bluuebunny/crossref_metadata_2025 huggingface dataset:
Modified Maze Procedure for Patients With Atrial Fibrillation Undergoing Simultaneous Open Heart Surgery
Authors: Kosakai Yoshio , Kawaguchi Akira T. , Isobe Fumitaka , Sasako Yoshikado , Nakano Kiyoharu , Eishi Kiyoyuki , Kito Yoshitsugu , Kawashima Yasunaru
Published: June 2012

Background
Persistent atrial fibrillation (AF) leaves patients symptomatic and at increased risk of thromboembolism even after otherwise successful cardiac surgery.

Methods and Results
To treat AF secondary to cardiac lesions requiring surgery, we combined a modified maze procedure in 101 patients simultaneously undergoing valvular procedures (87), repair of congenital anomalies (12), and other procedures (2), including 24 repeat operations. Duration of AF varied from 0.1 to 30 years (average±SD, 8.8±7.0 years); the f-wave voltage ranged from 0 to 0.45 mV (0.15±0.09 mV); and cardiothoracic ratio varied from 40% to 99% (63±9%). Aortic cross-clamp time varied from 75 to 229 minutes (138±31 minutes), with bypass time ranging from 119 to 326 minutes (217±42 minutes). There were two early deaths (2%), no late deaths, and one episode of transient neurological ischemic attack in follow-up ranging from 1.0 to 3.1 years, for a total of 190 patient-years. Postoperative rhythms were sinus in 83 patients (82%), junctional in 4 (4%), and persistent AF in 14 (14%), each of whom had mitral valve disease. Patients with other underlying pathology had complete recovery of atrial rhythm. A normal-sized A wave was detected in 88% for transtricuspid flow and in 73% for transmitral flow, suggesting concomitant recovery of atrial contraction. Among 36 patients without mechanical valves, 30 (83%) with atrial rhythm and contraction have been taken off anticoagulation therapy, including 10 who are free of all medication.

Conclusions
The results suggest that the combined approach is safe, effective, and indicated in patients who are judged capable of tolerating the procedure and likely to regain atrial rhythm.
Can Ischemic Preconditioning Ensure Optimal Myocardial Protection When Delivery of Cardioplegia Is Impaired?
Authors: Galiñanes Manuel , Argano Vincenzo , Hearse David J.
Published: June 2012

Background
Ischemic preconditioning is a potent protective intervention that is effective in all species studied. We have previously shown it to be as effective as cardioplegia; however, we have also shown that their combined use does not afford greater protection than the use of either alone. In the present study we investigated whether coincident ischemic preconditioning could compensate for inadequate cardioplegic protection when the delivery of cardioplegia was impaired, such as occurs in the presence of severe coronary stenosis or occlusion.

Methods and Results
Isolated rat hearts were subjected to 30 minutes of global ischemia followed by 40 minutes of reperfusion. Four groups of hearts (n=12 per group) were studied: group 1, controls (no intervention); group 2, cardioplegia administered to hearts with a proximally occluded coronary artery; group 3, ischemic preconditioning applied before ischemia; and group 4, ischemic preconditioning and cardioplegia given in combination to hearts with a proximally occluded coronary artery. The postischemic recovery of left ventricular (LV) developed pressure (LVDP), expressed as a percentage of preischemic values, was significantly greater (
P
<.05) in preconditioned hearts (64±3%) than in control hearts (24±4%) or hearts treated with suboptimal cardioplegia (43±5%). Hearts with preconditioning plus cardioplegia recovered to an extent similar to that seen with preconditioning alone (59±2%). LV end-diastolic pressure was greater in control hearts (58±4 mm Hg) than in hearts with cardioplegia (41±4 mm Hg;
P
<.05 versus group 1) despite the incomplete delivery of the cardioplegia; the best protection was observed in preconditioned hearts and hearts with preconditioning plus cardioplegia (24±1 and 26±2 mm Hg, respectively;
P
<.05 versus groups 1 and 2).

Conclusions
When the delivery of cardioplegia was impaired, myocardial protection (postischemic LVDP) was better served by ischemic preconditioning. Under the same conditions, the combination of cardioplegia plus preconditioning afforded superior protection compared with cardioplegia alone. These results may be of clinical interest since most patients who undergo surgery for ischemic heart disease suffer from severe coronary artery lesions that can prevent the adequate delivery of cardioplegia.
Does Cardiopulmonary Bypass Alone Elicit Myoprotective Preconditioning?
Authors: Burns Paul G. , Krukenkamp Irvin B. , Caldarone Christopher A. , Gaudette Glenn R. , Bukhari Emad A. , Levitsky Sidney
Published: June 2012

Background
Brief episodes of ischemia can precondition myocardium. Ischemic preconditioning (PC) has been proposed as an adjuvant method of improving myocardial protection during cardiac surgery. It is unknown whether CPB without an episode of ischemia generates the PC response.

