bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressure Overload Increases GATA4 Binding Activity via Endothelin-1
Authors: Hautala Nina , Tokola Heikki , Luodonpää Marja , Puhakka Jutta , Romppanen Hannu , Vuolteenaho Olli , Ruskoaho Heikki
Published: June 2012

Background
—The signaling cascades responsible for the activation of transcription factors in the hypertrophic growth of cardiac myocytes during hemodynamic overload are largely unknown. Several of the genes upregulated in the hypertrophied heart, including B-type natriuretic peptide (BNP) gene, are controlled by the cardiac-restricted zinc finger transcription factor GATA4.

Methods and Results
—An in vivo model of intravenous administration of arginine
8
-vasopressin (AVP) for up to 4 hours in conscious normotensive rats was used to study the signaling mechanisms for GATA activation in response to pressure overload. Gel mobility shift assays were used to analyze the
trans
-acting factors that interact with the GATA motifs of the BNP promoter. AVP-induced increase in mean arterial pressure was followed by a significant increase in the BNP and c-
fos
mRNA levels in both the endocardial and epicardial layers of the left ventricle, whereas GATA4 and GATA6 mRNA levels remained unchanged. Pressure overload within 15 to 60 minutes produced an increase in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activity, and at 30 minutes a 2.2-fold increase (
P
<0.001) in GATA4 binding was noted. The mixed endothelin-1 ET
A
/ET
B
receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited the pressure overload–induced increase in left ventricular BNP GATA4 binding activity. Bosentan alone had no statistically significant effect on GATA4 binding activity of the left ventricle in conscious animals.

Conclusions
—ET-1 is a signaling molecule that rapidly upregulates GATA4 DNA binding activity in response to pressure overload in vivo.
Chronic μ-Opioid Receptor Stimulation in Humans Decreases Muscle Sympathetic Nerve Activity
Authors: Kienbaum Peter , Heuter Thorsten , Michel Martin C. , Scherbaum Norbert , Gastpar Markus , Peters Jürgen
Published: June 2012

Background
—Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by μ-opioid receptor blockade during antagonist-supported detoxification under general anesthesia.

Methods and Results
—Fifteen young patients (30±1 years old, mean±SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65±10 mg/d for 21±6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of μ-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4±2 versus 22±2 bursts/min,
P
<0.0001) and antecubital venous norepinephrine plasma concentration (100±64 versus 256±48 pg/mL,
P
=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5±2 to 24±3 bursts/min) and norepinephrine (49±12 to 305±48 pg/mL) and epinephrine (13±2 to 482±67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82±4 to 108±3 mm Hg) and heart rate (70±3 to 86±4 beats/min).

Conclusions
—Chronic μ-opioid receptor stimulation by methadone decreases resting MSA in humans.
Defining the Optimal Activated Clotting Time During Percutaneous Coronary Intervention
Authors: Chew Derek P. , Bhatt Deepak L. , Lincoff A. Michael , Moliterno David J. , Brener Sorin J. , Wolski Katherine E. , Topol Eric J.
Published: June 2012

Background
—Unfractionated heparin has been the primary anticoagulant therapy for percutaneous coronary intervention for >20 years. Despite the availability of rapid “point of care” testing, little clinical data defining the optimal level of anticoagulation are available. Furthermore, recent reports have advocated the use of low-dose heparin regimens in the absence of large-scale, well-conducted studies to support this practice.

Methods and Results
—We pooled the data from 6 randomized, controlled trials of novel adjunctive antithrombotic regimens for percutaneous coronary interventions in which unfractionated heparin constituted the control arm. Patients were divided into 25-s intervals of activated clotting times (ACTs), from <275 s to >476 s. In a total of 5216 patients, the incidence of death, myocardial infarction, or any revascularization and major or minor bleeding at 7 days were calculated for each group and compared. An ACT in the range of 350 to 375 s provided the lowest composite ischemic event rate of 6.6%, or a 34% relative risk reduction in 7-day ischemic events compared with rates observed between 171 and 295 s by quartile analysis (
P
=0.001).

Conclusions
—Contrary to recent reports, the optimal suppression of ischemic events with unfractionated heparin therapy in patients undergoing percutaneous coronary intervention demands treatment to ACT levels that are substantially higher than currently appreciated. These data define a goal for heparin dosing within coronary interventions and establish a benchmark of optimal unfractionated heparin therapy against which future trials of novel antithrombotic regimens in percutaneous interventions can be compared.
Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile β
2
-Adrenoceptors
Authors: Brodde Otto-Erich , Büscher Rainer , Tellkamp Ralph , Radke Joachim , Dhein Stefan , Insel Paul A.
Published: June 2012

Background
—Recent evidence indicates that certain genotypes of β
2
-adrenoceptors (AR) may indicate an increased risk of cardiovascular disease or an increased rate of disease progression. Of particular importance, the Thr164Ile polymorphism, which is found in ≈4% of humans, shows decreased receptor signaling, blunted cardiac response when expressed in transgenic mice, and is associated with a decreased survival rate in patients with congestive heart failure.

