasma in the presence of acute myocardial infarction, apparently as a result of increased vWF concentration. This may contribute to the onset of acute coronary artery thrombosis and early reocclusion after reperfusion treatment.
Rapid Platelet-Function Assay
Authors: Smith Jeffrey W. , Steinhubl Steven R. , Lincoff A. Michael , Coleman Jacqueline C. , Lee Theodore T. , Hillman Robert S. , Coller Barry S.
Published: June 2012

Background
—The platelet glycoprotein (GP) IIb/IIIa receptor is important in mediating platelet thrombus formation, and the GP IIb/IIIa antagonist abciximab (c7E3 Fab; ReoPro) is effective in preventing thrombotic ischemic cardiovascular complications of unstable angina and percutaneous coronary interventions. Small-molecule antagonists of GP IIb/IIIa based on the Arg-Gly-Asp (RGD) sequence show similar benefit, and some of these agents are orally active. However, there may be significant interindividual variation in response to such antagonists, especially with chronic oral therapy. It will be essential to balance the beneficial antithrombotic effect of these drugs with their potential for causing bleeding. In response to this need, we have developed a rapid platelet-function assay (RPFA), a point-of-care system that provides a quantitative measure of the competence of the GP IIb/IIIa receptor as reflected in the ability of platelets to agglutinate fibrinogen-coated beads.

Methods and Results
—Polystyrene beads were coated with fibrinogen and placed in a cartridge along with a lyophilized peptide that activates the thrombin receptor. Anticoagulated whole blood was added to the cartridge, and then a microprocessor-controlled operation mixed the reagents and detected agglutination between platelets and coated beads. Quantitative digital results were displayed within 3 minutes. Because there is no dilution of the blood, the assay can be used to measure platelet activity in samples that have been treated with GP IIb/IIIa antagonists with high dissociation rates. RPFA results of whole-blood samples treated with different GP IIb/IIIa antagonists correlated well with both conventional turbidimetric platelet aggregation (
r
2
=0.95) and the percentage of free GP IIb/IIIa molecules in the sample (
r
2
=0.96). The mean difference in measurements between RPFA and aggregometry was –4% (±4% SD), and the mean difference in measurements between RPFA and free GP IIb/IIIa receptors was –2% (±6% SD).

Conclusions
—The RPFA provides rapid information on platelet function that mirrors turbidimetric platelet aggregation and reflects GP IIb/IIIa receptor blockade.
Noninvasive Measurements of Infarct Size After Thrombolysis With a Necrosis-Avid MRI Contrast Agent
Authors: Pislaru Sorin V. , Ni Yicheng , Pislaru Cristina , Bosmans Hilde , Miao Yi , Bogaert Jan , Dymarkowski Steven , Semmler Wolfhard , Marchal Guy , Van de Werf Frans J.
Published: June 2012

Background
—Gadophrin-2 is a new MRI contrast agent with high affinity for necrotic myocardium. The aim of the study was to evaluate whether noninvasive measurements of infarct size after thrombolysis are possible with gadophrin-2–enhanced MRI.

Methods and Results
—Coronary artery thrombosis was induced in 3 groups of dogs by the copper-coil technique. Thrombolytic therapy together with aspirin and heparin was initiated after 90 minutes of occlusion. One day (group A), 2 days (group B), or 6 days (group C) after infarction, gadophrin-2 was injected intravenously (50 μmol · kg
−1
). In vivo T1-weighted segmented turbo-FLASH, in vivo T2-weighted segmented half-Fourier turbo spin echo (HASTE), and T1- and T2-weighted spin-echo MRI of the excised heart were performed 24 hours after gadophrin-2 injection. Regions of strong enhancement were observed on T1-weighted images. Planimetry of short-axis MR images and of corresponding triphenyltetrazolium chloride (TTC)-stained left ventricular (LV) slices showed a close correlation between the enhanced areas and TTC-negative areas for both in vivo (
r
2
=0.98,
P
<0.0001; mean difference, 0.9±2.0% [SD] of the LV volume [LVV]) and postmortem (
r
2
=0.99,
P
<0.0001; mean difference, 0.9±1.4% of LVV) measurements. T2-weighted images overestimated the infarct size by 8.1±5.4% of LVV. The mean infarct size was 10.8±11.6% of LVV (group A), 22.4±11.7% (group B), and 5.1±9.3% (group C).