Methods and Results
To prove that PC occurs in sheep, groups 1 (non-CPB control) and 2 (non-CPB ischemic PC, three 5-minute episodes of normothermic regional ischemia) were studied. Groups 3 (CPB alone), 4 (CPB–alpha receptor blockade, phentolamine 5 mg/kg), and 5 (CPB–adenosine receptor blockade, 8-sulfophenyltheophylline 5 mg/kg) were placed on CPB for 30 minutes and subsequently weaned. All groups underwent 60 minutes of normothermic regional ischemia and 150 minutes of reperfusion. The area at risk (AR) was delineated by Monastryl blue pigment, whereas the infarct size (IS) was determined by tetrazolium staining. Body mass, left ventricular mass, and AR were not different between groups. Ischemic PC was demonstrated in this ovine model by a 54% reduction of IS relative to AR (group 1 versus group 2,
P
<.01). CPB alone produced a similar percentage IS reduction without ischemia (group 3 versus group 1,
P
<.01) that was prevented by either α-adrenergic receptor (group 4 versus group 3,
P
<.01) or adenosine receptor (group 5 versus group 3,
P
<.01) blockade.

Conclusions
CPB alone appears sufficient to elicit the PC response important for myocardial protection during cardiac surgery. These data suggest that myocardial α-adrenergic receptor and adenosine receptor stimulation are involved in initiating CPB-induced PC.
University of Wisconsin Solution Preserves Myocardial Calcium Current Response to Isoproterenol in Isolated Canine Ventricular Myocytes
Authors: Ono Katsushige , Gondo Naoki , Arita Makoto , Fozzard Harry A. , Hadama Tetsuo , Uchida Yuzo
Published: June 2012

Background
University of Wisconsin (UW) solution has been shown to be an effective solution for cold storage of various organs. This study was designed to evaluate the subcellular protective mechanism of UW solution during cardiac myocyte storage using patch-clamp techniques for the first time as a tool for the detection of myocyte viability.

Methods and Results
The protective effects of UW solution on the preservation of dihydropyridine-sensitive Ca
2+
channel current response to catecholamine were evaluated in canine cardiac ventricular cells by measurement of single channel open probability. Single ventricular myocytes were isolated and stored in UW solution, in Stanford (SF) solution, or in St Thomas’ (ST) solution at 4°C for 2, 6, 12, and 24 hours, and after each storage period, recordings were made of cell-attached single Ca
2+
channel currents. When 0.1 μmol/L isoproterenol was applied, percent mean open probability of the Ca
2+
channel tested in freshly isolated cells was 167±4% (n=24) of controls (100%). The response was decrescent with increased duration of the hypothermic storage and was only 130±12% (n=4) after 24 hours of storage in SF solution and 135±9% (n=7) in ST solution. However, it was significantly highly preserved as much as 165±9% (n=6) in UW solution. Ca
2+
channel kinetics and channel conductance were not changed after up to 24 hours of hypothermic storage.

Conclusions
Hypothermic storage of canine cardiac myocytes in UW solution preserved β-adrenergic response, which suggests that UW solution during cold storage preserved high-energy phosphates in myocytes that are responsible for Ca
2+
channel phosphorylations.
Creation of a Controlled Venoarterial Shunt
Authors: Slater James P. , Yamada Andre , Yano Oswaldo J. , Stennet Richard , Goldstein Daniel J. , Levin Howard R. , Spotnitz Henry M. , Oz Mehmet C.
Published: June 2012

Background
Right-side circulatory failure (RSCF), a common complication of heart transplant and left ventricular assist device recipients, results in decreased cardiac output because of diminished flow across the pulmonary circuit. We hypothesized that creation of a controlled venoarterial shunt would result in decompression of the right ventricle and improved systemic cardiac output at tolerable oxygen saturations.

Methods and Results
A venoarterial shunt was created in a large-animal model (calf, n=6). RSCF was induced by banding the pulmonary artery. Hemodynamic measures and blood gas determinations were obtained during nonshunted and shunted states. Pulmonary artery banding increased mean right ventricular systolic pressure from 44.9±2.1 mm Hg (mean±SEM) to 85.9±6.9 mm Hg (
P
<.05, paired
t
test) and decreased mean aortic flow from 7.8±1.0 to 4.2±1.1 L/min (
P
<.05). Flow through a venoarterial shunt at approximately 40% of cardiac output resulted in a decrease in right ventricular end-systolic pressure from 85.9±6.9 to 72.1±5.6 mm Hg (
P
<.01, ANOVA), a decrease in mean pulmonary artery pressure from 42.9±5.0 to 37.2±3.8 mm Hg (
P
<.01), and an increase in aortic flow from 4.2±.05 to 5.1 L/min (
P
<.01). Left ventricular stroke work decreased from 2.22±0.28 to 1.55±0.88 (
P
<.05). Carotid artery oxygen saturation did not change significantly (99.9±.02 to 97.6±1.7) during shunting.