Methods and Results
—In this study, we compared functional activity, ie, chronotropic (heart rate increases) and inotropic (duration of the electromechanical systole) responses to intravenously administered terbutaline, in 6 subjects (4 women and 2 men) who were heterozygous for Thr164Ile with the responses in 12 volunteers (6 women and 6 men) who were homozygous for wild-type (WT) β
2
-AR (ie, Arg16, Gln27, and Thr164). The β
2
AR polymorphism significantly affected the dose-response curves for terbutaline-induced inotropic and chronotropic responses: compared with WT individuals, subjects with the Thr164Ile receptor had substantial blunting in maximal increases in heart rate (WT, 29.7±3.9 beats/min; Ile164, 20.7±1.9 beats/min;
P
=0.016) and a shortening of the duration of electromechanical systole (WT, 51.9±4.5 ms; Ile164, 37.9±4.6 ms;
P
=0.02).

Conclusions
—These data show that humans with the Ile164 genotype show blunted cardiac β
2
-AR responsiveness, which may help explain the decreased survival of patients with this genotype in the setting of congestive heart failure.
Peripheral Flow Response to Transient Arterial Forearm Occlusion Does Not Reflect Myocardial Perfusion Reserve
Authors: Bøttcher Morten , Madsen Mette M. , Refsgaard Jens , Buus Niels Henrik , Dørup Inge , Nielsen Torsten Toftegaard , Sørensen Keld
Published: June 2012

Background
—Ultrasonographic evaluation of systemic arterial function is widely available, and a close relation of endothelial function in the coronary and brachial arteries has been documented. It is unknown, however, whether a similar correlation exists for their 2 microcirculatory territories and thus whether assessment of the systemic microcirculation can be used similarly as a surrogate marker of myocardial perfusion.

Methods and Results
—Twenty-three patients with documented coronary artery disease (CAD; 66±9 years old, 18 men), 16 patients with syndrome X (SX; 56±5 years old, 13 women), and 45 healthy control subjects (C; 34±9 years old, 22 men) were studied. Myocardial perfusion was measured at rest and after dipyridamole (0.56 mg · kg
−1
· min
−1
over 4 minutes) by PET, and brachial artery blood flow was measured at rest and after transient forearm ischemia by standard Doppler ultrasound techniques. Dipyridamole increased myocardial perfusion in all groups (mL · g
−1
· min
−1
: CAD, 0.89±0.27 versus 1.62±0.67,
P
<0.001; SX, 0.82±0.16 versus 1.67±0.49,
P
<0.001; and C, 0.82±0.15 versus 2.32±0.64,
P
<0.001). Postocclusion forearm flow increased similarly in all groups (CAD, 52±18 versus 174±77 mL/min,
P
<0.001; SX, 49±29 versus 202±82 mL/min,
P
<0.001; and C, 61±34 versus 229±108 mL/min,
P
<0.001). No significant correlations were found between peripheral and myocardial microcirculatory beds for either resting flow, hyperemic flow, or flow reserve in any of the groups (
r
2
<0.1,
P
=NS).

Conclusions
—The peripheral perfusion responses to transient forearm ischemia do not correlate with dipyridamole-induced myocardial hyperemia. The lack of correlation indicates different mechanisms of microvascular activation or regulation and confirms that extrapolations between findings in the 2 vascular beds are not suitable.
ABC Stenosis Morphology Classification and Outcome of Coronary Angioplasty
Authors: Maier Willibald , Mini Oliver , Antoni Joerg , Wischnewsky Manfred B. , Meier Bernhard
Published: June 2012

Background
—The American College of Cardiology/American Heart Association (ACC/AHA) stenosis morphology classification (MC) stratifies coronary lesions for probability of success and complications after coronary angioplasty (PTCA). Modern computing techniques were used to evaluate the individual predictive value of MC in random PTCA cases.

Methods and Results
—MC was attributed to the target lesions by consensus of 2 observers. The predictive value regarding procedural success (PS) and major adverse cardiac events (MACE) of MC was analyzed by conventional logistic regression analyses and by inductive machine learning models. The study was adequately powered for the methods applied with 325 target lesions of 250 cases. Overall, PS decreased and MACE increased from type A to type C lesions. Regression analysis identified no single factor as predictive. Logistic regression showed an error rate of 42%. Machine learning techniques achieved an individual predictive error of only 10%, which could be further reduced to 2% by addition of parameters. For PS, MC parameters showed a high ranking for building the model. For MACE, variables of the medical history showed more impact.

