bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelium-dependent vasodilation is attenuated in patients with heart failure.
Authors: Kubo S H , Rector T S , Bank A J , Williams R E , Heifetz S M
Published: June 2012

BACKGROUND

Endothelial cells produce a number of substances, collectively termed endothelium-derived relaxing factor (EDRF), that promote local relaxation of vascular smooth muscle. Although studies have demonstrated defects in endothelium-dependent vasodilation in animal models of hypertension, atherosclerosis, and heart failure, there are only limited data from human subjects because of the difficulty in obtaining fresh vascular segments.

METHODS AND RESULTS

To address the hypothesis that endothelium-dependent vasodilation is attenuated in patients with heart failure, we measured forearm blood flow responses to the intra-arterial administration of methacholine, a known stimulus of EDRF release through muscarinic receptors. In 14 normal subjects, a dosage range of methacholine increased forearm blood flow by 5.26 +/- 0.63, 10.50 +/- 0.63, and 13.22 +/- 0.86 ml/min/100 ml forearm volume (FAV); these responses were 1.98 +/- 0.46, 5.48 +/- 0.79, and 8.50 +/- 1.53 ml/min/100 ml FAV in 14 patients with heart failure. When pooled over all doses, the responses were strikingly less in the patients with heart failure (5.32 +/- 0.31 versus 9.52 +/- 0.60 ml/min/100 ml FAV; p = 0.0003). In a second study, the average difference in forearm blood flow responses between patients with heart failure and normal subjects with methacholine was significantly greater than the average difference between the groups with nitroprusside (4.04 +/- 1.10 versus 2.20 +/- 0.71 ml/min/100 ml FAV; p = 0.04). The decreased methacholine responses in the patients with heart failure were not related to age (r = 0.39; p = NS) or etiology because there was no difference in the responses between patients with ischemic heart disease and those with idiopathic cardiomyopathy.

CONCLUSIONS

These data suggest that endothelium-dependent vasodilation is attenuated in patients with heart failure. Although the mechanisms of the decreased endothelium-dependent responses in heart failure are not known, this impaired local vasodilation may contribute to abnormalities in vasoconstriction that are characteristic of heart failure.
Antithrombotic efficacy of recombinant tick anticoagulant peptide. A potent inhibitor of coagulation factor Xa in a primate model of arterial thrombosis.
Authors: Schaffer L W , Davidson J T , Vlasuk G P , Siegl P K
Published: June 2012

BACKGROUND

Tick anticoagulant peptide is a specific, potent inhibitor of blood coagulation factor Xa. The effects of recombinant tick anticoagulant peptide (rTAP) and standard heparin (SH) were compared in an anesthetized baboon model of arterial thrombosis where platelet deposition onto a Dacron vascular graft segment of an arteriovenous (AV) shunt was studied.

METHODS AND RESULTS

Animals were randomized to receive systemic administration of SH (10 or 100 U/kg i.v. bolus followed by 0.4 or 1.0 U/kg/min i.v. infusion, respectively) or rTAP (6.25, 12.5, or 25.0 micrograms/kg/min i.v. infusion). rTAP, but not SH, caused a significant (p less than 0.05), dose-dependent reduction of indium-111 labeled platelet and iodine-125 labeled fibrin (ogen) deposition onto the graft. Deposition was not significantly increased from baseline values during infusion of 12.5 or 25.0 micrograms/kg/min of rTAP. Blood flow was maintained at 64 +/- 9, 95 +/- 2, or 97 +/- 2% of baseline following infusion of 6.25, 12.5, or 25.0 micrograms/kg/min of rTAP, respectively. Both SH and rTAP significantly (p less than 0.05) decreased the systemic fibrinopeptide A (FPA) elevation during exposure to the Dacron graft. rTAP was fully antithrombotic at APTT values of 42.6 +/- 2.4 seconds (less than twofold basal value), while SH had no antithrombotic efficacy despite APTT values greater than 150 seconds (greater than fivefold basal value).

CONCLUSIONS

The demonstrated antithrombotic effect of rTAP in the absence of alterations in primary hemostasis suggests that controlling thrombin generation through inhibition of factor Xa may be a novel and effective pharmacological approach in the prevention of high-shear arterial thrombosis.
Predictors of in-hospital mortality after DC catheter ablation of atrioventricular junction. Results of a prospective, international, multicenter study.
Authors: Evans G T , Scheinman M M , Bardy G , Borggrefe M , Brugada P , Fisher J , Fontaine G , Huang S K , Huang W H , Josephson M
Published: June 2012

BACKGROUND

The Catheter Ablation Registry was the first international, multicenter, prospective study of the safety and efficacy of catheter ablation.