Conclusions
A controlled venoarterial shunt improved hemodynamics and cardiac output in a large animal model with RSCF. This strategy may be useful in the management of transplant and left ventricular assist device recipients with perioperative RSCF.
Outcomes of Coronary Artery Bypass Graft Surgery in 24 461 Patients Aged 80 Years or Older
Authors: Peterson Eric D. , Cowper Patricia A. , Jollis James G. , Bebchuk Judith D. , DeLong Elizabeth R. , Muhlbaier Lawrence H. , Mark Daniel B. , Pryor David B.
Published: June 2012

Background
Coronary artery bypass graft surgery is increasingly common in patients of age ≥80 years. Single-institution reviews have cited a wide range of mortality results after bypass surgery in this age group, in part because of limited sample sizes. Using claims data, we examined recent national trends in the use and outcomes of bypass surgery in the very elderly.

Methods and Results
From an examination of Medicare data from 1987 through 1990, we identified 24 461 patients of age ≥80 years who underwent bypass surgery. We compared surgical outcomes in these patients with those in Medicare patients of age 65 to 70 years. We found that the national use of bypass surgery in patients of age ≥80 years increased 67% between 1987 and 1990. Compared with patients of age 65 to 70 years, the very elderly had significantly longer postoperative hospital stays (mean, 14.3 versus 10.4 days), higher charges (mean, $48 200 versus $38 000), and greater costs (mean, $27 200 versus $21 700). In-hospital (11.5% versus 4.4%), 1-year (19.3% versus 7.9%), and 3-year mortality rates (28.8% versus 13.1%) after bypass surgery were also significantly higher in patients of age ≥80 years compared with younger patients. Although their initial surgical risk was high, octogenarians who underwent bypass surgery had a long-term survival rate similar to that of the general US octogenarian population.

Conclusions
The use of bypass surgery in patients of age ≥80 years is increasing. These very elderly patients face high surgical risks and accumulate significant hospital expenses. Further research is indicated to determine whether the long-term benefits from bypass surgery in the very elderly outweigh the increased procedural risks.
High Frequency–Induced Upregulation of Human Cardiac Calcium Currents
Authors: Piot Christophe , Lemaire Stéphanie , Albat Bernard , Seguin Jacques , Nargeot Joël , Richard Sylvain
Published: June 2012

Background
In mammalian heart cells, Ca
2+
influx through voltage-gated L-type Ca
2+
channels can be upregulated by high rates of stimulation. We have investigated this important adaptive regulation in human cardiomyocytes.

Methods and Results
Using the whole-cell patch-clamp technique, we found a high frequency–induced upregulation (HFIUR) of the dihydropyridine-sensitive L-type Ca
2+
current (I
Ca
) in human cardiomyocytes. I
Ca
was potentiated in a graded manner with increasing rates of stimulation between 0.3 and 5 Hz. Both moderate increase of I
Ca
peak amplitude and marked slowing of current decay contributed to large increases of Ca
2+
influx (up to 80%). The maximal potentiation of I
Ca
was reached rapidly after the change in the rate of stimulation (no more than a few seconds). β-Adrenergic stimulation of the cells by isoproterenol (1 μmol/L), which is well known to induce a slow (≈1 minute) cAMP-mediated potentiation of I
Ca
, could enhance (when present) or promote (when absent) the HFIUR of I
Ca
. As a consequence, the increasing effect of isoproterenol on Ca
2+
influx through Ca
2+
channels was dependent on the rate of stimulation. HFIUR of I
Ca
was altered in patients with ejection fraction lower than 40% and in patients pretreated with Ca
2+
antagonists or β-blockers.

Conclusions
Upregulation of Ca
2+
entry through voltage-gated Ca
2+
channels by high rates of beating may be involved in the frequency-dependent regulation of contractility (Bowditch “staircase”) of the human heart. This process, which is highly sensitive to β-adrenergic stimulation, may be crucial in adaptation to exercise and stress.
Ranolazine Stimulates Glucose Oxidation in Normoxic, Ischemic, and Reperfused Ischemic Rat Hearts
Authors: McCormack James G. , Barr Rick L. , Wolff Andrew A. , Lopaschuk Gary D.
Published: June 2012

Background
Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts.