Conclusions
—In this animal model, in vivo gadophrin-2–enhanced MRI could precisely determine infarct size after thrombolytic therapy. This technique may be very useful for the noninvasive evaluation of infarct size after reperfusion for AMI.
Clenbuterol Increases Stroke Power and Contractile Speed of Skeletal Muscle for Cardiac Assist
Authors: Petrou M. , Clarke S. , Morrison K. , Bowles C. , Dunn M. , Yacoub M.
Published: June 2012

Background
—Skeletal muscle assist (SMA) may be limited by loss of power, slowing of contraction and relaxation, and atrophy of the transformed latissimus dorsi muscle (LD). Clenbuterol (clen), a β
2
-adrenergic receptor agonist, was used to improve the performance of trained skeletal muscle in sheep.

Methods and Results
—The following 4 groups were used: A (n=6), untrained controls; B (n=6), left LD progressively transformed toward a slow-twitch and fatigue-resistant phenotype by electrical stimulation over 12 weeks (2.5 to 5 V, 240-μsec pulse duration, 35 Hz, 3 to 6 pulses per burst, and up to 40 bursts per minute); C (n=6), clen-treated (0.5 mg/kg SC) for 12 weeks; and D (n=6), clen+trained. In a terminal experiment, the mobilized LD was wrapped around a rubber aorta of a mock circulation and stimulated to contract 40 times per minute. Group A had an initial mean pressure augmentation (ΔP) of 24.6 mm Hg and stroke power of 2.28 W/kg, but both fell to <20% of their original values by 15 minutes because of fatigue (
P
<0.005). Group B was fatigue-resistant, with a ΔP and stroke power at 60 minutes of 13 mm Hg (70% of initial) and 0.34 W/kg (39% of initial), respectively. The performance of group C was similar to that of controls. In group D, however, the muscles were stronger at all time points than in B, with a ΔP of 23 mm Hg and stroke power of 2.66 W/kg at 60 minutes (
P
<0.01). The speeds of contraction (+dP/dt:ΔP) and relaxation (−dP/dt:ΔP) were significantly greater in group D than B. Protein analyses showed group D to have only a trend toward greater abundance of the fast isoforms of myosin heavy chain and sarcoplasmic reticulum Ca
2+
-ATPase (
P
>0.1).

Conclusions
—Clen improves the performance of trained skeletal muscle in a model of aortomyoplasty by unknown mechanisms. These findings may have important implications in SMA.
Noninvasive Diagnosis of Ischemia-Induced Wall Motion Abnormalities With the Use of High-Dose Dobutamine Stress MRI
Authors: Nagel Eike , Lehmkuhl Hans B. , Bocksch Wolfgang , Klein Christoph , Vogel Uta , Frantz Eckart , Ellmer Axel , Dreysse Stefan , Fleck Eckart
Published: June 2012

Background
—The analysis of wall motion abnormalities with dobutamine stress echocardiography (DSE) is an established method for the detection of myocardial ischemia. With ultrafast magnetic resonance tomography, identical stress protocols as used for echocardiography can be applied.

Methods and Results
—In 208 consecutive patients (147 men, 61 women) with suspected coronary artery disease, DSE with harmonic imaging and dobutamine stress magnetic resonance (DSMR) (1.5 T) were performed before cardiac catheterization. DSMR images were acquired during short breath-holds in 3 short-axis views and a 4- and a 2-chamber view (gradient echo technique). Patients were examined at rest and during a standard dobutamine-atropine scheme until submaximal heart rate was reached. Regional wall motion was assessed in a 16-segment model. Significant coronary heart disease was defined as ≥50% diameter stenosis. Eighteen patients could not be examined by DSMR (claustrophobia 11 and adipositas 6) and 18 patients by DSE (poor image quality). Four patients did not reach target heart rate. In 107 patients, coronary artery disease was found. With DSMR, sensitivity was increased from 74.3% to 86.2% and specificity from 69.8% to 85.7% (both
P
<0.05) compared with DSE. Analysis for women yielded similar results.

Conclusions
—High-dose dobutamine magnetic resonance tomography can be performed with a standard dobutamine/atropine stress protocol. Detection of wall motion abnormalities by DSMR yields a significantly higher diagnostic accuracy in comparison to DSE.
Coronary Heart Disease and Iron Status
Authors: Danesh John , Appleby Paul
Published: June 2012

Background
—Studies of iron status and coronary heart disease (CHD) have yielded conflicting results. In a systematic review (“meta-analysis”), we quantitatively assessed epidemiological associations reported in prospective studies.