Conclusions
—MC per se cannot individually predict PS or MACE. However, when all MC parameters are integrated together with additional lesion-specific and history variables, a high individual predictive value can be achieved. This technique may be clinically helpful for risk stratification in the catheterization laboratory and improvement of classification systems in interventional cardiology.
Long-Term Stable Correction of Low-Density Lipoprotein Receptor–Deficient Mice With a Helper-Dependent Adenoviral Vector Expressing the Very Low-Density Lipoprotein Receptor
Authors: Oka Kazuhiro , Pastore Lucio , Kim In-Hoo , Merched Aksam , Nomura Shuichi , Lee Hye-Jeong , Merched-Sauvage Maria , Arden-Riley Celeste , Lee Brendan , Finegold Milton , Beaudet Arthur , Chan Lawrence
Published: June 2012

Background
—Familial hypercholesterolemia (FH) that results from LDL receptor (LDLR) deficiency affects ≈1 in 500 persons in the heterozygous state and ≈1 in 1 million persons in the homozygous state. We tested a novel gene therapy strategy for the treatment of FH in a mouse model.

Methods and Results
—We delivered the VLDL receptor (VLDLR) to the liver of LDLR-deficient mice and compared the effect of a helper-dependent adenoviral vector with all viral coding sequences deleted (HD-Ad-mVLDLR) with a first-generation vector (FG-Ad-mVLDLR), an HD-Ad (HD-Ad-0) that contained no expression cassette, and dialysis buffer (DB). A single intravenous injection of HD-Ad-mVLDLR led to a lowering of plasma cholesterol that lasted ≥6 months. Acute liver toxicity (as measured with liver enzyme elevation) occurred after FG-Ad-mVLDLR but not after HD-Ad-mVLDLR, HD-Ad-0, or DB treatment. At 6 months, VLDLR was detected in the liver with Western blotting and with immunofluorescence staining only in HD-Ad-mVLDLR–treated mice. Aortic atherosclerosis was almost completely prevented in these animals.

Conclusions
—HD-Ad–mediated intravenous delivery of VLDLR to hepatocytes is well tolerated. It produces long-term lowering of plasma cholesterol and prevents atherosclerosis development in LDLR-deficient mice. These data provide support for the feasibility and safety of this approach for therapy of human subjects.
Serotonin-Induced Hypercontraction Through 5-Hydroxytryptamine 1B Receptors in Atherosclerotic Rabbit Coronary Arteries
Authors: Ishida Tatsuro , Kawashima Seinosuke , Hirata Ken-ichi , Sakoda Tsuyoshi , Shimokawa Yasushi , Miwa Yoichi , Inoue Nobutaka , Ueyama Tomomi , Shiomi Masashi , Akita Hozuka , Yokoyama Mitsuhiro
Published: June 2012

Background
—Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries.

Methods and Results
—Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT
1
–receptor agonists; the constrictor threshold concentrations and
ED
50
to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the
E
max
in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT
1B/1D
antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT
2
antagonist; 0.01 to 1 μmol/L), suggesting that the hypercontraction is most likely mediated by 5-HT
1B/1D
receptors through a pertussis toxin–sensitive pathway. Furthermore, simultaneous measurements of [Ca
2+
]
i
and isometric tension of fura-2–loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca
2+
]
i
in the smooth muscle. The 5-HT
1B
mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT
1D
nor 5-HT
2A
mRNA was detected in either group.

Conclusions
—Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca
2+
mobilization in response to serotonin. The 5-HT
1B
receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.
Trends in Acute Coronary Heart Disease Mortality, Morbidity, and Medical Care From 1985 Through 1997
Authors: McGovern Paul G. , Jacobs David R. , Shahar Eyal , Arnett Donna K. , Folsom Aaron R. , Blackburn Henry , Luepker Russell V.
Published: June 2012

Background
—Coronary heart disease (CHD) mortality continued to decline from 1985 to 1997.

Methods and Results
—We tabulated CHD deaths (ICD-9 codes 410 through 414) in the Minneapolis/St Paul, Minnesota, area. For 1985, 1990, and 1995, trained nurses abstracted the hospital records of patients 30 to 74 years old with a discharge diagnosis of acute CHD (ICD-9 codes 410 or 411). Acute myocardial infarction (AMI) events were validated and followed for 3-year all-cause mortality. Between 1985 and 1997, age-adjusted CHD mortality rates in Minneapolis/St Paul fell 47% and 51% in men and women, respectively; the comparable declines in US whites were 34% and 29%. In-hospital mortality declined faster than out-of-hospital mortality. The rate of AMI (ICD-9 code 410) hospital discharges declined almost 20% between 1985 and 1995, whereas the discharge rate for unstable angina (ICD-9 code 411) increased substantially. The incidence of hospitalized definite AMI declined ≈10%, whereas recurrence rates fell 20% to 30%. Three-year case fatality rates after hospitalized AMI decreased consistently by 31% and 41% in men and women, respectively. In-hospital administration of thrombolytic therapy, emergency angioplasty, ACE inhibitors, β-blockers, heparin, and aspirin increased greatly.