Methods and Results
Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate); with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-
3
H/U-
14
C]-glucose and FA oxidation with the use of [1-
14
C]- or [9,10-
3
H]-palmitate. In working hearts, 10 μmol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low FA, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were ≈10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 μmol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O
2
use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis.

Conclusions
Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O
2
and reduction in the buildup of H
+
, lactate, and harmful fatty acyl intermediates.
Blood Pressure in Young Blacks and Whites: Relevance of Obesity and Lifestyle Factors in Determining Differences
Authors: Liu Kiang , Ruth Karen J. , Flack John M. , Jones-Webb Rhonda , Burke Gregory , Savage Peter J. , Hulley Stephen B.
Published: June 2012

Background
Middle-aged black men and women have higher blood pressure, on average, than whites. However, this pattern is inconsistent in children and adolescents. This study explores how differences in lifestyle factors in young adulthood may influence blood pressure patterns in the two races.

Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) study is an ongoing collaborative investigation of lifestyle and the evolution of cardiovascular disease risk factors in a random sample of young adults ages 18 to 30 years at baseline (1985 to 1986). Data from four examinations over 7 years were analyzed with the use of a method that simultaneously examined cross-sectional and longitudinal relationships of lifestyle factors and blood pressure. This study included 1154 black women, 853 black men, 1126 white women, and 1013 white men. Blacks had higher systolic blood pressure and diastolic blood pressure than whites at every examination. Racial differences were much greater in women than in men and increased over time. Within each sex-race group, average diastolic blood pressure over four examinations was positively associated with baseline age, body mass index, and alcohol intake and negatively associated with physical activity, cigarette use, and intake of potassium and protein. Longitudinal change in diastolic blood pressure was positively associated with changes in body mass index and alcohol intake. After adjustment for obesity and other lifestyle factors, black-white diastolic blood pressure differences were reduced substantially: 21% to 75% for men and 49% to 129% for women. Results for systolic blood pressure were similar.

Conclusions
Differences in obesity and other lifestyle factors in young adults largely explain the higher baseline blood pressure and greater increase over time of blacks relative to whites.
Prospective 12-Year Follow-up Study of Clinical and Hemodynamic Sequelae After Deep Vein Thrombosis in Low-Risk Patients (Zürich Study)
Authors: Franzeck Ulrich K. , Schalch Ilse , Jäger Kurt A. , Schneider Ernst , Grimm Jörg , Bollinger Alfred
Published: June 2012

Background
No prospective study of the long-term sequelae of more than 10 years after acute deep vein thrombosis exists so far. Therefore, 58 low-risk patients with DVT were included in a prospective study to evaluate the natural history of postthrombotic syndrome.

Methods and Results
Clinical and hemodynamic examinations were performed at the time of admission; after 3, 6, and 12 months; after the 2nd, 3rd, 4th, 5th years; and finally after the 12th year. All patients received heparin initially and oral anticoagulants subsequently. After 12 years, 64% of the patients exhibited normal findings. Mild skin changes were found in 28%, marked trophic changes in 5%, and only one venous ulcer occurred. Regular use of compression stockings was reported by 54% of the patients with multilevel thrombosis. Although mean maximum venous outflow was significantly reduced from the acute event to 12 years later (
P
<.003) compared with the contralateral leg, a significant (
P
<.05) improvement was observed 6 months later. Recanalization of calf vein thrombosis was detected by Doppler sonography after 3 months. Sixty-four percent of the multilevel thromboses were recanalized completely or in part after 1 year; in 69%, valvular incompetence was found.

Conclusions
In contrast to earlier reports, this prospective study up to 12 years after deep vein thrombosis demonstrates a low incidence of postthrombotic syndrome by administration of oral anticoagulants and regular compression therapy. However, the adverse clinical event rate (mortality 14%) and a recurrence rate of 24% show that the prognosis after deep vein thrombosis does not appear favorable even in low-risk patients.
Utilization of the Coronary Balloon-Expandable Coil Stent Without Anticoagulation or Intravascular Ultrasound
Authors: Goods Christopher M. , Al-Shaibi Khaled F. , Yadav Sanjay S. , Liu Ming W. , Negus Brian H. , Iyer Sriram S. , Dean Larry S. , Jain Suresh P. , Baxley William A. , Parks J. Michael , Sutor Ronald J. , Roubin Gary S.
Published: June 2012

Background
The balloon-expandable coil stent has been proved effective in the management of acute and threatened closure after coronary balloon angioplasty and has been shown to reduce restenosis in patients with suboptimal results after coronary balloon angioplasty. Coronary artery stenting has been limited by the occurrence of stent thrombosis and comorbidity related to anticoagulation. This study was undertaken to determine whether anticoagulation may be removed from poststenting protocols, thus reducing comorbidity without increasing stent thrombosis.