Methods and Results
—Studies were identified by computer-assisted searches of the published literature, scanning of relevant reference lists, hand searching of relevant journals, and discussions with relevant authors. The following was abstracted: size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. Twelve studies were identified, involving a total of 7800 CHD cases, with several reporting on >1 marker of iron status. For serum ferritin, with 570 CHD cases in 5 studies, comparison of individuals with baseline values ≥200 versus <200 μg/L yielded a combined risk ratio of 1.0 (95% CI, 0.8 to 1.3). For transferrin saturation, with 6194 CHD cases in 5 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 0.9 (95% CI, 0.7 to 1.1). Comparisons of individuals in top and bottom thirds of baseline measurements also yielded nonsignificant risk ratios in combined analyses of studies involving total iron-binding capacity (combined risk ratio, 1.0; 95% CI, 0.7 to 1.5), serum iron (0.8; 95% CI, 0.7 to 1.0), and total dietary iron (0.8; 95% CI, 0.7 to 1.1).

Conclusions
—Published prospective studies do not provide good evidence to support the existence of strong epidemiological associations between iron status and CHD.
One-Year Survival Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock, and its Relation to Early Revascularization
Authors: Berger Peter B. , Tuttle Robert H. , Holmes David R. , Topol Eric J. , Aylward Philip E. , Horgan John H. , Califf Robert M.
Published: June 2012

Background
—Although 30-day survival is increased in patients with acute myocardial infarction complicated by cardiogenic shock who undergo coronary revascularization, the longer-term outcome in such patients and the duration of benefit from revascularization are unknown.

Methods and Results
—We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial and identified 36 333 who had not had cardiogenic shock (systolic blood pressure <90 mm Hg for ≥1 hour, group 1) and 1321 patients who had shock (group 2). Group 2 patients were older and sicker. At 1 year, 97.4% of group 1 patients were alive versus 88.0% of group 2 (
P
=0.0001). Among group 2 patients, 578 (44%) had undergone revascularization within 30 days (group 2A) and 728 (56%) had not (group 2B). Revascularization was not required by protocol but was selected by the attending physicians. At 1 year, 91.7% of group 2A patients were alive versus 85.3% of group 2B (
P
=0.0003). With the use of multivariable logistic regression analysis to adjust for differences in baseline characteristics of shock patients alive at 30 days, revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9],
P
=0.007).

Conclusions
—Most patients (88%) with acute myocardial infarction complicated by cardiogenic shock who are alive at 30 days survived at least 1 year. Shock patients who underwent revascularization within 30 days had improved survival at 1 year compared with shock patients who did not receive revascularization, even after adjustment for differences in baseline characteristics between the 2 groups.
Detection of
Chlamydia pneumoniae
But Not Cytomegalovirus in Occluded Saphenous Vein Coronary Artery Bypass Grafts
Authors: Bartels Claus , Maass Matthias , Bein Gregor , Malisius Rainer , Brill Nicole , Bechtel J. F. Matthias , Sayk Friedhelm , Feller Alfred C. , Sievers Hans-Hinrich
Published: June 2012

Background
—A causal relation between atherosclerosis and chronic infection with
Chlamydia pneumoniae
and/or cytomegalovirus (CMV) has been suggested. Whether the unresolved problem of venous coronary artery bypass graft occlusion is related to infection with
C pneumoniae
and/or CMV has not been addressed.

Methods and Results
—Thirty-eight occluded coronary artery vein grafts and 20 native saphenous veins were examined. Detection of
C pneumoniae
DNA was performed by use of nested polymerase chain reaction (PCR). Homogenisates from the specimen were cultured for identification of viable
C pneumoniae
. Both conventional PCR and quantitative PCR for detection of CMV DNA were applied. Differential pathological changes (degree of inflammation, smooth muscle cell proliferation [MIB-1]) were determined and correlated to the detection of both microorganisms.
C pneumoniae
DNA could be detected in 25% of occluded vein grafts. Viable
C pneumoniae
was recovered from 16% of occluded vein grafts. Except for 1 native saphenous vein, all control vessels were negative for both
C pneumoniae
detection and culture. All pathological and control specimens were negative for CMV DNA detection. Pathological changes did not correlate with
C pneumoniae
detection.

Conclusions
—Occluded aorto-coronary venous grafts harbor
C pneumoniae
but not CMV. The detection of
C pneumoniae
in occluded vein grafts warrants further investigation.
Differential Effects of a Segment of Slow Conduction on Reentrant Ventricular Tachycardia in the Rabbit Heart
Authors: Haberl Kai , Allessie Maurits
Published: June 2012

Background
—The purpose of this study was to compare differential effects of a segment of slow conduction during ventricular tachycardia (VT) due to depression of the action potential and electrical uncoupling.

