bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel
Authors: Shang Lijuan L. , Pfahnl Arnold E. , Sanyal Shamarendra , Jiao Zhe , Allen Jon , Banach Kathrin , Fahrenbach John , Weiss Daiana , Taylor W. Robert , Zafari A. Maziar , Dudley Samuel C.
Published: September 2007

Heart failure (HF) is associated with reduced cardiac Na
+
channel (SCN5A) current. We hypothesized that abnormal transcriptional regulation of this ion channel during HF could help explain the reduced current. Using human hearts explanted at the transplantation, we have identified 3 human C-terminal SCN5A mRNA splicing variants predicted to result in truncated, nonfunctional channels. As compared with normal hearts, the explanted ventricles showed an upregulation of 2 of the variants and a downregulation of the full-length mRNA transcript such that the E28A transcript represented only 48.5% (
P
<0.01) of the total SCN5A mRNA. This correlated with a 62.8% (
P
<0.01) reduction in Na
+
channel protein. Lymphoblasts and skeletal muscle expressing SCN5A also showed identical C-terminal splicing variants. Variants showed reduced membrane protein and no functional current. Transfection of truncation variants into a cell line stably transfected with the full-length Na
+
channel resulted in dose-dependent reductions in channel mRNA and current. Introduction of a premature truncation in the C-terminal region in a single allele of the mouse SCN5A resulted in embryonic lethality. Embryonic stem cell–derived cardiomyocytes expressing the construct showed reductions in Na
+
channel–dependent electrophysiological parameters, suggesting that the presence of truncated Na
+
channel mRNA at levels seen in HF is likely to be physiologically significant. In summary, chronic HF was associated with an increase in 2 truncated SCN5A variants and a decrease in the native mRNA. These splice variations may help explain a loss of Na
+
channel protein and may contribute to the increased arrhythmic risk in clinical HF.
Inhibition of Glycogen Synthase Kinase 3β During Heart Failure Is Protective
Authors: Hirotani Shinichi , Zhai Peiyong , Tomita Hideharu , Galeotti Jonathan , Marquez Juan Pablo , Gao Shumin , Hong Chull , Yatani Atsuko , Avila Jesús , Sadoshima Junichi
Published: September 2007

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3β in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3β (Tg-GSK-3β-DN) and tetracycline-regulatable wild-type GSK-3β. GSK-3β-DN significantly reduced the kinase activity of endogenous GSK-3β, inhibited phosphorylation of eukaryotic translation initiation factor 2Bε, and induced accumulation of β-catenin and myeloid cell leukemia-1, confirming that GSK-3β-DN acts as a dominant negative in vivo. Tg-GSK-3β-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the α-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater
E
max
after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3β induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3β-DN and nontransgenic mice, Tg-GSK-3β-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3β transgene in tetracycline-regulatable wild-type GSK-3β mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3β-DN in cardiac myocytes inhibited tumor necrosis factor-α–induced apoptosis, and the antiapoptotic effect of GSK-3β-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3β induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3β inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3β during heart failure could be compensatory.
Excessive Urinary Albumin Levels Are Associated With Future Cardiovascular Mortality in Postmenopausal Women
Authors: Roest Mark , Banga Jan Dirk , Janssen Wilbert M. T. , Grobbee Diederick E. , Sixma Jan J. , de Jong Paul E. , de Zeeuw Dick , van der Schouw Yvonne T.
Published: September 2007

Background
—Microalbuminuria is an early predictor of cardiovascular morbidity and mortality, in both diabetic patients and hypertensive patients. Little is known about the relation of microalbuminuria to cardiovascular disease in women of the general population.

Methods and Results
—We have studied the relation of urinary albumin levels to cardiovascular mortality in a cohort study of 12 239 postmenopausal women living in Utrecht, the Netherlands. The initial age was between 52 and 67 years. Women were followed on vital status between 1976 and 1995 (168 513 women-years). Albumin was determined in the urine of 561 cases and 557 controls. Data were analyzed by using a nested case-control design. The cardiovascular mortality rate (95% CI) for women who were in the highest quintile of urinary albumin levels was 13.2/1000 years (8.1 to 20.9) compared with 2.6/1000 years (2.3 to 3.1) in women without detectable urinary albumin. The age-adjusted rate ratio (95% CI) between these groups was 4.4 (2.6 to 7.6).

Conclusions
—This is the first large cohort study that confirms a predictive role of urinary albumin for the risk of future cardiovascular mortality independent of hypertension and diabetes. Our findings support the hypothesis that microalbuminuria is a reflection of vascular damage and a marker of early arterial disease in women from the general population.
Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin
Authors: Zou Yunzeng , Yao Atsushi , Zhu Weidong , Kudoh Sumiyo , Hiroi Yukio , Shimoyama Masaki , Uozumi Hiroki , Kohmoto Osami , Takahashi Toshiyuki , Shibasaki Futoshi , Nagai Ryozo , Yazaki Yoshio , Komuro Issei
Published: September 2007

Background
—Extracellular signal–regulated kinases (ERKs) and calcineurin have been reported to play important roles in the development of cardiac hypertrophy. We examined here the relation between calcineurin and ERKs in cardiomyocytes.