METHODS AND RESULTS

From August 1987 through March 1990, the study comprised 136 patients in whom only DC energy was used in attempted production of third-degree atrioventricular block to treat uncontrollable supraventricular tachycardias. Eight patients died during hospitalization for ablation. In seven (5.1%), the ablation may have contributed to their deaths. Causes of death included ventricular fibrillation (five patients, three with polymorphic ventricular tachycardia), progressive heart failure (one patient), and respiratory failure (two patients, one dying after resuscitation from ventricular fibrillation). Compared with survivors, patients who died were more likely to have had prior aborted sudden death (38% versus 2%, p less than 0.05), congestive heart failure (88% versus 22%, p less than 0.001), cardiomyopathy (50% versus 16%, p less than 0.05), lower baseline systolic blood pressure (106 versus 138 mm Hg, p less than 0.001), prolonged baseline and postablation corrected QT interval (p less than 0.01), and markedly reduced ejection fraction (27% versus 52%, p less than 0.001). Ablation successfully produced third-degree atrioventricular block in 88% of the patients who died and in 83% of survivors.

CONCLUSIONS

Catheter ablation of the atrioventricular junction with DC energy carries a significant, previously unrecognized risk of death (5.1%), particularly from lethal arrhythmias, when applied to patients with severe left ventricular dysfunction. Great care should be taken in these seriously ill patients to guard against postablation ventricular arrhythmias.
Three-dimensional reconstruction of human coronary and peripheral arteries from images recorded during two-dimensional intravascular ultrasound examination.
Authors: Rosenfield K , Losordo D W , Ramaswamy K , Pastore J O , Langevin R E , Razvi S , Kosowsky B D , Isner J M
Published: June 2012

BACKGROUND

Intravascular ultrasound provides high-resolution images of vascular lumen, plaque, and subjacent structures in the vessel wall; current instrumentation, however, limits the operator to viewing a single, tomographic, two-dimensional image at any one time. Comparative analysis of serial two-dimensional images requires repeated review of the video playback recorded during the two-dimensional examination, followed by a "mind's eye" type of imagined reconstruction.

METHODS AND RESULTS

Computer-based, automated three-dimensional reconstruction was used to generate a tangible format with which to assess and compare a "stacked" series of two-dimensional images. Three-dimensional representations were prepared from sequential images obtained during intravascular ultrasound examination in 52 patients, 50 of whom were studied before and/or after percutaneous revascularization. Conventional two-dimensional ultrasound images were acquired by means of a systematic, timed pullback of the ultrasound catheter through the respective vascular segments. Images were then assembled in automated fashion to create a three-dimensional depiction of the vessel lumen and wall. Computer-enhanced three-dimensional reconstructions were generated in both sagittal and cylindrical formats. The sagittal format resulted in a longitudinal profile similar to that obtained during angiographic examination; in contrast to angiography, however, the sagittal reconstruction offered 360 degrees of limitless orthogonal views of the plaque and arterial wall as well as the vascular lumen. The cylindrical format yielded a composite view of a given vascular segment, and a hemisected version of the cylindrical reconstruction enabled en face inspection of the reconstructed luminal surface. Sagittal reconstructions facilitated analysis of dissections and plaque fractures resulting from percutaneous revascularization, and the hemisected cylindrical reconstructions enhanced analysis of endovascular prostheses.

CONCLUSIONS

This preliminary experience demonstrates that computer-based three-dimensional reconstruction may further augment the use of intravascular ultrasound in assessing vascular pathology and guiding interventional therapy.
Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery.
Authors: Horrow J C , Van Riper D F , Strong M D , Brodsky I , Parmet J L
Published: June 2012

BACKGROUND

Desmopressin-induced release of tissue plasminogen activator from endothelial cells may explain the absence of its hemostatic effect in patients undergoing cardiac surgery. Prior administration of the antifibrinolytic drug tranexamic acid might unmask such an effect, and combination therapy might thereby improve postoperative hemostasis.

METHODS AND RESULTS

A double-blinded design randomly allocated 163 adult patients undergoing coronary revascularization, valve replacement, both procedures, or repair of atrial septal defect to four treatment groups: placebo, tranexamic acid given as 10 mg/kg over 30 minutes followed by 1 mg.kg-1.hr-1 for 12 hours initiated before skin incision, desmopressin given as 0.3 micrograms/kg over 20 minutes after protamine infusion, and both drugs. One surgeon performed all operations. Blood loss consisted of mediastinal tube drainage over 12 hours. Follow-up visits sought evidence of myocardial infarction and stroke. Desmopressin decreased neither the 12-hour blood loss nor the amount of homologous red cells transfused. Tranexamic acid alone significantly reduced 12-hour blood loss, by 30% (mean, 318 versus 453 ml; p less than 0.0001), without enhancement by desmopressin. Tranexamic acid also decreased the proportion of patients receiving homologous blood within 12 hours of operation (8% versus 21%, p = 0.024) and within 5 days of operation (22% versus 41%, p = 0.011).

CONCLUSIONS

Desmopressin exerts no hemostatic effect, with or without prior administration of antifibrinolytic drug. Prophylactic tranexamic acid alone appears economical and safe in decreasing blood loss and transfusion requirement after cardiac surgery.
First-pass entry of nonionic contrast agent into the myocardial extravascular space. Effects on radiographic estimates of transit time and blood volume.
Authors: Canty J M , Judd R M , Brody A S , Klocke F J
Published: June 2012

BACKGROUND

Almost all x-ray-based techniques intended to assess regional myocardial perfusion from myocardial concentration-time curves following the administration of soluble contrast agents assume that these agents behave as intravascular indicators and can therefore provide measurements of intravascular transit time and intramyocardial blood volume.