Methods and Results
—In 33 Langendorff-perfused rabbit hearts, a ring of anisotropic left ventricular subepicardium was created by a cryoprocedure. Reentrant VT was produced by incremental pacing. Slow conduction in a segment of the ring was created by selective perfusion of the LAD with 10 mmol/L potassium or 0.75 mmol/L heptanol. As a result, VT cycle length increased from 193±34 to 235±37 ms (potassium) and 227±42 ms (heptanol). Reset curves were made by applying premature stimuli proximal to the area of depressed conduction. In a ring of uniform anisotropic tissue, the reset curve was almost completely flat. Electrical uncoupling of part of the ring (nonuniform anisotropy) resulted in a mixed reset curve. In both substrates, early premature beats failed to terminate VT. Depression of part of the ring by increasing K
+
resulted in a completely sloped reset curve, indicating a gap of partial excitability. Under these conditions, in 19 of 24 hearts, premature beats terminated VT by conduction block in the high K
+
area.

Conclusions
—The nature of the area of slow conduction determines the type of reset response and the ability to terminate VT.
Comparison of Quantitative Coronary Angiography, Intravascular Ultrasound, and Coronary Pressure Measurement to Assess Optimum Stent Deployment
Authors: Hanekamp Clara E. E. , Koolen Jacques J. , Pijls Nico H. J. , Michels H. Rolf , Bonnier Hans J. R. M.
Published: June 2012

Background
—Although intravascular ultrasound (IVUS) is the present standard for the evaluation of optimum stent deployment, this technique is expensive and not routinely feasible in most catheterization laboratories. Coronary pressure–derived myocardial fractional flow reserve (FFR
myo
) is an easy, cheap, and rapidly obtainable index that is specific for the conductance of the epicardial coronary artery. In this study, we investigated the usefulness of coronary pressure measurement to predict optimum and suboptimum stent deployment.

Methods and Results
—In 30 patients, a Wiktor-i stent was implanted at different inflation pressures, starting at 6 atm and increasing step by step to 8, 10, 12, and 14 atm, if necessary. After every step, stent deployment was evaluated by quantitative coronary angiography (QCA), IVUS, and coronary pressure measurement. If any of the 3 techniques did not yield an optimum result, the next inflation was performed, and all 3 investigational modalities were repeated until optimum stent deployment was present by all of them or until the treating physician decided to accept the result. Optimum deployment according to QCA was finally achieved in 24 patients, according to IVUS in 17 patients, and also according to coronary pressure measurement in 17 patients. During the step-up, a total of 81 paired IVUS and coronary pressure measurements were performed, of which 91% yielded concordant results (ie, either an optimum or a suboptimum expansion of the stent by both techniques,
P
<0.00001). On the contrary, QCA showed a low concordance rate with IVUS and FFR
myo
(48% and 46%, respectively).

Conclusions
—In this study, using a coil stent, both IVUS and coronary pressure measurement were of similar value with respect to the assessment of optimum stent deployment. Therefore, coronary pressure measurement can be used as a cheap and rapid alternative to IVUS for that purpose.
Lowering LDL Cholesterol
Authors: Gotto Antonio M. , Grundy Scott M.
Published: June 2012

Abstract
—The benefit of cholesterol-lowering therapy in the prevention of coronary heart disease (CHD) is well established. The secondary prevention Scandinavian Simvastatin Survival Study (4S) and the primary prevention West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated that lipid lowering with a statin can dramatically and cost-effectively reduce CHD morbidity and mortality with no increase in noncardiovascular mortality. The Cholesterol and Recurrent Events (CARE) trial extended benefit to CHD patients without high cholesterol. Post hoc analyses of data from these large trials are contributing to speculation, driven by subset analyses and meta-analyses, about whether cholesterol intervention should be target based, as current guidelines recommend. Whereas CARE data support the importance of baseline LDL cholesterol (LDL-C), with greatest clinical event risk reduction in the upper part of the LDL-C range in the trial, 4S found no difference in outcome according to baseline LDL-C in a quartile analysis, and WOSCOPS found no linear relation between decrease in LDL-C and decrease in relative risk for CHD. Furthermore, WOSCOPS showed no additional clinical benefit with LDL-C lowering beyond ≈24%. Questions raised by such analyses require answers from prospective, hypothesis-based data, and at present there is no compelling argument for moving away from LDL-C targets. The hypothesis-based findings of 4S, CARE, and WOSCOPS support current clinical guidelines, and lowering LDL-C may reduce risk more substantially than might have been predicted.
Caval Contribution to Flow in the Branch Pulmonary Arteries of Fontan Patients With a Novel Application of Magnetic Resonance Presaturation Pulse
Authors: Fogel Mark A. , Weinberg Paul M. , Rychik Jack , Hubbard Anne , Jacobs Marshall , Spray Thomas L. , Haselgrove John
Published: June 2012

Background
—A complete understanding of fluid mechanics in Fontan physiology includes knowledge of the caval contributions to right (RPA) and left (LPA) pulmonary arterial blood flow, total systemic venous return, and relative blood flow to each lung.