Methods and Results
—Isoproterenol activated ERKs in cultured cardiomyocytes of neonatal rats, and the activation was abolished by chelation of extracellular Ca
2+
with EGTA, blockade of L-type Ca
2+
channels with nifedipine, or depletion of intracellular Ca
2+
stores with thapsigargin. Isoproterenol-induced activation of ERKs was also significantly suppressed by calcineurin inhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isoproterenol failed to activate ERKs in either the cultured cardiomyocytes or the hearts of mice that overexpress the dominant negative mutant of calcineurin. Isoproterenol elevated intracellular Ca
2+
levels at both systolic and diastolic phases and dose-dependently activated calcineurin. Inhibition of calcineurin also attenuated isoproterenol-stimulated phosphorylation of Src, Shc, and Raf-1 kinase. The immunocytochemistry revealed that calcineurin was localized in the Z band, and isoproterenol induced translocation of calcineurin and ERKs into the nucleus.

Conclusions
—Calcineurin, which is activated by marked elevation of intracellular Ca
2+
levels by the Ca
2+
-induced Ca
2+
release mechanism, regulates isoproterenol-induced activation of ERKs in cardiomyocytes.
Ultrasonic Echolucent Carotid Plaques Predict Future Strokes
Authors: Grønholdt Marie-Louise M. , Nordestgaard Børge G. , Schroeder Torben V. , Vorstrup Sissel , Sillesen Henrik
Published: September 2007

Background
—We tested prospectively the hypothesis that stroke development can be predicted by echolucency of carotid atherosclerotic plaques in previously symptomatic and asymptomatic patients.

Methods and Results
—We followed incidence of ipsilateral ischemic strokes for 4.4 years in 111 asymptomatic and 135 symptomatic patients with ≥50% relevant carotid artery stenosis. At inclusion, echogenicity of carotid plaques and degree of stenosis were evaluated with high-resolution B-mode ultrasound with computer-assisted image processing and Doppler ultrasound, respectively. We observed 44 ipsilateral ischemic strokes. In symptomatic patients, relative risk of ipsilateral ischemic stroke for echolucent versus echorich plaques was 3.1 (95% CI, 1.3 to 7.3), whereas for 80% to 99% versus 50% to 79% stenosis, the relative risk was 1.4 (95% CI, 0.7 to 3.0). Relative to symptomatic patients with echorich 50% to 79% stenotic plaques, those with echorich 80% to 99% stenotic plaques, echolucent 50% to 79% stenotic plaques, and echolucent 80% to 99% stenotic plaques had relative risks of ipsilateral ischemic strokes of 3.1 (95%CI, 0.7 to 14), 4.2 (95% CI, 1.2 to 15), and 7.9 (95% CI, 2.1 to 30), equivalent to absolute risk increases of 11%, 18%, and 28%. This was not observed in previously asymptomatic patients.

Conclusions
—Echolucent plaques causing ≥50% diameter stenosis by Doppler ultrasound are associated with risk of future stroke in symptomatic but not asymptomatic individuals. This suggests that measurement of echolucency, together with degree of stenosis, may improve selection of patients for carotid endarterectomy.
Maternal and Paternal History of Myocardial Infarction and Risk of Cardiovascular Disease in Men and Women
Authors: Sesso Howard D. , Lee I-Min , Gaziano J. Michael , Rexrode Kathryn M. , Glynn Robert J. , Buring Julie E.
Published: September 2007

Background

Few studies have examined the effects of paternal and maternal history of myocardial infarction (MI), including age at MI, on cardiovascular disease (CVD) risk, particularly among women.

Methods and Results

We prospectively studied 22 071 men from the Physicians’ Health Study and 39 876 women from the Women’s Health Study with data on parental history and age at MI. Among men, 2654 CVD cases developed over 13.0 years; among women, 563 CVD cases occurred over 6.2 years. Compared with men with no parental history, only maternal, only paternal, and both maternal and paternal history of MI conferred relative risks (RRs) of CVD of 1.71, 1.40, and 1.85; among women, the respective RRs were 1.46, 1.15, and 2.05. For men, maternal age at MI of <50, 50 to 59, 60 to 69, 70 to 79, and ≥80 years had RRs of 1.00, 1.88, 1.88, 1.67, and 1.17; for women, the RRs for maternal age at MI of <50, 50 to 59, and ≥60 years were 2.57, 1.33, and 1.52. Paternal age at MI of <50, 50 to 59, 60 to 69, 70 to 79, and ≥80 years in men had RRs of 2.19, 1.64, 1.42, 1.16, and 0.92; in women, for paternal age at MI of <50, 50 to 59, and ≥60 years, the RRs were 1.63, 1.33, and 1.13.