Conclusions
—Declining out-of-hospital death rates, declining incidence and recurrence of AMI in the population, and marked improvements in the survival of AMI patients all contributed to the 1985 to 1997 decline of CHD mortality in the Minneapolis/St Paul metropolitan area. The effects of early and late medical care seem to have had the greatest contribution to rates during this time period.
Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K
ATP
Channels by Diazoxide
Authors: Wang Yigang , Takashi En , Xu Meifeng , Ayub Ahmar , Ashraf Muhammad
Published: June 2012

Background
—The mitochondrial K
ATP
(mitoK
ATP
) channel has been shown to confer short- and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoK
ATP
channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoK
ATP
channels.

Methods and Results
—PKC was downregulated by prolonged (24-hour) treatment with phorbol 12-myristate 13-acetate (4 μg/kg body weight) before subsequent experiments in rats. Langendorff-perfused rat hearts were subjected to 40 minutes of ischemia followed by 30 minutes of reperfusion. Effects of PKC downregulation on the activation of mitoK
ATP
channels and other interventions on hemodynamic, biochemical, and pathological changes were assessed. Subcellular localization of PKC isoforms by Western blot analysis and immunocytochemistry demonstrated that PKC-α and PKC-δ were translocated to the sarcolemma and that PKC-δ was translocated to the mitochondria after diazoxide treatment. In hearts treated with diazoxide (80 μmol/L), a significant improvement in cardiac function and an attenuation of cell injury were observed. In PKC-downregulated hearts, protection was abolished because mitoK
ATP
channels could not be activated by diazoxide.

Conclusions
—These data suggest that PKC activation is required for the opening of mitoK
ATP
channels during protection against ischemia and that this effect is linked to isoform-specific translocation of PKC-δ to the mitochondria.
Activation of Heat-Shock Factor by Stretch-Activated Channels in Rat Hearts
Authors: Chang Jiang , Wasser Jeremy S. , Cornelussen Richard N.M. , Knowlton A.A.
Published: June 2012

Background

—

Previously, we have observed that the isolated, erythrocyte-perfused rabbit heart has increased levels of heat-shock protein (HSP) 72 after a mild mechanical stress. We hypothesized that stretch-activated ion channels (SACs) mediated this increase.

Methods and Results

—

To test this hypothesis, we subjected isolated, perfused rat hearts to mechanical stretch. Gel mobility shift assay showed that heat-shock factor (HSF) was activated in hearts with mechanical stretch, but not in controls. Supershift experiments demonstrated that HSF1 was the transcription factor. Northern blots revealed the concomitant increase in HSP72 mRNA in stretched rat hearts. In a separate set of experiments, gadolinium, an inhibitor of SACs, was added to the perfusate. Gadolinium inhibited the activation of HSF and decreased HSP72 mRNA level. Because gadolinium can inhibit both SACs and L-type calcium channels, we perfused a group of hearts with diltiazem, a specific L-type calcium channel blocker, to eliminate the involvement of L-type calcium channels. Diltiazem failed to inhibit the activation of HSF.

Conclusions

—

Stretch in the rat heart results in activation of HSF1 and an increase in HSP72 mRNA through SACs. This represents a novel mechanism of HSF activation and may be an important cardiac signaling pathway for hemodynamic stress.
Successful Ventricular Defibrillation by the Selective Sodium-Hydrogen Exchanger Isoform-1 Inhibitor Cariporide
Authors: Gazmuri Raúl J. , Ayoub Iyad M. , Hoffner Elizabeth , Kolarova Julieta D.
Published: June 2012

Background

—

Sodium-hydrogen exchanger isoform-1 (NHE-1) activation worsens functional myocardial abnormalities associated with ischemia and reperfusion. We hypothesize that these abnormalities may limit cardiac resuscitation from ventricular fibrillation (VF) and investigated whether NHE-1 inhibition with the benzoylguanidine derivative cariporide could improve resuscitability, postresuscitation myocardial function, and short-term survival in isolated heart and intact rat models of VF.