Methods and Results
—Ten Fontan patients underwent cine MRI. Three cine scans of the pulmonary arteries were performed: (1) no presaturation pulse, (2) a presaturation pulse labeling inferior vena cava (IVC) blood (signal void), and (3) a presaturation pulse labeling superior vena cava (SVC) blood. The relative signal decrease is proportional to the amount of blood originating from the labeled vena cava. This method was validated in a phantom. Whereas 60±6% of SVC blood flowed into the RPA, 67±12% of IVC blood flowed toward the LPA. Of the blood in the LPA and RPA, 48±14% and 31±17%, respectively, came from the IVC. IVC blood contributed 40±16% to total systemic venous return. The distributions of blood to each lung were nearly equal (RPA/LPA blood=0.94±11).

Conclusions
—In Fontan patients with total cavopulmonary connection, SVC blood is directed toward the RPA and IVC blood is directed toward the LPA. Although the right lung volume is larger than the left, an equal amount of blood flow went to both lungs. LPA blood is composed of equal amounts of IVC and SVC blood because IVC contribution to total systemic venous return is smaller than that of the SVC. This technique and these findings can help to evaluate design changes of the systemic venous pathway to improve Fontan hemodynamics.
Homocysteine Increases Nitric Oxide Synthesis in Cytokine-Stimulated Vascular Smooth Muscle Cells
Authors: Ikeda Uichi , Ikeda Michiyo , Minota Seiji , Shimada Kazuyuki
Published: June 2012

Background
—Elevated plasma homocysteine levels have been reported to be an independent risk factor for vascular disease. However, there have been no reports concerning the effects of homocysteine on the production of nitric oxide (NO), another modulator of vascular function and proliferation, by the vascular smooth muscle.

Methods and Results
—We investigated the effects of homocysteine on NO synthesis by measuring the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells (VSMCs). Incubation of cultures with interleukin (IL)-1β 10 ng/mL for 24 hours caused a significant increase in nitrite generation. The IL-1β–induced nitrite production by VSMCs was significantly increased by homocysteine in a dose-dependent manner. This effect of homocysteine was significantly inhibited in the presence of
N
G
-monomethyl-
l
-arginine or actinomycin D. The homocysteine-induced nitrite production was accompanied by increased inducible NO synthase mRNA and protein accumulation. Cysteine, glutathione, or hydrogen peroxide also increased nitrite accumulation in IL-1β–stimulated VSMCs. Coincubation with the radical scavenger catalase or superoxide dismutase markedly reduced homocysteine-induced nitrite accumulation.

Conclusions
—Homocysteine enhances NO synthesis in IL-1β–stimulated VSMCs, and oxidative products are involved in the effect of homocysteine.
Mechanism of angiotensin I converting enzyme inhibition by SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) in vivo. Further evidence for extrapulmonary conversion.
Authors: Oparil S , Koerner T , O'Donoghue J K
Published: June 2012

The mechanism by which the angiotensin I (AI) converting enzyme inhibitor SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Glu-Ile-Pro-Pro) blocks the pressor response to exogenous AI was studied in vivo in the intact anesthetized dog. When administered as a single dose 250 times that of injected AI (250 nmoles/kg) into either the pulmonary or systemic circulation, SQ20,881 produced inhibition of pulmonary conversion of exogenous AI to AII that lasted for more than 6 hours as judged by the absence of immunoreactive or labeled AII in the pulmonary venous effluent. In contrast, the pressor response to exogenous AI began to reappear within 1 hour of SQ20,881 administration. Six hours following SQ20,881, the pressor response to AI had nearly returned to normal, still in the absence of demonstrable intrapulmonary conversion and without release of detectable amounts of AII into the pulmonary venous effluent. These experiments demonstrated that AI has a pressor effect in the presence of SQ20,881 that is independent of pulmonary conversion. Studies with (Des-Asp) AII and (Des-Asp, Arg) AII showed that the delayed pressor response to AI following SQ20,881 administration could not be accounted for by circulating peptide metabolites of AI or AII. A competitive inhibitor of AII, (D-Asp, Ile) AII completely blocked the returning pressor response, suggesting that extrapulmonary generation of AII was responsible. The data strongly suggest that the systemic vascular bed taken as a whole contains large amounts of AI converting enzyme that is capable of rapid generation of AII without releasing the peptide into circulation. The extrapulmonary enzyme is more resistant to long-lasting blockade by SQ20,881 than pulmonary converting enzyme. The physiological role of extrapulmonary conversion systemic and local circulatory homeotasis remains to be assessed.
Micromethod for the assay of renin of seven species.
Authors: Haas E , Lewis L , Scipione P , Koshy T J
Published: June 2012