Conclusions

An early history of parental MI (<60 years) conferred a greater risk of CVD than did MI at older ages. However, an increased risk of CVD remained for maternal age at MI of 70 to 79 years in men and ≥60 years in women, which suggests that any maternal history of MI may be important.
Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease
Authors: Schartl Michael , Bocksch Wolfgang , Koschyk Dietmar H. , Voelker Wolfram , Karsch Karl R. , Kreuzer Jörg , Hausmann Dirk , Beckmann Stephan , Gross Michael ,   for the German Atorvastatin Intravascular Ultrasound Study Investigators (GAIN)
Published: September 2007

Background

We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs led to a lesser progression of atherosclerosis and to different changes in plaque echogenicity in patients with coronary artery disease.

Methods and Results

This study was a 12-month, open-label, randomized, multicenter trial, which used serial 3D intracoronary ultrasound to calculate plaque volume and plaque echogenicity. After transcatheter therapy, 131 patients were randomized (atorvastatin n=65, usual care n=66). The target plaque had to be a minor lesion (ie, a diameter stenosis of <50% on angiography). After 12 months, mean LDL-C was reduced from 155 to 86 mg/dL in the atorvastatin group and from 166 to 140 mg/dL in the usual care group. Mean absolute plaque volume showed a larger increase in the usual care group compared with the atorvastatin group (usual care 9.6±28.1 mm
3
, atorvastatin 1.2±30.4 mm
3
;
P
=0.191). The hyperechogenicity index of the plaque increased to a larger extent for the atorvastatin group than for the usual care group, with a significant treatment effect for the percent change (atorvastatin 42.2%, usual care 10.1%;
P
=0.021).

Conclusions

One year of lipid-lowering therapy to <100 mg/dL LDL-C most likely led to a slowdown of plaque growth of minor lesions. The significantly larger increase in plaque hyperechogenicity is most likely due to a change in plaque composition.
Exercise Pathophysiology in Patients With Primary Pulmonary Hypertension
Authors: Sun Xing-Guo , Hansen James E. , Oudiz Ronald J. , Wasserman Karlman
Published: September 2007

Background

Patients with primary pulmonary hypertension (PPH) have a pulmonary vasculopathy that leads to exercise intolerance due to dyspnea and fatigue. To better understand the basis of the exercise limitation in patients with PPH, cardiopulmonary exercise testing (CPET) with gas exchange measurements, New York Heart Association (NYHA) symptom class, and resting pulmonary hemodynamics were studied.

Methods and Results

We retrospectively evaluated 53 PPH patients who had right heart catheterization and cycle ergometer CPET studies to maximum tolerance as part of their clinical workups. No adverse events occurred during CPET. Reductions in peak O
2
uptake (V̇
o
2
), anaerobic threshold, peak O
2
pulse, rate of increase in V̇
o
2
, and ventilatory efficiency were consistently found. NYHA class correlated well with the above parameters of aerobic function and ventilatory efficiency but less well with resting pulmonary hemodynamics.

Conclusions

Patients with PPH can safely undergo noninvasive cycle ergometer CPET to their maximal tolerance. The CPET abnormalities were consistent and characteristic and correlated well with NYHA class.
Independent Association Between Plasma Leptin Levels and Heart Rate in Heart Transplant Recipients
Authors: Winnicki Mikolaj , Phillips Bradley G. , Accurso Valentina , van de Borne Philippe , Shamsuzzaman Abu , Patil Kirti , Narkiewicz Krzysztof , Somers Virend K.
Published: September 2007

Background

Leptin, the protein product of the ob gene, has been linked to a faster heart rate in animal and human studies. The interaction between leptin and heart rate in the denervated heart is not known. Therefore, we studied the relationship between plasma leptin levels and heart rate in heart transplant recipients.

Methods and Results

We studied 32 male patients (mean age, 56.5±9.3 years; range, 41 to 74 years) after orthotopic heart transplantation. All subjects underwent a physical examination, anthropometric measurements, blood chemistry analysis, and office blood pressure measurements. A blood sample was collected from each subject while fasting. In univariate analysis, heart rate was related to leptin levels (
r
=0.47,
P
=0.007) but heart rate was not related to systolic or diastolic blood pressure, mean arterial pressure, body mass index, or catecholamines. Leptin levels were only strongly associated with heart rate and body mass index (
r
=0.73,
P
<0.0001). In multivariate analysis, heart rate was independently and positively associated with leptin levels (F=2.61,
P
=0.017). We also observed a strong, independent association between leptin levels and body mass index (F=5.8,
P
<0.00001).

Conclusions

We show an independent association between leptin levels and heart rate in heart transplant recipients. We speculate that this may be due, in part, to a direct effect of leptin on heart rate, conceivably mediated through cardiac leptin receptors.
Abnormal Longitudinal, Base-to-Apex Myocardial Perfusion Gradient by Quantitative Blood Flow Measurements in Patients With Coronary Risk Factors
Authors: Hernandez-Pampaloni Miguel , Keng Felix Y.J. , Kudo Takashi , Sayre James S. , Schelbert Heinrich R.
Published: September 2007

Background

A longitudinal, base-to-apex myocardial perfusion gradient has been described in patients with coronary artery disease (CAD) and was attributed to diffuse coronary luminal narrowing. We asked whether an abnormal perfusion gradient also existed in patients without CAD but with coronary risk factors. We measured myocardial blood flow (MBF) with
13
N-ammonia and PET at rest and during hyperemia in patients with coronary risk factors but without CAD.