METHODS AND RESULTS

We tested this assumption by comparing a conventional nonionic contrast agent (ioversol) to a particulate emulsion (ethiodol) that remained in the vascular space in closed-chest dogs during pharmacological vasodilation. Using fast computed tomography (CT), pairs of myocardial CT intensity-time curves were obtained following sequential bolus aortic administration of the two contrast agents. The emulsion (particle size less than 3 microns) was almost completely washed out of the myocardial region of interest within a few seconds, as would be anticipated for a vascular indicator. At the onset of recirculation, CT intensity for ethiodol fell to 5 +/- 1% (SEM) of peak values in normally perfused areas and to 10 +/- 4% of peak values in an area in which flow had been reduced by 50% by a chronically implanted coronary artery occluder (p = NS). In comparison, the diffusible nonionic contrast agent ioversol showed substantial intramyocardial retention at the onset of recirculation. At the time of recirculation, CT intensities for ioversol averaged 36 +/- 2% of peak values in normally perfused nonstenotic areas and 54 +/- 4% of peak values in stenotic areas (p less than 0.01). Using residue function analysis for a diffusible indicator, first-pass extractions of the conventional nonionic agent averaged 33 +/- 2% in normally perfused areas and 50 +/- 3% in stenotic areas (p less than 0.01). Because of the significant first-pass myocardial retention of ioversol, both mean myocardial appearance time and intramyocardial blood volume were consistently overestimated.

CONCLUSIONS

Soluble radiographic contrast agents, like other small molecules, enter the interstitial space to a degree, which is important because it affects estimates of myocardial perfusion based on transit time and intramyocardial blood volume. Indicator dilution models intended to quantify myocardial perfusion with conventional radiographic contrast agents need to account for this extravascular exchange.
Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine.
Authors: Patel M B , Stewart J M , Loud A V , Anversa P , Wang J , Fiegel L , Hintze T H
Published: June 2012

BACKGROUND

We have previously shown that chronic elevation of plasma norepinephrine leads to a functional independent increase in left ventricular weight. The goals of the present study were to determine quantitatively the component of the myocardium that accounted for the observed structural changes and to determine the function of the hypertrophied myocardium.

METHODS AND RESULTS

Mongrel dogs were chronically instrumented for measurement of arterial and left ventricular pressures, left ventricular internal diameter, and left ventricular wall thickness. Subcutaneous osmotic pumps were implanted to release norepinephrine continuously for 28 days. Hemodynamics were measured with dogs in the quietly resting state and during infusions of isoproterenol at 0.1 and 0.5 micrograms/kg/min before and on days 14 and 28 during the infusion of norepinephrine. The hemodynamic response to 10 micrograms/kg phenylephrine, given as a bolus, was also assessed before norepinephrine and 28 days during the infusion of norepinephrine, and the end-systolic pressure-diameter or wall-stress-diameter relations were calculated. On day 28, hearts were arrested in diastole and perfusion fixed in situ. Tissue samples were prepared for electron microscopy and morphometry. Hemodynamic studies showed that isoproterenol (0.5 micrograms/kg/min) reduced mean arterial pressure (MAP) to the same point on each experimental day, and the increases in indexes of contractility were reduced during norepinephrine infusion. Left ventricular dP/dtmax increased 131 +/- 24% on control day, only 67 +/- 20% on day 14, and 55 +/- 18% on day 28. Similar changes were observed in dP/dt/DP40 and dP/dt/end-diastolic circumference. However, Emax, the slope of the end-systolic pressure-diameter or wall stress diameter relations, was unchanged, suggesting that inotropic state was not altered. Morphometric studies showed that the cross-sectional area of myocytes increased by 55%, but myocyte and capillary densities decreased by 34% and 29%, respectively (p less than 0.05) in dogs with high norepinephrine levels. There were no differences in volume fractions of myocytes, capillary lumen, or interstitium or capillary-to-myocyte ratio.

CONCLUSIONS

The myocardium of dogs with high norepinephrine levels shows reduced inotropic response to beta-adrenergic stimulation despite the increases in left ventricular mass and left ventricular wall thickness, which are a result of growth of the cardiac myocytes and characteristic of concentric hypertrophy. These data suggest that chronic adrenergic stimulation of the heart reduces the beta-receptor coupling to the contractile response without importantly compromising left ventricular function.
Staged reperfusion attenuates myocardial stunning in dogs. Role of transient acidosis during early reperfusion.
Authors: Hori M , Kitakaze M , Sato H , Takashima S , Iwakura K , Inoue M , Kitabatake A , Kamada T
Published: June 2012

BACKGROUND

Acidosis during early reperfusion is reported to be beneficial for myocardial stunning. We tested in 31 dogs the hypothesis that staged reperfusion is beneficial to myocardial stunning.