Methods and Results
Between September 1994 and May 1995, 369 patients received balloon-expandable coil stents in native coronary arteries at our institution. Of these patients, 216 were selected for a protocol of aspirin and ticlopidine (for 1 month) without anticoagulation. Eligibility for this protocol followed satisfaction of certain procedural and angiographic criteria. These criteria included adequate coverage of intimal dissections, absence of residual filling defects, and normal (TIMI grade 3) flow in the stented vessel after high-pressure balloon inflations. Intravascular ultrasound was not used to guide stent deployment. The stenting procedure was planned in 37% of patients and unplanned in 63% of patients, including 25 (12%) for acute or threatened closure. During the 30-day follow-up period, stent thrombosis occurred in 2 patients (0.9%), there was 1 death (0.5%), and 2 patients (0.9%) underwent coronary bypass surgery. Vascular access-site complications occurred in 4 patients (1.9%), and bleeding that required blood transfusion occurred in 4 patients (1.9%).

Conclusions
Patients who receive the coronary balloon-expandable coil stent with optimal angiographic results without intravascular ultrasound guidance can be managed safely with a combination of aspirin and ticlopidine without anticoagulation.
Insulin Sensitivity and Atherosclerosis
Authors: Howard George , O’Leary Daniel H. , Zaccaro Daniel , Haffner Steve , Rewers Marian , Hamman Richard , Selby Joe V. , Saad Mohammed F. , Savage Peter , Bergman Richard
Published: June 2012

Background
Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted.

Methods and Results
The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (S
I
) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. There was a significant negative association between S
I
and the IMT of the carotid artery both in Hispanics and in non-Hispanic whites. This effect was reduced but not totally explained by adjustment for traditional cardiovascular disease risk factors, glucose tolerance, measures of adiposity, and fasting insulin levels. There was no association between S
I
and the IMT of the carotid artery in blacks. The association between S
I
and the IMT was stronger for the internal carotid artery than for the common carotid artery in all ethnic groups.

Conclusions
Higher levels of insulin sensitivity are associated with less atherosclerosis in Hispanics and non-Hispanic whites but not in blacks. This effect is partially mediated by traditional cardiovascular risk factors.
Systemic Endothelin Receptor Blockade Decreases Peripheral Vascular Resistance and Blood Pressure in Humans
Authors: Haynes William G. , Ferro Charles J. , O’Kane Kevin P. J. , Somerville David , Lomax Charmaine C. , Webb David J.
Published: June 2012

Background
Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ET
A/B
receptor antagonist, TAK-044, in healthy men.

Methods and Results
Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L·min
−1
·m
−2
compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilatation.

Conclusions
The endothelin ET
A/B
receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically.
Change in Aortic End-Systolic Pressure by Alterations in Loading Sequence and Its Relation to Left Ventricular Isovolumic Relaxation
Authors: Kohno Fujimasa , Kumada Toshiaki , Kambayashi Masashi , Hayashida Wataru , Ishikawa Noboru , Sasayama Shigetake
Published: June 2012

Background
A brief, sustained constriction of the descending and the ascending aortas produces systolic loads at different times during ejection, and descending intervention prolongs left ventricular (LV) relaxation more than ascending intervention. Although alterations in the sequence of loading the ventricle have been suggested as a cause of such load-induced relaxation abnormalities, the relation of the loading system to relaxation has been unclear.

Methods and Results
LV peak systolic pressure was elevated by approximately 40 mm Hg by constricting the descending and ascending aortas in seven anesthetized dogs. The descending intervention increased aortic end-systolic pressure (AoESP, 110.4±9.3 to 150.8±11.5 mm Hg;
P
<.05), reduced aortic flow (
P
<.05), and prolonged LV relaxation (time constant [T], 31.9±4.4 to 69.8±12.8 ms;
P
<.05). LV ejection time was reduced, but the systolic time interval was unchanged. In contrast, ascending intervention decreased AoESP (111.9±11.4 to 101.5±10.3 mm Hg;
P
<.05), reduced aortic flow (
P
<.05), and prolonged T (31.2±5.4 to 42.2±8.3 ms;
P
<.05), whereas ejection time and systolic time interval increased (both
P
<.01). Prolongation of T was significantly greater during descending intervention (
P
<.05) and was associated with an increase in AoESP during descending intervention but a decrease in AoESP during ascending intervention.