Methods and Results

—

In the isolated rat heart, VF was induced for 25 minutes. Perfusion was interrupted for the initial 10 minutes and restarted at 10% of baseline flow for the remaining 15 minutes (simulating chest compression). Cariporide ameliorated ischemic contracture, prevented postresuscitation diastolic dysfunction, and favored earlier return of contractile function. In the intact rat, cariporide, injected into the right atrium before chest compression was started (after 6 minutes of untreated VF), prompted spontaneous defibrillation between minutes 7 and 9 of chest compression in 6 of 8 rats. In contrast, electrical defibrillation was required in each of 8 control rats after completion of a predetermined 16-minute interval of VF. After resuscitation, cariporide-treated rats had less ventricular ectopic activity and normalized their hemodynamic function faster. Electrical defibrillation was then timed in control rats to match the time when spontaneous defibrillation occurred in cariporide-treated rats. With comparable VF duration, postresuscitation hemodynamic dysfunction was ameliorated by cariporide, but only when more severe ischemia was modeled by prolongation of the interval of untreated VF from 6 to 10 minutes.

Conclusion

—

NHE-1 inhibition may represent a novel and remarkably effective intervention for resuscitation from VF.
Combined Assessment of Myocardial Perfusion and Regional Left Ventricular Function by Analysis of Contrast-Enhanced Power Modulation Images
Authors: Mor-Avi Victor , Caiani Enrico G. , Collins Keith A. , Korcarz Claudia E. , Bednarz James E. , Lang Roberto M.
Published: June 2012

Background

Echocardiographic contrast media have been used to assess myocardial perfusion and to enhance endocardial definition for improved assessment of left ventricular (LV) function. These methodologies, however, have been qualitative or have required extensive offline image analysis. Power modulation is a recently developed imaging technique that provides selective enhancement of microbubble-generated reflections. Our goal was to test the feasibility of using power modulation for combined quantitative assessment of myocardial perfusion and regional LV function in an animal model of acute ischemia.

Methods and Results

Coronary balloon occlusions were performed in 18 anesthetized pigs. Transthoracic power modulation images (Agilent 5500) were obtained during continuous intravenous infusion of the contrast agent Definity (DuPont) at baseline and during brief coronary occlusion and reperfusion and were analyzed with custom software. At each phase, myocardial perfusion was assessed by calculation, in 6 myocardial regions of interest, of mean pixel intensity and the rate of contrast replenishment after high-power ultrasound impulses. LV function was assessed by calculation of regional fractional area change from semiautomatically detected endocardial borders. All ischemic episodes caused detectable and reversible changes in perfusion and function. Perfusion defects, validated with fluorescent microspheres, were visualized in real time and confirmed by a significant decrease in pixel intensity in the left anterior descending coronary artery territory after balloon inflation and reduced rate of contrast replenishment. Fractional area change decreased significantly in ischemic segments and was restored with reperfusion.

Conclusions

Power modulation allows simultaneous online assessment of myocardial perfusion and regional LV wall motion, which may improve the echocardiographic diagnosis of myocardial ischemia.
Multicenter patency trial of intravenous anistreplase compared with streptokinase in acute myocardial infarction. The TEAM-2 Study Investigators.
Authors: Anderson J L , Sorensen S G , Moreno F L , Hackworthy R A , Browne K F , Dale H T , Leya F , Dangoisse V , Eckerson H W , Marder V J
Published: June 2012

Thrombolytic therapy has been shown to improve clinical outcome when administered early after the onset of symptoms of acute myocardial infarction; the mechanism of benefit is believed to be reestablishment and maintenance of coronary artery patency. Anistreplase is a second generation thrombolytic agent that is easily administered and has a long duration of action. To compare anistreplase (30 units/2-5 min) and therapy with the Food and Drug Administration-approved regimen of intravenous streptokinase (1.5 million units/60 min), a randomized, double-blind, multicenter patency trial was undertaken in 370 patients less than 76 years of age with electrocardiographic ST segment elevation who could be treated within 4 hours of symptom onset. Coronary patency was determined by reading, in a blinded fashion, angiograms obtained early (90-240 minutes; mean, 140 minutes) and later (18-48 hours; mean, 28 hours) after beginning therapy. Early total patency (defined as Thrombolysis in Myocardial Infarction grade 2 or 3 perfusion) was high after both anistreplase (132/183 = 72%) and streptokinase (129/176 = 73%) therapy, and overall patency patterns were similar, although patent arteries showed "complete" (grade 3) perfusion more often after anistreplase (83%) than streptokinase (72%) (p = 0.03). Similarly, residual coronary stenosis, determined quantitatively by a validated computer-assisted method, was slightly less in patent arteries early after anistreplase (mean stenosis diameter, 74.0%) than streptokinase (77.2%, p = 0.02). In patients with patent arteries without other early interventions, reocclusion risk within 1-2 days was defined angiographically and found to be very low (anistreplase = 1/96, streptokinase = 2/94). Average coronary perfusion grade was greater, and percent residual stenosis was less, at follow-up than on initial evaluation and did not differ between treatment groups. Enzymatic and electrocardiographic evolution was not significantly different in the two groups. Despite rapid injection, anistreplase was associated with only a small (4-5 mm Hg), transient (at 5-10 minutes) mean differential fall in blood pressure. In-hospital mortality rates were comparable for anistreplase and streptokinase (5.9%, 7.1%). Stroke occurred in one (0.5%) and three (1.6%) patients, respectively; one stroke was hemorrhagic. Other serious bleeding events and adverse experiences occurred uncommonly and with similar frequency in the two groups. Thus, for the end points of our study (patency, safety), anistreplase and streptokinase showed overall favorable and relatively comparable outcomes, with a few differences.(ABSTRACT TRUNCATED AT 400 WORDS)
Expression and distribution of atrial natriuretic peptide in human hypertrophic ventricle of hypertensive hearts and hearts with hypertrophic cardiomyopathy.
Authors: Takemura G , Fujiwara H , Mukoyama M , Saito Y , Nakao K , Kawamura A , Ishida M , Kida M , Uegaito T , Tanaka M
Published: June 2012