METHODS AND RESULTS

Contractile dysfunction was observed 3 hours after the onset of reperfusion after 15 minutes of occlusion of the coronary artery. In the staged reperfusion, pH of the coronary venous blood was lower for 20 minutes and fractional shortening was significantly improved compared with the control reperfusion group. When we increased pH of the reperfused myocardium by an intracoronary infusion of sodium bicarbonate, beneficial effects of the staged reperfusion were abolished. Furthermore, an intracoronary infusion of hydrogen chloride, which mimicked the changes in pH in coronary venous blood of the staged reperfusion, attenuated myocardial stunning.

CONCLUSIONS

These results indicate that acidosis during staged reperfusion primarily attenuates myocardial stunning. This procedure is clinically applicable for attenuation of reperfusion injury.
ACC/AHA guidelines for cardiac catheterization and cardiac catheterization laboratories. American College of Cardiology/American Heart Association Ad Hoc Task Force on Cardiac Catheterization.
Authors: Pepine C J , Allen H D , Bashore T M , Brinker J A , Cohn L H , Dillon J C , Hillis L D , Klocke F J , Parmley W W , Ports T A
Published: June 2012

It is evident that the practice of cardiac catheterization has undergone, and continues to undergo, marked change. Most prominent are the recent very rapid proliferation of catheterization laboratories in general and the development of newer types of catheterization laboratory. No uniform definitions exist for these newer laboratories, so meaningful communication is difficult. The new settings are of particular concern because their location, mobility, organization, and ownership raise questions about the quality of patient care. Most difficult to address are the questions about patient safety and physician conflict of interest. There are no objective data in peer-reviewed literature to support the reported safety and cost savings of these newer settings. Through deliberations, surveys, interviews, and correspondence with the cardiology community embraced by the ACC and the AHA, the task force generally found that in freestanding catheterization laboratories, access to emergency hospitalization may be delayed, and appropriate oversight may be lacking. Additionally, opportunities for self-referral may be fostered and the perception of commercialism and entrepreneurial excess in practice created. All of these problems must be avoided. The growth and development of some freestanding facilities, particularly the mobile laboratories, do not seem to have been driven by an increased need in remote communities or for temporary support but rather almost exclusively by a desire to capture market share. Accordingly, a series of definitions, guidelines, and recommendations for the laboratories as well as for patient selection has been developed. The consensus was that a very restrictive and cautious attitude to the newer settings is appropriate at this time. The justification for development or expansion of cardiac catheterization services must be patient need. Documentation of this need must be based on objective estimates of the number of patients with known or suspected cardiac disease who meet generally accepted indications for laboratory study. Concerns about the lack of data from prospective clinical trials of patient safety in such a group necessitate a very cautious attitude toward any new catheterization services, in particular those without in-house cardiac surgical support. In view of the lack of appropriately controlled safety and need data for hospital-based, mobile, or freestanding laboratories operating without on-site (accessible by gurney) cardiac surgery facilities, the task force reaffirms the position that further development of these services cannot be endorsed at this time. In addition, there is reason for major concern that such proliferation in catheterization services may contribute to increasing costs and troubling ethical questions.
Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation.
Authors: Yoshibayashi M , Nishioka K , Nakao K , Saito Y , Matsumura M , Ueda T , Temma S , Shirakami G , Imura H , Mikawa H
Published: June 2012

BACKGROUND

To elucidate the pathophysiological significance of endothelin in pulmonary hypertension associated with congenital heart defects, we measured plasma endothelin-like immunoreactivity (ET-LI) concentrations by using radioimmunoassay in 18 patients with pulmonary hypertension (PH group; age, 6 months to 12 years) in comparison with 27 patients without pulmonary hypertension (non-PH group; age, 6 months to 12 years).

METHODS AND RESULTS

Blood samples were obtained from the vena cava, right atrium, right ventricle, left or right pulmonary artery, and pulmonary vein or the pulmonary arterial wedge position (pulmonary venous blood) during cardiac catheterization. Plasma ET-LI concentrations in the PH group were significantly higher than those in the non-PH group at all sampling sites. In the PH group, plasma ET-LI concentration showed a significant increase between the right ventricle and pulmonary artery and between the pulmonary artery and pulmonary vein. The increment of plasma ET-LI concentrations from the right ventricle to the pulmonary vein was significantly larger in the PH group than in the non-PH group and was significantly correlated with pulmonary artery pressure.

CONCLUSIONS

Plasma ET-LI concentrations were elevated in patients with pulmonary hypertension; the elevation was due to the increased production of ET-LI in pulmonary circulation, indicating the possible involvement of endothelin in the pathophysiology of pulmonary hypertension.
Determinants of normal coronary artery dimensions in humans.
Authors: Leung W H , Stadius M L , Alderman E L
Published: June 2012

BACKGROUND

Studies of normal human coronary dimensions have been performed primarily in postmortem hearts. We evaluated the influence of age, body habitus, and regional myocardial mass on coronary dimensions in living patients with normal coronary vessels.