Methods and Results

Regional MBF was measured in absolute units with
13
N-ammonia and PET at rest and during dipyridamole hyperemia in 36 patients with coronary risk factors (age, 55±10 years) and in 36 age-matched (age, 53±10 years) and in 28 young (age, 25±5 years) normal subjects. MBF was determined globally, for each of the 3 coronary territories, and in the mid and mid-to-apical sections of the left ventricle (LV). Myocardial perfusion on qualitative analysis was normal at rest and during hyperemia, and no flow defects were present. MBF in absolute units was similar in the 3 coronary territories. However, hyperemic MBFs in the mid-to-apical LV section were lower than in the mid LV section in the “at-risk” group (2.04±0.61 versus 1.71±0.40 mL · min
−1
· g
−1
;
P
<0.004) but not in the age-matched or in the young normal subjects.

Conclusions

The abnormal longitudinal, base-to-apex perfusion gradient observed during dipyridamole MBF suggests the presence of a functional and/or structural alteration of the coronary circulation associated with coronary risk factors, possibly reflecting developing coronary atherosclerosis or preclinical CAD.
Nebivolol Reverses Endothelial Dysfunction in Essential Hypertension
Authors: Tzemos Nikolaos , Lim Pitt O. , MacDonald Thomas M.
Published: September 2007

BackgroundVascular endothelial dysfunction may predict future atherosclerosis. Hence, an antihypertensive agent that reverses endothelial dysfunction and lowers blood pressure might improve the prognosis of patients with hypertension. We hypothesized that nebivolol, a vasodilating β-blocker, could improve endothelial dysfunction. We tested this hypothesis by comparing the effects of nebivolol and atenolol on endothelial function.

Methods and ResultsTwelve hypertensive patients with a mean ambulatory blood pressure of 154±7/97±10 mm Hg were randomized after a 2-week placebo run-in period (baseline) in a double-blind, crossover fashion to 8-week treatment periods with either 5 mg of nebivolol with 2.5 mg of bendrofluazide or 50 mg of atenolol with 2.5 mg of bendrofluazide. Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine and NG-monomethyl-l-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide release, respectively. Sodium nitroprusside was used as an endothelium-independent control. Nebivolol/bendrofluazide and atenolol/bendrofluazide each lowered the clinic blood pressure to the same extent (132±7/82±6 and 132±9/83±8 mm Hg, respectively;P<0.001 from baseline). The vasodilatory response to acetylcholine was significantly increased with nebivolol/bendrofluazide (maximum percentage change in forearm blood flow [mean±SEM], 435±27%,P<0.001) but not with atenolol/bendrofluazide. Similarly, the endothelium-dependent vasoconstrictive response to L-NMMA was significantly improved only with nebivolol treatment (percentage change in forearm blood flow, −54±5%;P<0.001). The response to sodium nitroprusside was not different between treatments, suggesting that the endothelium-independent pathway was unaffected.

ConclusionsNebivolol/bendrofluazide increased both stimulated and basal endothelial nitric oxide release, whereas for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on nitric oxide bioactivity. Thus, nebivolol may offer additional vascular protection in treating hypertension.
Eptifibatide and 7E3, but Not Tirofiban, Inhibit α
v
β
3
Integrin–Mediated Binding of Smooth Muscle Cells to Thrombospondin and Prothrombin
Authors: Lele Manjiri , Sajid Mansoor , Wajih Nadeem , Stouffer George A.
Published: September 2007

Background

Our objective was to determine whether abciximab, eptifibatide, or tirofiban inhibited ligand binding to α
v
β
3
integrins on human aortic smooth muscle cells (HASMCs) or human umbilical vein endothelial cells (HUVECs). Abciximab binds α
IIb
β
3
on platelets and α
v
β
3
on HUVECs with similar affinity, whereas eptifibatide and tirofiban are thought to be highly specific for α
IIb
β
3
. The conclusion that eptifibatide does not bind vascular α
v
β
3
integrins may be premature, however, because recent studies have demonstrated that the affinity of α
v
β
3
for various ligands, including antagonists, is subject to modulation.

Methods and Results

Abciximab and 7E3, the anti–β
3
integrin monoclonal antibody from which abciximab was derived, bound α
v
β
3
on HASMCs in a specific and saturable manner and with an affinity similar to binding to α
IIb
β
3
on platelets. 7E3 and eptifibatide inhibited α
v
β
3
-mediated attachment of HASMCs to thrombospondin (TSP) and prothrombin but had no effect on α
v
β
5
- or β
1
-mediated HASMC attachment to vitronectin-, collagen-, or fibronectin-coated or noncoated tissue culture plates. The inhibitory effect of eptifibatide was similar in magnitude and not additive to that of 7E3. Eptifibatide and 7E3 inhibited α
v
β
3
-mediated attachment of HUVECs. Tirofiban had only nonspecific effects on HASMC attachment to extracellular matrix proteins. In cell proliferation assays, eptifibatide inhibited α
v
β
3
-mediated responses to soluble TSP by HASMCs and β
3
integrin–expressing HEK cells.