Renin was extracted and purified from human, dog, hog, rat, beef, rabbit and sheep kidneys. The renin "concentration" of these preparations was determined and expressed in international (Goldblatt) units by measuring the pressor effect produced by intravascular injection into normal dogs of a permanent colony. The renin "activity" was determined by bioassay, in the rat, of the angiotensin produced by incubation in vitro with renin substrate prepared from the serum of nephrectomized dogs. The rate of angiotensin formation was proportional to the concentration of renin, independent of the substrate concentration, and rather similar for renin of all seven species (mean rate = 55 x 10(4) ng angiotensin/unit renin/16 hrs). Due to this uniformity, either of the two international reference preparations of renin (human or hog) from the World Health Organization can serve as an internal standard in the assay of reninof each of the seven species, to express their concentration in terms of the international unit. Renin substrate from hog plasma was suitable for the assay of human, dog and hog renin (mean rate = 55 x 10(4)). However, it reacted much more slowly with the renin of rat, beef, rabbit and sheep (mean rate = 9 x 10(4)) and was, therefore, less suitable for their assay.
Plasma renin activity, reactivity, concentration and substrate following hypertension during pregnancy. Effect of oral contraceptive agents.
Authors: Kotchen T A , Kotchen J M , Guthrie G P , Cottrill C M
Published: June 2012

Plasma renin activity is suppressed in approximately 25% of patients with essential hypertension, and the rate of in vitro angiotensin I production after addition of exogenous renin (renin reactivity) is increased in plasma of hypertensive patients. We have recently observed that blood pressure (116 +/- 1.5/68 +/- 1.7 mm Hg) of young women who had hypertension during a first pregnancy 3--6 years earlier (n = 63) was higher (p less than 0.005) than blood pressure (109 +/- 1.4/61 +/- 1.7 mm Hg) of women who remained normotensive during pregnancy (n = 52). To determine if alterations of the renin-angiotensin axis observed in patients with established hypertension also occur in young adults with relatively high blood pressure, plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate (PRS) and plasma renin reactivity (PRR) were compared in these two groups of subjects. Overall, PRA and PRC were inversely related to systolic blood pressure (p less than 0.02). Excluding women on oral contraceptive agents, the PRA response to standardized treadmill exercise was suppressed (less than 1.0 ng/ml/hr) in 19% of women with a history of hypertension during pregnancy and in no women who remained normotensive throughout a previous pregnancy; PRR did not differ (p greater than 0.8) in the two groups of young mothers (27.1 ng/ml/30 min +/- 1.2 SE VS 26.2 ng/ml/30 min +/- 0.9 SE). Thus, renin suppression, but not increased PRR, precedes the onset of hypertension. Oral contraceptive usage was associated with higher systolic blood pressures, increased PRS, and low PRC. Highest blood pressures and lowest PRA occurred in women with a history of hypertension during pregnancy who were taking oral contraceptive agents at the time of study.
Angiotensin and sodium balance: their role in chronic two-kidney Goldblatt hypertension.
Authors: Otsuka Y , Carretero O A , Albertini R , Binia A
Published: June 2012

The purpose of this study was twofold: 1) to determine whether the failure of rats with chronic renovascular hypertension to respond to the angiotensin II antagonist (AIIA) with a decrease in mean blood pressure (BP) was dur to the agonistic effect of the antagonist; and, 2) if this was not the case, to examine whether a positive sodium balance impaired the reversal of the hypertension, after unclamping, in the rats that did not respond to angiotensin inhibitors. For this purpose, rats with chronic, two-kidney Goldblatt hypertension (one renal artery clamped and contralateral untouched) were tested for their BP response to the AIIA (1-Sar-8-Ala-angiotensin II) and to the converting enzyme inhibitor (CEI) SQ20,881, which is devoid of agonistic effect. Approximately 50% of the rats responded to both inhibitors either with no change or with a decrease in BP of less than 20 mm Hg (nonresponders). The other 50% had a decrease in BP of 20 mm Hg or greater (responders). The decrease in BP produced by the AIIA and the CEI correlated significantly (r = 0.76). Nonresponders to both inhibitors were unclamped or sham unclamped. A positive sodium balance was produced before surgery by injecting either 400 or 1000 microEq of sodium and was maintained for 12 hours. Direct BP significantly decreased 12 hours after surgery in the unclamped rats despite a continuous positive sodium balance. In the sham unclamped rats, BP did not change. These data indicate that the failure to respond to the AIIA is not due to the agonistic effect of this peptide. Furthermore, these data suggest that a positive sodium balance is not a major pathogenetic factor in maintaining the high BP in the nonresponder rats, since a positive sodium balance failed to maintain the hypertension after unclamping.
The role of angiotensin in the control of blood pressure during sodium depletion.
Authors: Conway J , Hatton R , Keddie J , Dawes P
Published: June 2012