METHODS AND RESULTS

Arteriographically normal coronary angiograms were analyzed from the following groups of subjects: group 1 (age, 15-34 years) consisted of 30 post-cardiac transplant patients with donor hearts from male subjects aged 15-34 years, group 2 (age, 35-54 years) consisted of 12 post-cardiac transplant patients with donor hearts from male subjects aged 35-54 years and 26 male subjects investigated for atypical chest pain, and group 3 (age, 55-74 years) consisted of 26 male subjects investigated for atypical chest pain. All angiograms were performed after sublingual nitroglycerin. Measurements of the dimensions of the left main, proximal left anterior descending, proximal left circumflex, and proximal right coronary arteries were made using a computer-assisted edge-detection algorithm. The regional myocardial mass supplied by each vessel was derived from echocardiographically derived total left ventricular mass and a semiquantitative angiographic territory scoring system based primarily on the number and length of its terminal nutrient branches.

CONCLUSIONS

Linear regression analysis showed that coronary vessel cross-sectional area and total coronary cross-sectional area increase with regional myocardial mass and decrease linearly with age. Multivariate regression analysis revealed that regional myocardial mass and age were independent predictors of cross-sectional area for each vessel and for the total coronary cross-sectional area. We speculate that age-related decline in physical activity, in part, may be responsible.
Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy.
Authors: Woodley S L , Gilbert E M , Anderson J L , O'Connell J B , Deitchman D , Yanowitz F G , Mealey P C , Volkman K , Renlund D G , Menlove R
Published: June 2012

BACKGROUND

We investigated the effects of bucindolol, a nonselective, non-ISA beta-blocker with mild-vasodilatory properties, in patients with congestive heart failure from ischemic dilated cardiomyopathy (ISCDC, n = 27) and compared the results with those in subjects with heart failure from idiopathic dilated cardiomyopathy (IDC, n = 22).

METHODS AND RESULTS

Patients were randomized in a double-blind fashion to receive 12 weeks' treatment with either bucindolol or placebo, with randomization stratified for IDC or ISCDC: Invasive (right heart catheterization) and noninvasive (echo, MUGA, central venous norepinephrine, exercise treadmill studies, and symptom scores) tests of heart failure severity were determined at baseline and end of the study. For all subjects (ISCDC plus IDC), relative to placebo treatment, bucindolol-treated patients had significant improvement in ejection fraction, left ventricular size and filling pressure, stroke work index, symptom score, and central venous norepinephrine. However, most of these differences could be attributed to improvement in the IDC subgroup, as the only parameter with a statistically significant degree of improvement in the bucindolol-treated ISCDC subgroup was left ventricular size.

CONCLUSIONS

We conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.
Microcirculatory dysfunction following perfusion with hyperkalemic, hypothermic, cardioplegic solutions and blood reperfusion. Effects of adenosine.
Authors: Keller M W , Geddes L , Spotnitz W , Kaul S , Duling B R
Published: June 2012

BACKGROUND

Cardioplegic solutions have been used to enhance myocardial preservation during cardiac surgery. The benefits derived from preventing myocardial ischemia with cardioplegic solutions may, however, be countered by tissue damage that occurs when the myocardium is reperfused with oxygenated blood. Furthermore, cardioplegia-induced endothelial dysfunction may contribute to depressed myocardial function postoperatively. The endothelium of coronary arteries and vein grafts is damaged by crystalloid cardioplegic solutions. There is less known about the effects of cardioplegic solutions on the microvasculature.

METHODS AND RESULTS

The hypothesis that microvascular damage occurs following perfusion with hyperkalemic, crystalloid, cardioplegic solutions and blood reperfusion, leading to decreased blood flow and increased neutrophil accumulation, was tested in a model system. Intravital microscopic observations were performed during a 20-minute perfusion of the hamster cremaster muscle with cardioplegic solutions (10 degrees C) via the femoral artery with the iliac occluded and during a subsequent 2-hour blood reperfusion period (iliac open). Arteriolar vasoconstriction (27% decrease in diameter, p less than 0.05) and a 25% decrease in the density of perfused capillaries (p less than 0.05) occurred during reperfusion in hamsters receiving crystalloid cardioplegic solution (16 meq K+) compared to control hamsters (no cardioplegic solution given). Neutrophils accumulated on venular endothelium in treated animals (250% increase, p less than 0.05) and extravascularly (myeloperoxidase levels 2.0 +/- 0.4 U/g versus 1.3 +/- 0.3 U/g in control, p less than 0.05). The addition of adenosine (10(-4) M) and albumin (2 g%) to the cardioplegic perfusate, accompanied by the administration of adenosine (10(-4) M) during reperfusion, produced arteriolar vasodilation (34% diameter increase, p less than 0.05) and inhibited extravascular neutrophil accumulation (myeloperoxidase level of 1.5 +/- 0.2 U/g, p greater than 0.05 versus control). Capillary perfusion, however, was still significantly diminished (28% decrease, p less than 0.05.)

CONCLUSIONS

We conclude that injury manifest by decreased microvascular blood flow and increased neutrophil accumulation in tissues occurs after perfusion with hypothermic, hyperkalemic, crystalloid cardioplegic solutions and blood reperfusion. Adenosine seems to partially attenuate this injury by dilating arterioles and decreasing extravascular neutrophil accumulation.
Spectrum of heart malformations in mice with situs solitus, situs inversus, and associated visceral heterotaxy.
Authors: Icardo J M , Sanchez de Vega M J
Published: June 2012

BACKGROUND

We present a study of the heart malformations found in a collection of mouse fetuses of the iv/iv strain between days 16.5 and 18.5 of gestation.