Conclusions

Eptifibatide and 7E3, but not tirofiban, specifically inhibit α
v
β
3
-mediated binding of human smooth muscle and endothelial cells.
Clinical and Economic Impact of Diabetes Mellitus on Percutaneous and Surgical Treatment of Multivessel Coronary Disease Patients
Authors: Abizaid Alexandre , Costa Marco A. , Centemero Marinella , Abizaid Andrea S. , Legrand Victor M.G. , Limet Robert V. , Schuler Gerhard , Mohr Friedrich W. , Lindeboom Wietze , Sousa Amanda G.M.R. , Sousa J. Eduardo , van Hout Ben , Hugenholtz Paul G. , Unger Felix , Serruys Patrick W.
Published: September 2007

Background

Our aims were to compare coronary artery bypass grafting (CABG) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study (ARTS) trial and to determine the costs of these 2 treatment strategies.

Methods and Results

Patients (n=1205) were randomly assigned to stent implantation (n=600; diabetic, 112) or CABG (n=605; diabetic, 96). Costs per patient were calculated as the product of each patient’s use of resources and the corresponding unit costs. Baseline characteristics were similar between the groups. At 1 year, diabetic patients treated with stenting had the lowest event-free survival rate (63.4%) because of a higher incidence of repeat revascularization compared with both diabetic patients treated with CABG (84.4%,
P
<0.001) and nondiabetic patients treated with stents (76.2%,
P
=0.04). Conversely, diabetic and nondiabetic patients experienced similar 1-year event-free survival rates when treated with CABG (84.4% and 88.4%). The total 1-year costs for stenting and CABG in diabetic patients were $12 855 and $16 585 (
P
<0.001) and in the nondiabetic groups, $10 164 for stenting and $13 082 for surgery.

Conclusions

Multivessel diabetic patients treated with stenting had a worse 1-year outcome than patients assigned to CABG or nondiabetics treated with stenting. The strategy of stenting was less costly than CABG, however, regardless of diabetic status.
Normal Flow (TIMI-3) Before Mechanical Reperfusion Therapy Is an Independent Determinant of Survival in Acute Myocardial Infarction
Authors: Stone Gregg W. , Cox David , Garcia Eulogio , Brodie Bruce R. , Morice Marie-Claude , Griffin John , Mattos Luiz , Lansky Alexandra J. , O’Neill William W. , Grines Cindy L.
Published: September 2007

Background

—

Whereas survival after lytic therapy for myocardial infarction is strongly dependent on early administration, it is unknown whether the otherwise excellent outcomes in patients undergoing primary PTCA for acute myocardial infarction, in whom TIMI-3 flow rates of >90% may be achieved, can be further improved by early reperfusion.

Methods and Results

—

Among 2507 patients enrolled in 4 PAMI trials undergoing primary PTCA, spontaneous reperfusion (TIMI-3 flow) was present in 16% at initial angiography. Compared with patients without TIMI-3 flow, those with TIMI-3 flow before PTCA had greater left ventricular ejection fraction (57±10% versus 53±11%,
P
=0.003) and were less likely to present in heart failure (7.0% versus 11.6%,
P
=0.009). Patients with initial TIMI-3 flow had significantly lower in-hospital rates of mortality, new-onset heart failure, and hypotension and had a shorter hospital stay. Cumulative 6-month mortality was 0.5% in patients with initial TIMI-3 flow, 2.8% with TIMI-2 flow, and 4.4% with initial TIMI-0/1 flow (
P
=0.009). By multivariate analysis, TIMI-3 flow before PTCA was an independent determinant of survival (odds ratio 2.1,
P
=0.04), even when corrected for by postprocedural TIMI-3 flow.

Conclusions

—

Patients undergoing primary PTCA in whom TIMI-3 flow is present before angioplasty present with greater clinical and angiographic evidence of myocardial salvage, are less likely to develop complications related to left ventricular failure, and have improved early and late survival. These data warrant prospective randomized trials of pharmacological strategies to promote early reperfusion before definitive mechanical intervention in acute myocardial infarction.
Catheter Ablation in Patients With Multiple and Unstable Ventricular Tachycardias After Myocardial Infarction
Authors: Soejima Kyoko , Suzuki Makoto , Maisel William H. , Brunckhorst Corinna B. , Delacretaz Etienne , Blier Louis , Tung Stanley , Khan Hafiza , Stevenson William G.
Published: September 2007

Background

—

Extensive lines of radiofrequency (RF) lesions through infarct (MI) can ablate multiple and unstable ventricular tachycardias (VTs). Methods for guiding ablation that minimize unnecessary RF applications are needed. This study assesses the feasibility of guiding RF line placement by mapping to identify a reentry circuit isthmus.