Conclusions
Descending intervention induced greater prolongation of T than ascending intervention. Prolongation of T was closely related to an increase in AoESP in the descending intervention but a decrease in AoESP in the ascending intervention. These data suggest that not only the loading sequence but also the pressure level at the onset of isovolumic relaxation determines LV relaxation.
Plasmin Promotes an Endothelium-Dependent Adhesion of Neutrophils
Authors: Montrucchio G. , Lupia E. , De Martino A. , Silvestro L. , Savu S. Rizea , Cacace G. , De Filippi P.G. , Emanuelli G. , Camussi G.
Published: June 2012

Background
The adhesion of leukocytes to the endothelium and the edema of vessel wall may cause vascular reocclusion after thrombolytic therapy. The aim of this study was to evaluate the role of platelet activating factor (PAF) and P-selectin on the adherence of polymorphonuclear neutrophils (PMN) to the endothelium and of PAF on the increased vascular permeability induced by tissue-type plasminogen activator, streptokinase, and plasmin.

Methods and Results
We studied (1) the adhesion of
111
In-labeled PMN to human umbilical cord vein–derived cultured endothelial cells (HUVEC), (2) the transfer of
125
I-labeled albumin across HUVEC monolayers, and (3) the adhesion of PMN to isolated bovine coronary arteries under flow conditions. It was found that the adhesion of PMN, induced by tissue-type plasminogen activator, streptokinase, and plasmin, correlated with the synthesis of PAF by HUVEC and was inhibited by WEB 2170, a PAF receptor antagonist. The adhesion of PMN was also inhibited by the treatment of HUVEC with anti–P-selectin antibodies or of PMN with soluble P-selectin or with anti-CD18 monoclonal antibodies. Plasmin also increased the permeability of HUVEC monolayers, an effect that was partially prevented by WEB 2170. Moreover, plasmin promoted the synthesis of PAF from isolated bovine coronary arteries and the adherence of PMN to the endothelium under flow conditions. The pretreatment of PMN with WEB 2170 or with soluble P-selectin prevented adhesion.

Conclusions
The synthesis of PAF by endothelial cells at the site of plasmin generation and the endothelial expression of P-selectin may render the endothelial cell surface proadhesive for neutrophils and may favor a local increase in vascular permeability.
Clinical Implications of the ‘No Reflow’ Phenomenon
Authors: Ito Hiroshi , Maruyama Atsushi , Iwakura Katsuomi , Takiuchi Shin , Masuyama Tohru , Hori Masatsugu , Higashino Yorihiko , Fujii Kenshi , Minamino Takazo
Published: June 2012

Background
Recent studies demonstrated that the “no reflow” phenomenon after coronary reflow implies the presence of advanced myocardial damage. In this study, we verified the prognostic value of the detection of this phenomenon by studying complications, left ventricular morphology, and in-hospital survival after acute myocardial infarction (AMI).

Methods and Results
The study population consisted of 126 patients with a first anterior AMI. All patients received coronary reflow within 24 hours of onset of symptoms and underwent myocardial contrast echocardiography (MCE) before and shortly after coronary reflow with an intracoronary injection of sonicated microbubbles. From contrast reperfusion patterns, patients were divided into two subsets: those with MCE no reflow (47 patients, 37%) and those with MCE reflow (79 patients). There was no difference in the frequency of arrhythmia or coronary events between the two subsets. Pericardial effusion and early congestive heart failure were observed more frequently in patients with MCE no reflow than in those with MCE reflow (26% versus 4%,
P
<.05; 45% versus 15%,
P
<.05, respectively). Congestive heart failure tended to be prolonged in those with MCE no reflow, and 3 patients (7%) of this subset died of pump failure. Left ventricular end-diastolic volume progressively increased in the convalescent stage in patients with MCE no reflow (early versus late, 145±43 versus 169±60 mL,
P
<.001), whereas it decreased in those with MCE reflow (154±42 versus 144±44 mL,
P
<.01).

Conclusions
The substantial size of the MCE no reflow phenomenon at coronary reflow conveys useful information about an outcome of coronary intervention and left ventricular remodeling in individual patients with anterior wall AMI, although these are suggestive results in a limited number of patients.
Platelet Function in Acute Myocardial Infarction Treated With Direct Angioplasty
Authors: Gawaz Meinrad , Neumann Franz-Josef , Ott Ilka , Schiessler Alexander , Schömig Albert
Published: June 2012

Background
In acute myocardial infarction (AMI), platelets play a key role in thrombotic processes that limit the patency of the recanalized, infarct-related coronary artery and contribute to reperfusion injury. Platelet function in the course of AMI treated by direct percutaneous transluminal coronary angioplasty (PTCA) has not been evaluated.