METHODS AND RESULTS

One hundred hearts were serially sectioned and studied by segmental analysis with a light microscope. Forty additional hearts were analyzed with a scanning microscope. Forty percent of the hearts were found to be malformed. The most frequently occurring heart malformations were persistence of the sinus venosus (9%), common atrium (17%), common atrioventricular canal (24%), double-outlet right ventricle (12%), Fallot's tetralogy (8%), and transposition of the great arteries (5%). These malformations do not usually occur in isolation but rather appear in the formation of complex cardiopathies. The most severe and frequent is the combination of persistence of sinus venosus, common atrium, common atrioventricular canal, and double-outlet right ventricle; this is the "bulboventricular heart." The morphology of each lesion, as well as the degree of association, is similar to that found in human hearts with complex cardiopathies. Some of these cardiopathies appear to be directly related to formation of the cardiac loop. The iv/iv mouse appears to constitute an excellent model with which to study the etiology and pathogenesis of complex heart defects in humans. These hearts show a high phenotypic variability in the presentation of heart lesions. From a genetic viewpoint, there is a basic defect--the bulboventricular heart--which can be considered congenital. The other malformations can be considered formes frustes of the defect type.

CONCLUSIONS

The iv gene is a developmental gene that affects basic developmental mechanisms. In this regard, heart lesions may not be the primary result of the abnormal gene activity but rather are secondary to defective interactions during cardiac development.
Thrombolysis in unstable angina. Randomized double-blind trial of t-PA and placebo.
Authors: Freeman M R , Langer A , Wilson R F , Morgan C D , Armstrong P W
Published: June 2012

BACKGROUND

Because coronary thrombosis is important in the pathogenesis of unstable angina and correlates with in-hospital cardiac events, we hypothesized that thrombolytic therapy would decrease cardiac events.

METHODS AND RESULTS

We randomized 70 patients with unstable angina to tissue-type plasminogen activator (t-PA) (0.49 MU/kg for 1 hour followed by 0.07 MU/kg per hour for 9 hours) or placebo. All patients received full doses of intravenous heparin for 96 hours and aspirin (325 mg beginning at 72 hours). The primary end points of the study were in-hospital death, myocardial infarction, and urgent revascularization. Three secondary end points were also evaluated. Myocardial perfusion was assessed with resting planar thallium scintigraphy 90 minutes after initiation of therapy. Silent ischemia was assessed with 48-hour Holter monitoring for ST shift beginning at time of initiation of drug therapy. Coronary angiography was performed at 18 +/- 6 hours and analyzed quantitatively to assess the stenosis responsible for unstable angina, the presence of intraluminal filling defects consistent with intracoronary thrombus, and stenosis morphology and severity. There was no difference in total in-hospital cardiac events between patients receiving t-PA (5% or 14%) and those receiving placebo (7% or 20%) (p = 0.83). Resting thallium defects were larger in the patients receiving t-PA than in those receiving placebo (130 +/- 118 versus 76 +/- 84 degrees, p less than 0.04), and this difference persisted when corrected for previous infarction. Although the numbers of patients with ST shift were similar, the duration of ST shift was significantly longer in the patients receiving t-PA than with placebo (20 +/- 46 versus 3 +/- 10 minutes, p less than 0.045). The frequency of intracoronary thrombi in patients with stenoses greater than 50% was significantly less in patients treated with t-PA (11 of 22, 52%) as compared with placebo (23 of 25, 92%) (p = 0.002), but there was no significant difference in minimal lesion cross-sectional area (0.49 +/- 0.42 versus 0.57 +/- 1.08 cm2, p = 0.75) or ulceration index (0.79 +/- 0.16 versus 0.77 +/- 0.15, p = 0.71) of the culprit artery.

CONCLUSIONS

We conclude that a prolonged infusion of t-PA in unstable angina reduces intracoronary thrombi but does not significantly decrease in-hospital cardiac events. The sample size, however, does not provide sufficient power to rule out a treatment effect. Paradoxically, there appears to be an increase in ST shift and worsening of myocardial perfusion with t-PA compared with therapy with heparin alone.
Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation.
Authors: Carry M , Korley V , Willerson J T , Weigelt L , Ford-Hutchinson A W , Tagari P
Published: June 2012

BACKGROUND

Experimental cardiac ischemia in some animal models results in the activation of the enzyme 5-lipoxygenase and the subsequent production of leukotrienes, potent proinflammatory lipid mediators, by the affected myocardium. Furthermore, prototype antileukotriene drugs can show some beneficial effects on infarct size and cardiac function in these models. Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode.