Methods and Results

—

Catheter mapping and ablation were performed in 40 patients (MI location: inferior, 28; anterior, 7; and both, 5) with an electroanatomic mapping system to measure the infarct region and ablation lines. The initial line was placed in the MI region either through a circuit isthmus identified from entrainment mapping or a target identified from pace mapping. A total of 143 VTs (42 stable, 101 unstable) were induced. An isthmus was identified in 25 patients (63%; 5 with only stable VTs, 5 with only unstable VTs, and 15 with both VTs). Inducible VTs were abolished or modified in 100% of patients when the RF line included an isthmus compared with 53% when RF had to be guided by pace mapping (
P
=0.0002); those with an isthmus identified received shorter ablation lines (4.9±2.4 versus 7.4±4.3 cm total length,
P
=0.02). During follow-up, spontaneous VT decreased markedly regardless of whether an isthmus was identified. VT stability and number of morphologies did not influence outcome.

Conclusions

—

A 4- to 5-cm line of RF lesions abolishes all inducible VTs in more than 50% of patients. Less ablation is required if a reentry circuit isthmus is identified even when multiple and unstable VTs are present.
Cardiac Hypertrophy After Transplantation Is Associated With Persistent Expression of Tumor Necrosis Factor-α
Authors: Stetson Sonny J. , Perez-Verdia Ale , Mazur Wojceich , Farmer John A. , Koerner Michael M. , Weilbaecher Donald G. , Entman Mark L. , Quiñones Miguel A. , Noon George P. , Torre-Amione Guillermo
Published: September 2007

Background

—

The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-α (TNF-α) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-α may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-α after heart transplantation.

Methods and Results

—

To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (
P
<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (
P
<0.0001), collagen I (
P
<0.0001), collagen III (
P
<0.0001), and myocyte size (
P
<0.0001). These changes were associated with persistent myocardial TNF-α expression.

Conclusions

—

We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-α may contribute to the development of cardiac allograft hypertrophy.
Predictors of Outcome of Biventricular Repair in Infants With Multiple Left Heart Obstructive Lesions
Authors: Schwartz Marcy L. , Gauvreau Kimberlee , Geva Tal
Published: September 2007

Background

—

Decisions regarding surgical strategy in patients with multiple left heart obstructive or hypoplastic lesions often must be made in the newborn period and are seldom reversible. Predictors of outcome of biventricular repair have not been well defined in this heterogeneous group of patients, and risk factors described for critical aortic valve stenosis have been shown to be inapplicable to patients with other left heart obstructive lesions. The goal of this study was to identify echocardiographic predictors of outcome of biventricular repair for infants with multiple left heart obstructive lesions.

Methods and Results

—

Patients with ≥2 areas of left heart obstruction or hypoplasia, diagnosed at ≤3 months of age, who had not previously undergone surgical or catheter intervention and maintained biventricular physiology were included (n=72). Failure of biventricular repair was defined as takedown to a univentricular repair, cardiac transplantation, and/or death (n=14; 19%). This group was compared with the patients who survived a biventricular approach (n=58). Multiple categorical, morphometric and calculated variables were examined on the basis of the initial echocardiograms. By multivariate analysis, predictors of failure included moderate/large ventricular septal defect (OR=22,
P
=0.001), unicommissural aortic valve (OR=16,
P
=0.006), and lower mitral valve dimension
z
-score (OR=2.2,
P
=0.02) or lower left ventricular end-diastolic volume
z
-score (OR=1.9,
P
=0.03).

Conclusions

—

Moderate/large ventricular septal defect, unicommissural aortic valve, and hypoplastic mitral valve or left ventricle are independent risk factors for failure of biventricular repair for infants with multiple left heart obstructive lesions. Combinations of these risk factors may be useful in selecting surgical strategy.
Shock Reduction Using Antitachycardia Pacing for Spontaneous Rapid Ventricular Tachycardia in Patients With Coronary Artery Disease
Authors: Wathen Mark S. , Sweeney Michael O. , DeGroot Paul J. , Stark Alice J. , Koehler Jodi L. , Chisner Michael B. , Machado Christian , Adkisson Wayne O. ,   for the PainFREE ℞ Investigators
Published: September 2007

Background

Implantable cardioverter-defibrillators (ICDs) can terminate some ventricular tachycardias (VTs) painlessly with antitachycardia pacing (ATP). ATP has not routinely been applied for VT >188 bpm because of concerns about efficacy, risk of acceleration, and delay of definitive shock therapy. This prospective, multicenter study evaluated the efficacy of empirical ATP to terminate fast VT (FVT; >188 bpm).