Methods and Results
In 15 patients with anterior AMI, peripheral venous blood samples were obtained before and 4, 8, 24, and 48 hours after recanalization of the occluded artery by PTCA. Fifteen patients who had stable coronary heart disease and were undergoing elective balloon angioplasty served as control subjects. Fibrinogen receptor function and surface expression of P-selectin on platelets were determined by flow cytometry. In addition, we evaluated generation of platelet-derived microparticles and the effect of systemic plasma from patients with AMI on normal platelet function and on platelet adhesion to human endothelial cells in culture. We found fibrinogen receptor activity and P-selectin expression on circulating platelets 8 hours after direct PTCA are decreased (
P
<.01). This coincided with a decrease in peripheral platelet count (
P
<.05) and an increase in generation of microparticles (
P
<.002). Twenty-four to 48 hours after PTCA, fibrinogen receptor activity and P-selectin expression increased again. Systemic plasma obtained before and after direct PTCA sensitized normal platelets to hyperaggregate in vitro (
P
<.001) and stimulated platelet adhesion to endothelial cells in culture (
P
<.01). None of the changes found in AMI were detectable in the control group.

Conclusions
After transient apparent deactivation of circulating platelets, probably caused by sequestration of hyperactive platelets, the level of platelet activation increases in patients with AMI treated by direct PTCA. These findings underscore the need for novel antiplatelet strategies in AMI.
Heparin-Coated Palmaz-Schatz Stents in Human Coronary Arteries
Authors: Serruys Patrick W. , Emanuelsson Håkan , van der Giessen Wim , Lunn Anthony C. , Kiemeney Ferdinand , Macaya Carlos , Rutsch Wolfgang , Heyndrickx Guy , Suryapranata Harry , Legrand Victor , Goy Jean Jacques , Materne Pierre , Bonnier Hans , Morice Marie-Claude , Fajadet Jean , Belardi Jorge , Colombo Antonio , Garcia Eulogio , Ruygrok Peter , de Jaegere Peter , Morel Marie-Angèle
Published: June 2012

Background
The purpose of the Benestent-II Pilot Study was to evaluate the safety of delaying and eliminating anticoagulant therapy in patients receiving a heparin-coated stent in conjunction with antiplatelet drugs.

Methods and Results
The study consisted of three initial phases (I, II, III) during which resumption of heparin therapy after sheath removal was progressively deferred by 6, 12, and 36 hours. In phase IV, coumadin and heparin were replaced by 250 mg ticlopidine and 100 mg aspirin. Of the 207 patients with stable angina pectoris and a de novo lesion in whom heparin-coated stent implantation was attempted, implantation was successful in 202 patients (98%). Stent thrombosis did not occur during all four phases, and the overall clinical success rate at discharge was 99%. Bleeding complications requiring blood transfusion or surgery fell from 7.9% in phase I to 5.9%, 4%, and 0% in the three following phases. Hospital stay was 7.4, 6.1, 7.2, and 3.1 days for the consecutive phases. The restenosis rate for the combined four phases was 13% (15% in phase I, 20% in phase II, 11% in phase III, and 6% in phase IV). The overall rate of reintervention for the four phases was 8.9%. At 6 months, 84%, 75%, 94%, and 92% of the patients of phases I to IV, respectively, were event free. For the four phases, the event-free rate was 86%, which compares favorably with the rate observed in the Benestent-I study (80%; relative risk, 0.68 [0.45 to 1.04]).

Conclusions
The implantation of stents coated with polyamine and end-point–attached heparin in stable patients with one significant de novo coronary lesion is well tolerated, is associated with no (sub)acute stent thrombosis, and results in a favorable event-free survival after 6 months.
Acute Cardiovascular Effects of OPC-18790 in Patients With Congestive Heart Failure
Authors: Feldman Marc D. , Pak Peter H. , Wu Clarence C. , Haber Howard L. , Heesch Christian M. , Bergin James D. , Powers Eric R. , Cowart T. Douglas , Johnson William , Feldman Arthur M. , Kass David A.
Published: June 2012

Background
OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy.

Methods and Results
Pressure-volume (PV) analysis was performed in 17 patients who received either 5 μg·kg
−1
·min
−1
(low dose, n=10) or 10 μg·kg
−1
·min
−1
(high dose, n=7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an ≈40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was ≈0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered.

Conclusions
OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.
Exploration of the Precision of Classifying Sudden Cardiac Death
Authors: Pratt Craig M. , Greenway Patricia S. , Schoenfeld Mark H. , Hibben Mary Lou , Reiffel James A.
Published: June 2012

Background
As cardiovascular clinical trials improve in sophistication and therapies target specific cardiac mechanisms of death, a more objective and precise system to identify specific cause of death is needed. Ideally, sudden cardiac death would describe patients dying of ventricular tachycardia and ventricular fibrillation. In this context, we explored the precision of current sudden death classification and implications for clinical trials.