METHODS AND RESULTS

Urinary leukotriene excretion was measured by reversed-phase high-performance liquid chromatography and specific radioimmunoassay on admission with acute chest pain and again on day 3 in the following patient groups: acute myocardial infarction (AMI), AMI and clinical evidence of early reperfusion after treatment with recombinant tissue-type plasminogen activator (rt-PA), diagnosis of unstable angina (UA) based on clinical history and coronary arteriography, controls with nonischemic chest pain who underwent coronary arteriography, and age-matched controls and normal hospital employees. In 16 patients with diagnosis of AMI, LTE4 excretion on admission (331 +/- 99 pg/mg creatinine sulfate; mean +/- SEM) was considerably higher than that measured on day 3 (195 +/- 59 pg/mg creatinine sulfate). In a subgroup of seven subjects treated with rt-PA resulting in early reperfusion, day 1 excretion was similar (215 +/- 50 pg/mg) but had significantly declined by day 3 (65 +/- 16 pg/mg; p less than 0.01). Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate). This had declined significantly (p less than 0.05) by day 3 (at which time chest pain had resolved) to 94 +/- 31 pg/mg creatinine sulfate, an excretion rate comparable with that measured in eight similarly aged subjects (64 +/- 12 pg/mg creatinine).

CONCLUSIONS

This study suggests that peptide leukotrienes are released during episodes of myocardial ischemia and provides clinical evidence for involvement of their biosynthetic enzyme, 5-lipoxygenase, during and after acute myocardial infarction and unstable angina attacks. Thus, potent and specific orally active leukotriene biosynthesis inhibitors may have therapeutic potential in limiting myocardial damage and functional abnormalities after acute ischemia.
Myocardial beta-adrenergic receptor expression and signal transduction after chronic volume-overload hypertrophy and circulatory congestion.
Authors: Hammond H K , Roth D A , Insel P A , Ford C E , White F C , Maisel A S , Ziegler M G , Bloor C M
Published: June 2012

BACKGROUND

The volume-overload, high-output state induced by aortocaval fistula is unique because it is not generally associated with marked abnormalities of contractile function. Thus, changes in beta-adrenergic receptor (beta AR) expression should reflect more directly the influence of neurohumoral adrenergic tone, clarifying the manner in which peripheral (neurohumoral) versus primary myocardial factors are operative in decreased beta AR-dependent signal transduction.

METHODS AND RESULTS

We examined the beta-adrenergic receptor-responsive adenylyl cyclase pathway in hearts from pigs subjected to volume-overload hypertrophy with circulatory congestion. Nine pigs underwent initial pharmacological and hemodynamic studies, and, 5 weeks after aortocaval fistula placement, when signs of circulatory congestion were evident, these measurements were repeated. Biochemical analyses of plasma and myocardium from these animals and seven normal animals were compared. Experimental animals showed signs of circulatory congestion (tachypnea, weight gain, pulmonary rales) within 3-4 weeks of fistula placement. Necropsy showed ascites and biventricular cardiac hypertrophy, but no fibrosis or inflammation was present on histological inspection. Heart rate responsiveness to beta AR stimulation was blunted, with ED50, for isoproterenol increased 133% (p less than 0.001) after development of circulatory congestion. Biochemical analyses of the beta AR-responsive adenylyl cyclase pathway showed uniform decreases in beta AR number in right atrium, right ventricle, and left ventricle (36-41% decreases, p less than 0.005). Downregulation was selective for beta 1-receptors, and remaining receptors in the right and left ventricles showed low-affinity agonist binding, suggesting an uncoupling from Gs. All measures of adenylyl cyclase activity were diminished significantly in membrane homogenates from the right atrium (mean reduction, 50 +/- 10%) and left ventricle (mean reduction, 44 +/- 8%) after volume overload. Finally, we found that amounts of cardiac Gs, as measured in reconstitution assays, were decreased in both the right atrium (p less than 0.02) and the left ventricle (p less than 0.01) of volume-overloaded animals but that levels of pertussis toxin substrate were unchanged.

CONCLUSIONS

Biochemical findings occurred in the absence of myocardial inflammation or fibrosis and without pharmacological interventions, suggesting that circulatory congestion, with attendant elevation in plasma norepinephrine, may be a sufficient stimulus to induce such changes. The data are compatible with a catecholamine-driven beta AR pathway desensitization. Thus, a primary defect in intrinsic contractile function is not a necessary component for abnormalities of the myocardial beta AR-responsive adenylyl cyclase pathway.
Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis.
Authors: Levi M , Biemond B J , van Zonneveld A J , ten Cate J W , Pannekoek H
Published: June 2012

BACKGROUND

We investigated the effect of inhibition of plasminogen activator inhibitor-1 (PAI-1) activity by a murine monoclonal anti-human PAI-1 antibody (MAI-12) on in vitro thrombolysis and on in vivo thrombolysis and thrombus extension in an experimental animal model for thrombosis.