Sodium depletion was induced in dogs to raise plasma renin activity (PRA) from 1.11 to 26.48 ng/ml/hr. Little overall change in blood pressure (BP) occurred, but cardiac output (CO) and central venous pressure fell, while total peripheral resistance and heart rate (HR) increased. A nonapeptide converting enzyme inhibitor (CEI) produced a fall in BP which was linearly related to log. PRA; the intercept with PRA was at 1.05 ng/ml/hr, close to the average value for dogs on a normal diet. The fall in BP with this agent was not accompanied by an increase in HR or CO. When Sar1-Ala8 angiotensin II was used to antagonize the action of angiotensin, the fall in BP was also linearly related to log. PRA. However, for a given level of PRA this fall in BP was less than that achieved with CEI and the intercept of BP fall with PRA was 2.6 ng/ml/hr. Again with this agent there was little change in HR or CO as BP was reduced. Thus, both antagonists lowered peripheral resistance without exciting the homeostatic reflexes indicating that, as PRA rose above the normal resting level, the angiotensin generated had both a direct and indirect effect in maintaining BP.
Factors controlling plasma renin and aldosterone during pregnancy.
Authors: Bay W H , Ferris T F
Published: June 2012

The response of plasma renin activity (PRA) and plasma aldosterone (PA) to change in sodium intake was evaluated in pregnant women during the third trimester. After 7 days on a 10 mEq sodium diet, PRA rose from 20.6 +/- 6.2 to 59.6 +/- 11.6 ng/ml/hr and PA from 47 +/- 11 to 127 +/- 27 ng% in pregnant women compared to PRA from 5 +/- 1.2 to 18.9 +/- 5.2 ng/ml/hr and PA from 7.7 +/- 1 to 42 +/- 3 ng% in nonpregnant controls. Pregnant women conserved sodium normally with urinary sodium excretion and weight loss similar to nonpregnant women. After 6 days on a 300 mEq sodium intake, PRA and PA in pregnant women were significantly higher, 10.2 +/- 1.4 ng/ml/hr and 22 +/- 3 ng%, respectively, compared to 1.5 +/- 0.3 ng/ml/hr and 7.3 +/- 1 ng% in controls. On both low- and high sodium intake there was a positive correlation between PRA and PA in pregnant women. Plasma prostaglandin E (PGE) was 0.45 +/- 0.06 ng/ml in pregnant women compared to 0.1 +/- 0.01 ng/ml in control women (p less than 0.01) and urinary PGE excretion was 2780 +/- 357 ng/24 hr in 28 pregnant women compared to 1191 +/- 142 ng/24 hrs (p less than 0.01) in 14 nonpregnant controls. These findings indicate that although renin and aldosterone secretion respond to change in sodium intake in pregnancy, the cause of the increased renin secretion of pregnancy may be secondary to the increase that occurs in prostaglandin synthesis.
Some theories of hypertension: fact and fancy.
Authors: Mendlowitz M
Published: June 2012

1. Various theories on the origin and development of hypertension offered over the years have been assessed critically. 2. It is concluded that no one theory is adequate at the present time to encompass all the known facts. 3. Continuously expanded understanding of hypertensive mechanisms, however, help in the individualization and therefore the improvement of various modalities of therapy, including treatment with presently available agents, as well as with those which may be developed in the future.
Chronic hypothalamic stimulation in awake rats fails to induce hypertension.
Authors: Buñag R D , Riley E
Published: June 2012