Methods and Results
Deaths were analyzed in 834 patients who received an automatic implantable cardioverter-defibrillator (ICD). Three arrhythmia experts used a standard prospective classification system to classify deaths into accepted categories: sudden cardiac, nonsudden cardiac, and noncardiac. New aspects to this study included analysis of autopsy results and ICD interrogation for arrhythmias at the time of death. All of the patients receiving the ICD previously had documented sustained ventricular tachycardia/fibrillation or cardiac arrest. Of the 109 subsequent deaths in the 834-patient database, 17 (16%) were classified as sudden cardiac. Compared with the nonsudden cardiac and noncardiac categories, sudden cardiac death was more often identified in outpatients (59% versus 10%) and witnessed less often (41% versus 86%; both
P
<.001). The autopsy information contradicted and changed the clinical perception of a “sudden cardiac death” in 7 cases (myocardial infarction [n=1], pulmonary embolism [n=2], cerebral infarction [n=1], ruptured thoracic [n=1], and abdominal aortic aneurysms [n=2]). Interpretable ICD interrogation was available in 53% of the deaths (47% unavailable: buried, programmed off, or other technical reasons). When evaluated, only 7 of 17 “sudden deaths” were associated with ICD discharges near the time of death.

Conclusions
Even in a group of patients with an ICD, deaths classified as sudden cardiac frequently were not associated with ventricular tachycardia or ventricular fibrillation and were often noncardiac. It is possible to create a wide range of sudden cardiac death rates (more than fourfold) using the identical clinical database despite objective, prespecified criteria. Autopsy results frequently reveal noncardiac causes of clinical events simulating sudden cardiac death. ICD interrogation revealed that ICD discharges were often related to terminal arrhythmias incidental to the primary pathophysiological process leading to death.
Oral Antiplatelet, Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Antagonist
Authors: Mousa Shaker A. , DeGrado William F. , Mu Dun-Xu , Kapil Ram P. , Lucchesi Benedict R. , Reilly Thomas M.
Published: June 2012

Background
Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs.

Methods and Results
In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts’ model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and <0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (
P
<.01) in an electrolytically induced carotid artery thrombosis model in dogs.

Conclusions
These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.
Does Antithrombotic Therapy Influence Residual Thrombus After Thrombolysis of Platelet-Rich Thrombus?
Authors: Mruk Jozef S. , Zoldhelyi Pierre , Webster Mark W.I. , Heras Magda , Grill Diane E. , Holmes David R. , Fuster Valentin , Chesebro James H.
Published: June 2012

Background
Thrombolysis to normal flow in patients with acute myocardial infarction preserves left ventricular function and decreases mortality. Failure of early reperfusion, reocclusion, or residual thrombus may be due to concurrent activation of the platelet-coagulation system. Thus, we hypothesized that the best concomitant antithrombotic therapy (recombinant [r]-hirudin, heparin, or aspirin) will maximally accelerate thrombolysis by r–tissue-type plasminogen activator (rTPA) and reduce residual thrombus.

Methods and Results
Occlusive thrombi were formed in the carotid arteries of 29 pigs (by balloon dilatation followed by endarterectomy at the site of injury-induced vasospasm) and matured for 30 minutes before rTPA was started, with or without antithrombotic therapy. Thrombolysis was assessed with the use of angiography and measurement of residual thrombus. Pigs were allocated to one of five treatments: placebo, rTPA, rTPA plus r-hirudin, rTPA plus heparin, or rTPA plus intravenous aspirin. No placebo-treated pig reperfused. Two of six animals treated with rTPA alone reperfused compared with seven of seven animals treated with rTPA plus r-hirudin (reperfusion time, 33±10 minutes), six of seven animals treated with rTPA plus heparin (reperfusion time, 110±31 minutes), and two of six animals with rTPA plus aspirin. The activated partial thromboplastin time was prolonged in only the rTPA plus r-hirudin group (25±0.1 times baseline) and the rTPA plus heparin group (5.3±0.2 times baseline). Residual
111
In-platelet and
125
I-fibrin(ogen) depositions were lower in the heparin-treated group and lowest in the r-hirudin–treated group (heparin versus hirudin, respectively; incidence of residual macroscopic thrombus was six of six animals versus two of seven [
P
=.01];
125
I-fibrin(ogen), 170±76 versus 48±6 ×10
6
molecules/cm
2
[
P
=.02];
111
In-platelets, 47±15 versus 13±2 ×10
6
/cm
2
,
P
=.10). No pigs developed spontaneous bleeding.

Conclusions
Thrombin inhibition with heparin or r-hirudin significantly accelerated thrombolysis of occlusive platelet-rich thrombosis, but only the best antithrombotic therapy (r-hirudin) eliminated or nearly eliminated residual thrombus.