METHODS AND RESULTS

Thrombolysis, mediated by recombinant tissue-type plasminogen activator (rt-PA), was studied in an in vitro system consisting of fibrinogen, plasminogen, and thrombin. Addition of purified platelets during clot formation inhibited rt-PA-mediated thrombolysis in a dose-dependent manner. Platelet-dependent thrombolysis resistance could be completely neutralized by the monoclonal antibody MAI-12, supporting the notion that the observed resistance is due to PAI-1 released from alpha-granules of platelets. Subsequently, we monitored in vivo thrombolysis and thrombus extension of human whole blood thrombi that were allowed to form in rabbit jugular veins. During thrombus formation, either MAI-12 or an irrelevant antibody was incorporated. Thrombolysis and thrombus extension were simultaneously measured during endogenous thrombolysis or upon administration of different dosages of rt-PA. We observed that endogenous thrombolysis was enhanced in the presence of MAI-12 compared with the control antibody. Significantly, thrombus extension was partially prevented by MAI-12 and not by the control antibody irrespective of whether exogenous rt-PA was systematically administered.

CONCLUSIONS

These observations further confirm the essential role of PAI-1 in the regulation of the thrombolytic system and support the exploration of adjunctive therapy based on inhibition of PAI-1 activity in thrombolytic strategies.
Baroreflex sensitivity and heredity in essential hypertension.
Authors: Parmer R J , Cervenka J H , Stone R A
Published: June 2012

BACKGROUND

Abnormalities in baroreflex control of heart rate may be important in the pathogenesis of essential hypertension.

METHODS AND RESULTS

To investigate the influence of heredity on baroreflex function, we measured baroreflex sensitivity in 40 untreated patients with essential hypertension grouped by the presence (FH+) or absence (FH-) of a family history of hypertension and in 24 normotensive counterparts. Baroreflex sensitivity was assessed by both high-pressure (phenylephrine bolus) and low-pressure (amyl nitrite inhalation) stimuli. Subject groups were matched for age, blood pressure, body weight, and race. Baroreflex sensitivity (in milliseconds per millimeter of mercury) assessed by amyl nitrite inhalation was 24.3 +/- 2.8 in FH- normotensives, 12.3 +/- 1.7 in FH+ normotensives, 15.4 +/- 3.3 in FH- hypertensives, and 8.1 +/- 1.2 in FH+ hypertensives. Baroreflex sensitivity assessed by phenylephrine bolus was 28.8 +/- 5.6 in FH- normotensives, 19.3 +/- 2.8 in FH+ normotensives, 19.1 +/- 2.0 in FH- hypertensives, and 13.6 +/- 1.3 in FH+ hypertensives. Two-factor analysis of variance showed significant effects on baroreflex sensitivity for blood pressure status (normotensive versus hypertensive) and for family history of hypertension. After control line (controlling) for the effects of several variables, including age, mean arterial pressure, body weight, and race through multiple linear regression analysis, the effect of family history of hypertension on baroreflex sensitivity was still highly significant. Indeed, of all variables investigated, family history of hypertension was the strongest unique baroreflex sensitivity predictor.

CONCLUSIONS

These data suggest that the impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension.
Electrogram criteria for identification of appropriate target sites for radiofrequency catheter ablation of accessory atrioventricular connections.
Authors: Calkins H , Kim Y N , Schmaltz S , Sousa J , el-Atassi R , Leon A , Kadish A , Langberg J J , Morady F
Published: June 2012

BACKGROUND

Catheter ablation of accessory atrioventricular (AV) connections using radiofrequency current has been demonstrated to be effective in the majority of patients with the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardia involving a concealed accessory AV connection. However, electrogram criteria have not been established to guide attempts at radiofrequency catheter ablation.

METHODS AND RESULTS

The characteristics of local electrograms recorded at successful and unsuccessful sites of radiofrequency catheter ablation were determined in 132 patients. Electrograms recorded at a total of 438 sites were analyzed: 338 recorded during ablation of 90 manifest accessory AV connections and 100 recorded during ablation of 44 concealed accessory AV connections. During ablation of manifest accessory AV connections, the independent predictors of outcome were electrogram stability (p less than 0.001), the interval between activation of the ventricular electrogram and onset of the QRS complex (p less than 0.001), and the presence of an accessory AV connection potential (p less than 0.001). Radiofrequency energy delivery at sites demonstrating stable electrograms, a probable or possible accessory AV connection potential, and activation of the local ventrical electrogram before the onset of the QRS complex had a 57% probability of success compared with a 3% probability of success at sites without these features. During ablation of concealed accessory AV connections, the independent predictors of outcome were electrogram stability (p = 0.02), the presence of an accessory AV connection potential (p = 0.05), and the presence of retrograde continuous electrical activity (p = 0.04). Sites demonstrating a stable local electrogram, an accessory AV connection potential, and retrograde continuous electrical activity had an 82% probability of success compared with only a 5% probability of success at sites demonstrating none of these features.

CONCLUSIONS

The local electrogram parameters of greatest importance in predicting the success or failure of radiofrequency catheter ablation of accessory AV connections are electrogram stability, the presence of an accessory AV connection potential, and the timing of ventricular activation relative to the QRS complex (for manifest accessory AV connections) or retrograde continuous electrical activity (for concealed accessory AV connections). Awareness of these variables during attempts at radiofrequency catheter ablation of accessory AV connections may minimize the number of unnecessary applications of radiofrequency energy.