Methods and Results

Two hundred twenty coronary artery disease patients received ICDs for standard indications. Empirical, standardized therapy was programmed so that all FVT episodes (average cycle length [CL] 240 to 320 ms, 250 to 188 bpm) were treated with 2 ATP sequences (8-pulse burst pacing train at 88% of the FVT CL) before shock delivery. A total of 1100 episodes of spontaneous ventricular tachyarrhythmias occurred during a mean of 6.9±3.6 months of follow-up. Fifty-seven percent were classified as slow VT (CL≥320 ms), 40% as FVT (240 ms≤CL<320 ms), and 3% as ventricular fibrillation (CL<240 ms). A total of 446 FVT episodes, mean CL=301±24 ms, occurred in 52 patients (median 2 episodes per patient). ATP terminated 396 FVT episodes (89%), with an adjusted efficacy of 77% (95% CI 68% to 83%). VT acceleration caused by ATP occurred in 10 FVT episodes (4%). FVT arrhythmic syncope occurred on 9 occasions (2%) in 4 patients.

Conclusions

FVT (CL<320 ms) is common in ICD patients. ATP can terminate 3 of 4 of these episodes with a low incidence of acceleration and syncope. ATP for FVT may safely reduce the morbidity of painful shocks.
Late Results of Pediatric Cardiac Surgery in Finland
Authors: Nieminen Heta P. , Jokinen Eero V. , Sairanen Heikki I.
Published: September 2007

Background

This population-based study characterizes the history and progress of pediatric cardiac surgery in Finland. For the first time, all defects and procedures are included in an outcome study, reflecting the true effectiveness of operative treatment.

Methods and Results

All data relating to the operations were collected retrospectively from hospital records. Current patient status was obtained from the population registry. Survival was evaluated with the Kaplan-Meier method applied to all patients and separately to subgroups of patients with the most common defects. The survival rates were compared with those of an age- and sex-matched general population. During the 37 years (1953 to 1989), 6461 patients underwent surgery; 96% of them were traced. The number of operations and the constellation of defects treated increased dramatically over time. Actuarial survival for the 45 years ended October 28, 1998 (the ending date of this study) was 78% for patients versus 93% for the general population. Survival and the number of operations per patient varied widely with the defect. The survival of patients with a surgically closed atrial septal defect was comparable to that of the general population, and such patients rarely needed a reoperation, whereas only 15% of patients with univentricular heart survived for 34 years, and almost all needed at least 2 operations.

Conclusions

The overall survival of patients with cardiac defects corrected surgically in childhood is good compared with their estimated natural course. The increasing number of surgically treatable defects and the growing number of operations per patient reflect the increasing ability to treat more difficult cases.
Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors
Authors: Sanada Shoji , Kitakaze Masafumi , Papst Philip J. , Asanuma Hiroshi , Node Koichi , Takashima Seiji , Asakura Masanori , Ogita Hisakazu , Liao Yulin , Sakata Yasuhiko , Ogai Akiko , Fukushima Tomi , Yamada Junko , Shinozaki Yoshiro , Kuzuya Tsunehiko , Mori Hidezo , Terada Naohiro , Hori Masatsugu
Published: September 2007

Background

—

Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size–limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs.

Methods and Results
—

Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal–regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X. Both PDEIII-Is and db-cAMP reduced infarct size (19.1±4.1%, 17.5±3.3%, and 20.3±4.8%, respectively, versus 36.1±6.2% control,
P
<0.05 each). Furthermore, the effect of olprinone was blunted by either H89 (35.5±6.4%) or SB203580 (32.6±5.9%), but not by GF109203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influence infarct size.

Conclusions

—

Pretreatment with PDEIII-Is has cardioprotective effects via cAMP-, PKA-, and p38 MAPK–dependent but PKC-independent mechanisms in canine hearts.
Heart Failure With a Normal Ejection Fraction
Authors: Zile Michael R. , Gaasch William H. , Carroll John D. , Feldman Marc D. , Aurigemma Gerard P. , Schaer Gary L. , Ghali Jalal K. , Liebson Philip R.
Published: September 2007

Background

The diagnosis of diastolic heart failure is generally made in patients who have the signs and symptoms of heart failure and a normal left ventricular (LV) ejection fraction. Whether the diagnosis also requires an objective measurement of parameters that reflect the diastolic properties of the ventricle has not been established.

Methods and Results

We hypothesized that the vast majority of patients with heart failure and a normal ejection fraction exhibit abnormal LV diastolic function. We tested this hypothesis by prospectively identifying 63 patients with a history of heart failure and an echocardiogram suggesting LV hypertrophy and a normal ejection fraction; we then assessed LV diastolic function during cardiac catheterization. All 63 patients had standard hemodynamic measurements; 47 underwent detailed micromanometer and echocardiographic-Doppler studies. The LV end-diastolic pressure was >16 mm Hg in 58 of the 63 patients; thus, 92% had elevated end-diastolic pressure (average, 24±8 mm Hg). The time constant of LV relaxation (average, 51±15 ms) was abnormal in 79% of the patients. The E/A ratio was abnormal in 48% of the patients. The E-wave deceleration time (average, 349±140 ms) was abnormal in 64% of the patients. One or more of the indexes of diastolic function were abnormal in every patient.