Daily electrical stimulation of the posterior hypotalamus for 12 weeks in awake rats caused persistent cardioacceleration but barely increased systolic pressure. Subsequent postmortem examination showed extensive fibrosis at sites of electrode implantation in both stimulated and unstimulated rats. Because Folkow and Rubinstein had succeeded in elevating blood pressure progressively by stimulating the "hypothalamic defence area," chronic stimulation was repeated following their stereotaxic coordinates. Systolic pressure rose but the elevation was significant only on Weeks 8 and 10. To maintain behavioral effects during chronic stimulation, current strengths had to be increased periodically, and stimulated rats gained weight more rapidly than unstimulated controls. Both these findings indicated that electrical stimulation had damaged the brain, but since local fibrosis made histologic verification difficult, additional experiments were done to determine if functional deficits could be detected. Upon further hypothalamic stimulation, electrical thresholds were higher and pressor and sympathetic nerve responses were smaller in rats that had been stimulated chronically than in those that had not. Although our results do not disprove the hypothesis that centrally-induced sympathetic hyperactivity initiates hypertension, they show that blood pressure cannot be elevated by hypothalamic stimulation alone when the brain has been injured.
Central hemodynamics in the developmental stage of spontaneous hypertension in the unanesthetized rat.
Authors: Smith T L , Hutchins P M
Published: June 2012

The hemodynamic alterations associated with the developmental phase of high blood pressure were investigated in the spontaneously hypertensive rat (SHR). All hemodynamic measurements were made in unanesthetized, unrestrained SHR and Wistar-Kyoto (WKY) rats instrumented with chronic electromagnetic flow probes on the ascending aorta and arterial pressure catheters. Rats were studied at 30-41 days, 80 days, and 120 days of age. Hemodynamics of SHRs and WKYs in the 30-41 day group were monitored daily. Spontaneously hypertensive rats demonstrated a higher cardiac index than WKYs (p less than 0.05) from 32 through 41 days of age. Total peripheral resistance (TPR) was not elevated in SHRs at this time. Heart rate and stroke index were elevated in SHRs (p less than 0.05) from 34 through 41 days, however, stroke volume was not. At 80 and 120 days SHRs had higher mean arterial pressure (MAP) and TPR than WKYs (p less than 0.05), although cardiac index was not significantly different. This hemodynamic pattern of a hyperkinetic circulation prior to the development of hypertension supports the theory of total body autoregulation. A transient increase in cardiac index precedes an increase in TPR, which then normalizes cardiac index while elevating MAP.
Studies on renin activation in normal human plasma.
Authors: Eggena P , Barrett J D , Wiedman C E , Sambhi M P
Published: June 2012

The phenomenon of plasma renin activattion by acid dialysis and preincubation with trypsin was studied in normal human plasma. Activation of plasma renin by exposure to pH 3.3 was shown to require at least one dialysis step and could be inhibited by the presence of Trasylol, indicating the involvement of a protease in acid activation. Amniotic fluid exposed to pH 1.5 to destroy renin and renin substrate was also found to contain an enzyme capable of activating plasma renin. The Michaelis-Menten constant Km and the molecular weight of activated "renin" were found to be similar to those of normal plasma renin. Inactive renins or renin-like enzymes were partially purified from plasma by affinity chromatography on concanavalin A, precipitation with (NH4)2SO4 and isoelectric focusing. Trypsin and acid exposure gave similar results with regard to the activation of this zymogen, suggesting that trypsin and acid dialysis may increase plasma renin activity by the same mechanism.
Exchangeable sodium in angiotensinogenic and nonangiotensinogenic renovascular hypertension.
Authors: Albertini R , Binia A , Otsuka Y , Carretero O A
Published: June 2012

Previous studies have suggested that angiotensin II and sodium can act as alternative mechanisms in maintaining high blood pressure in chronic renovascular hypertension, In the present study, exchangeable sodium was measured in rats in which angiotensin II has been confirmed or excluded as the main cause of the hypertension. To determine the degree of participation of angiotensin II in the maintenance of the high blood pressure, we studied the mean blood pressure response to an angiotensin antagonist (1-Sar-8-Ala-angiotensin II) and to a converting enzyme inhibitor (SQ20,881). Rats with a decrease in blood pressure of less than 20 mm Hg, in response to both inhibitors, were classified as nonresponders; those with a decrease of 20 mm Hg or more, as responders. Fifty percent of the rats with two-kidney hypertension were nonresponders, and they had lower blood pressure and plasma renin activity than the responders. Further, these two-kidney, hypertensive, nonresponder rats had normal exchangeable sodium. The two-kidney hypertensive responders, on the other hand, had significantly higher exchangeable sodium than both the two-kidney, hypertensive nonresponders and the two-kidney control rats. These results suggest that angiotensin II and exchangeable sodium do not play a major role in the maintenance of the high blood pressure in the two-kidney hypertensive nonresponders. However, there appears to be an abnormal relationship between renin and exchangeable sodium in the two-kidney hypertensive responders that could contribute to the maintenance of the hypertension.