To investigate the ventricular expression of atrial natriuretic peptide (ANP) in human hypertrophic hearts, we conducted an immunohistochemical study of 130 endomyocardial biopsy specimens obtained from the right side of the ventricular septum (RVB), left ventricular free wall (LVB), or both from a total of 80 patients: 44 patients with hypertrophic cardiomyopathy (HCM), 14 with apical hypertrophic cardiomyopathy (APH), 13 with hypertensive hearts (HHD), and nine without hypertrophy (controls). No patients had apparent congestive heart failure. ANP was not seen in ventricular myocytes in controls but was identified in biopsy specimens of hypertrophic hearts, and its distribution was characteristic in each hypertrophic group: 15 RVB (37%) and two LVB (7%) of the HCM group, one RVB (7%) and two LVB (18%) of the APH group, and zero RVB (0%) and five LVB (46%) of the HHD group. Clinical data (including echocardiographic, hemodynamic, and angiographic data) were not directly related to ventricular ANP expression in HCM, APH, or HHD with one exception. In HHD patients, LVB specimens with ANP showed greater ventricular wall thickness than LVB specimens without ANP. According to histological data, however, the ANP-present RVB specimens of HCM or ANP-present LVB specimens of HHD had greater myocyte size than did the ANP-absent specimens. In addition, in HCM patients, the ANP-present RVB specimens showed more severe fibrosis and myofiber disarray than did the ANP-absent specimens. We conclude that a failing state and hemodynamic overload are not likely to be indispensable for ANP expression in human hypertrophic ventricles and that ventricular ANP expression occurs as a response to disease-specific changes: hemodynamic overload in HHD and histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis in HCM, which may reflect the characteristic distribution of intraventricular ANP.
Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure.
Authors: Chen J S , Wang W , Bartholet T , Zucker I H
Published: June 2012

The autonomic components of the baroreflex control of heart rate were evaluated in conscious mongrel dogs before and after 4-6 weeks of ventricular pacing (250 beats/min). Arterial baroreflex sensitivity (BRS) was determined by the slopes of linear regression of pulse interval versus the preceding systolic arterial pressure in response to bolus injections of either phenylephrine or nitroglycerin. BRS was significantly depressed in the heart failure state [nitroglycerin slope, 5.0 +/- 2.7 (mean +/- SD) versus 16.6 +/- 5.1 msec/mm Hg, p less than 0.005; phenylephrine slope, 15.0 +/- 14.8 versus 32.0 +/- 26.7 msec/mm Hg, p less than 0.005]. There was no depression in BRS in dogs that were used as time controls or were acutely paced for 30 minutes. After beta 1-adrenergic blockade with metoprolol, the resting heart rate in the heart failure state was depressed more than in the normal state (-17.0 +/- 5.0% versus -3.2 +/- 3.4%, p less than 0.001). Atropine significantly increased resting heart rate more in the normal state than in the heart failure state (115.8 +/- 36.7% versus 25.4 +/- 14.5%, p less than 0.005). Thus, dogs in the heart failure state appear to have high resting cardiac sympathetic tone and low resting vagal tone. For nitroglycerin administration, metoprolol depressed BRS by 47.6 +/- 26.3% in the normal state and by 63.6 +/- 58.5% in the heart failure state. Atropine decreased the BRS by 86.7 +/- 7.8% in the normal state and by 39.5 +/- 30.2% in the heart failure state.(ABSTRACT TRUNCATED AT 250 WORDS)
Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study.
Authors: Roberts R , Rogers W J , Mueller H S , Lambrew C T , Diver D J , Smith H C , Willerson J T , Knatterud G L , Forman S , Passamani E
Published: June 2012