Conclusions

Objective measurement of LV diastolic function serves to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without the measurement of parameters that reflect LV diastolic function.
Coexpression of Endothelin-Converting Enzyme-1 and Endothelin-1 in Different Stages of Human Atherosclerosis
Authors: Ihling Christian , Szombathy Thomas , Bohrmann Bernd , Brockhaus Manfred , Schaefer Hans E. , Loeffler Bernd M.
Published: September 2007

Background

—

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis.

Methods and Results

—

To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1
+
cells were simultaneously ECE-1
+
. Most importantly, there were significantly more ET-1
+
cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE
+
cells in the different compartments of the arterial wall.

Conclusion

—

Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.
Macrophage Accumulation Associated With Rat Cardiac Allograft Rejection Detected by Magnetic Resonance Imaging With Ultrasmall Superparamagnetic Iron Oxide Particles
Authors: Kanno Shinichi , Wu Yi-Jen Lin , Lee Paul C. , Dodd Stephen J. , Williams Mangay , Griffith Bartley P. , Ho Chien
Published: September 2007

Background
—

Acute cardiac allograft rejection continues to be the cause of graft loss and contributes to the morbidity and mortality after cardiac transplantation. In this study, we report a new method for detecting organ rejection in transplantation with an MR-based technique using dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles. These particles (≈27 nm in diameter) are known to shorten relaxation times in MRI experiments.

Methods and Results
—

A new rat model of heterotopic heart and lung transplantation has been developed for MRI experiments. Allotransplantations (DA→BN) were performed (n=8), with syngeneic transplantations (BN→BN) serving as controls (n=8). MR images were obtained with a gradient echo method. At postoperative day 7, allotransplants developed moderate rejection as determined histopathologically. A significant reduction in MR signal intensity was observed after USPIO injection into rats with allotransplanted hearts. Syngeneic transplants showed no differences in MR signal intensity before and after USPIO injections. After injection of USPIO particles at postoperative day 6, a group of allotransplanted rats was treated with cyclosporin A (3 mg/kg). Animals treated with cyclosporin A for 7 days showed no reduction in MR signal intensity after USPIO reinjection at day 14, whereas animals treated for 4 days showed a significant decrease in MR signal intensity in the transplanted hearts indicative of acute graft rejection. Pathological analysis of these animals revealed that dextran-coated USPIO particles were taken up by the infiltrating macrophages that accumulated within the rejecting cardiac graft.

Conclusions
—

This MRI method offers promise as a noninvasive method for detecting transplant allograft rejection.
Immunopathogenesis of Atherosclerosis
Authors: Lehr Hans-Anton , Sagban Tolga Atilla , Ihling Christian , Zähringer Ulrich , Hungerer Klaus-Dieter , Blumrich Matthias , Reifenberg Kurt , Bhakdi Sucharit
Published: September 2007

Background
—

On the basis of our concept that atherosclerosis has an immunopathological background, we tested whether activation of the innate immune system influences its progression.

Methods and Results
—

Hypercholesterolemic (0.5% wt/wt diet) rabbits received either repeated intravenous injections of endotoxin (
Escherichia coli
lipopolysaccharide 1.25 to 2.5 μg, once per week) or a self-limiting cutaneous
Staphylococcus aureus
infection with or without a quinolone antibiotic. Measured laboratory parameters, including LDL and HDL cholesterols, were similar in the different groups of hypercholesterolemic animals. All endotoxin-treated animals developed transient episodes of fever after endotoxin administration. The extent of atherosclerosis was evaluated by computer-assisted morphometry in the aortas en face (Sudan IV) and by histology at 8 weeks after start of the experiments. Endotoxin-treated animals exhibited significantly accelerated atherosclerosis compared with control animals (141±38 versus 45±16 mm
3
total lesion volume, n=7 to 9 rabbits each,
P
<0.001).

Conclusions
—

Nonspecific stimulation of the innate immune system accelerates cholesterol-induced atherosclerosis. These data support the concept that atherosclerosis has an immunopathological component and render it improbable that a single infectious agent should assume particular importance in its initiation or progression.
Activated Protein C Prevents Endotoxin-Induced Hypotension in Rats by Inhibiting Excessive Production of Nitric Oxide
Authors: Isobe Hirotaka , Okajima Kenji , Uchiba Mitsuhiro , Mizutani Akio , Harada Naoaki , Nagasaki Akitoshi , Okabe Kazutoshi
Published: September 2007

Background
—

Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-α (TNF-α) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-α production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock.

Methods and Results
—

Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO
2
−
/NO
3
−
. The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-α and expression of TNF-α mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor DIP-APC, an active site-blocked APC, showed any effect on these ET-induced changes. Both inhibition of TNF-α production by leukocytopenia and treatment with anti-rat TNF-α antibody produced effects similar to those induced by APC. Aminoguanidine, a selective inhibitor of iNOS, inhibited both the hypotension and the increases in plasma levels of NO
2
−
/NO
3
−
in this animal model.

Conclusions
—

These observations strongly suggest that APC inhibits iNOS induction by decreasing TNF-α production, leading to the prevention of ET-induced hypotension. Furthermore, such effects of APC were not dependent on its anticoagulant effects but rather on its serine protease activity.