In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality.
Nifedipine reduces the incidence of myocardial infarction and transient ischemia in patients undergoing coronary bypass grafting.
Authors: Seitelberger R , Zwölfer W , Huber S , Schwarzacher S , Binder T M , Peschl F , Spatt J , Holzinger C , Podesser B , Buxbaum P
Published: June 2012

A randomized study was performed on 104 patients undergoing elective coronary artery bypass grafting to examine whether the infusion of nifedipine (n = 53) reduces the incidence of perioperative myocardial ischemia and necrosis in the early postoperative period. Continuous hemodynamic and three-channel Holter monitoring was performed for 24 hours and serial assessment of serum enzymes and 12-lead electrocardiography were performed for 36 hours postoperatively. Nifedipine (minimum dose, 10 micrograms/kg/hr for 24 hours) was applied from the onset of extracorporal circulation. The control group (n = 51) received nitroglycerin (minimum dose, 1 micrograms/kg/min for 24 hours). Using the combined analyses of electrocardiography and Holter recordings, myocardial ischemia was defined as being either a transient ischemic event (TIE), transient coronary spasm (TCS), or myocardial infarction (MI). The two groups did not differ with respect to preoperative New York Heart Association classification, age, history of myocardial infarction, extracorporal circulation and aortic cross-clamp time, number of distal anastomoses, or systemic and pulmonary hemodynamics. The incidence of perioperative myocardial ischemia was substantially lower in the nifedipine than in the nitroglycerin group [TIE: three of 53 patients (6%) versus nine of 50 patients (18%), p less than 0.001; MI: two of 53 patients (4%) versus six of 50 patients (12%), p less than 0.001; and TCS: none of 53 patients (0%) versus two of 50 patients (4%), p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)
Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans.
Authors: Funck-Brentano C , Kibleur Y , Le Coz F , Poirier J M , Mallet A , Jaillon P
Published: June 2012

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.
Relation between leisure-time physical activity and blood pressure in older women.
Authors: Reaven P D , Barrett-Connor E , Edelstein S
Published: June 2012

Although there is some evidence that physical activity may decrease blood pressure in young and middle-aged women, the physical activity-blood pressure association in older women has rarely been studied. As part of an ongoing community-based study of chronic disease, 641 Caucasian women between the ages of 50 and 89 years had blood pressure measured following the Hypertension Detection and Follow-up Program protocol. They also answered selected Health Interview Survey questions about their leisure-time activity and were classified into categories of light (58%), moderate (24%), heavy (6%), or no physical activity (12%) by the estimated metabolic rate required for each activity. Women who engaged in any physical activity were significantly younger and thinner than sedentary women and had lower fasting and 2-hour postchallenge insulin levels. They did not differ in alcohol consumption, cigarette use, or prevalence of coronary heart disease or diabetes. Rates of systolic and diastolic hypertension were significantly lower in women participating in light, moderate, or heavy physical activity compared with sedentary women. Blood pressure levels decreased with each increase in reported activity intensity (p less than 0.005 for trend), with systolic blood pressure approximately 20 mm Hg lower in the heaviest activity group compared with systolic blood pressure in sedentary women. Intergroup differences remained statistically significant after adjustment for age and body mass index. Although physical activity was associated with lower fasting and 2-hour postchallenge insulin levels (p less than 0.01 for trend), adjustment for insulin levels did not alter blood pressure differences among activity groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral clofilium produces sustained lowering of defibrillation energy requirements in a canine model.
Authors: Dorian P , Wang M , David I , Feindel C
Published: June 2012

The effect of long-term oral administration of antiarrhythmic drugs on defibrillation energy requirements is not well understood. We examined the effect of clofilium, a drug that prolongs cardiac action potential duration without slowing cardiac conduction, on defibrillation energy requirements and ventricular effective refractory periods in a canine model during a 3-week period. Epicardial patch electrodes were implanted in 12 dogs, and baseline testing was conducted under fentanyl anesthesia on day 7. An oral clofilium (100 mg/day) regimen was started on day 8. Six clofilium-treated and six control dogs underwent repeated testing on days 14, 21, and 28 after surgery. Truncated trapezoidal shocks were given repeatedly at various stored energies in random order; delivered current and impedance were measured; and delivered energy was calculated. The energy and current for 50% success in defibrillation (E50 and I50, respectively) were determined. For control animals, E50 increased by a mean 34 +/- 78%, 60 +/- 83%, and 69 +/- 122% compared with baseline (day 7) on days 14, 21, and 28, respectively. In contrast, E50 in clofilium-treated dogs decreased by 39 +/- 62%, 24 +/- 33%, and 32 +/- 15% on days 14, 21, and 28, respectively. Mean current requirements (I50) remained relatively stable compared with baseline in control animals (-7 +/- 39%, +25 +/- 36%, +40 +/- 75% on days 14, 21, and 28, respectively). After clofilium administration I50 decreased by 36 +/- 22%, 32 +/- 17%, and 33 +/- 17% on days 14, 21, and 28, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Transvascular intracardiac applications of a miniaturized phased-array ultrasonic endoscope. Initial experience with intracardiac imaging in piglets.
Authors: Valdes-Cruz L M , Sideris E , Sahn D J , Murillo-Olivas A , Knudson O , Omoto R , Kyo S , Gulde R
Published: June 2012

BACKGROUND

Recent advances in miniaturization of phased-array and mechanical ultrasound devices have resulted in exploration of alternative approaches to cardiac and vascular imaging in the form of transesophageal or intravascular imaging. Preliminary efforts in adapting phased-array endoscopes designed for transesophageal use to a transvascular approach have used full-sized phased-array devices introduced directly into the right atrium in open-chested animals. The purpose of this study was to assess the feasibility of using a custom-made, very small phased-array endoscope for intracardiac imaging introduced intravascularly through a jugular venous approach in young piglets.

METHODS AND RESULTS

Experimental atrial septal defects created in four piglets (3-4 weeks old) had been closed with a buttoned atrial septal defect closure device consisting of an occluder in the left atrium and a counteroccluder in the right atrium. Five to 15 days after atrial septal defect closure, the piglets were returned to the experimental laboratory, where a 6.3-mm, 17-element, 5-MHz phased-array probe mounted on a 4-mm endoscope was introduced through a cutdown incision of the external jugular vein and advanced to the right atrium. From the right atrium all four cardiac chambers, their inflows and outflows, and all four valves were well imaged with minimal superior and inferior rotation. High-resolution imaging of the atrial septum defined with anatomical accuracy, later verified by autopsy, the exact placement of both the occluder and counteroccluder in the left and right sides of the atrial septal defects and the absence of any shunting across the atrial septum in any of the four animals.

CONCLUSIONS

Our efforts indicate that transvascular passage of small phased-array probes can be easily accomplished and is a promising technique for detailed visualization of cardiac structures. This approach may provide an alternative to transesophageal echocardiography, particularly for guiding interventional procedures such as placement of transcatheter closure devices in pediatric patients.
Catheter modification of the atrioventricular junction with radiofrequency energy for control of atrioventricular nodal reentry tachycardia.
Authors: Lee M A , Morady F , Kadish A , Schamp D J , Chin M C , Scheinman M M , Griffin J C , Lesh M D , Pederson D , Goldberger J
Published: June 2012

BACKGROUND

The utility of transcatheter application of radiofrequency energy to eliminate atrioventricular nodal reentrant tachycardia (AVNRT) was investigated.

METHODS AND RESULTS

Thirty-nine patients (mean age, 53 +/- 20 years; range 14-86 years) with medically refractory AVNRT underwent perinodal ablation with radiofrequency energy. A custom-designed 6F catheter with a large (3-mm-long) distal electrode and interelectrode pacing of 2 mm was used in the majority of cases. The catheter used for ablation was initially positioned across the tricuspid anulus to obtain the largest His bundle electrogram, then withdrawn to obtain the largest atrial:ventricular electrogram ratio, with a small His bundle electrogram (less than or equal to 100 microV). Each application of radiofrequency energy (350-550 kHz, 16.2 +/- 5.2 W) was stopped after 60 seconds or if PR prolongation or an impedance rise was noted. The endpoints of the procedure were persistent modification of atrioventricular nodal conduction (either first-degree atrioventricular block or impairment of ventriculoatrial conduction) and noninducibility of AVNRT before and during isoproterenol administration. Radiofrequency energy was applied a mean of 6.8 +/- 3.5 times per session. After a mean follow-up of 8 +/- 3.0 months, 32 of the 39 patients (82%) have been free of AVNRT, and did not have high grade AV block. Three patients (8%) developed complete atrioventricular block and had pacemakers implanted. Two patients had unsuccessful initial procedures, and two patients had initially successful ablations but had recurrences of tachycardia 4-6 weeks later. Elimination of AVNRT appeared to be due to effects on the retrograde fast pathway in most patients.

CONCLUSIONS

Radiofrequency ablation of the perinodal right atrium appears to be safe and effective for treatment of typical AVNRT: