bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts
Authors: Bartunek Jozef , Weinberg Ellen O. , Tajima Minori , Rohrbach Susanne , Lorell Beverly H.
Published: June 2012

Background
—We have previously shown that the acute molecular growth response of new protein synthesis and protein kinase C activation in response to angiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy compared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT
2
) receptors in hypertrophied hearts relative to controls. Activation of AT
2
receptors is proposed to counteract growth effects of AT
1
receptor in response to Ang II. Thus, we tested the hypothesis that in hypertrophied hearts, the AT
2
receptor mediates inhibitory effects on the new cardiac protein synthesis in response to acute Ang II stimulation.

Methods and Results
—Flaccid buffer-perfused adult normal and hypertrophied rat hearts were perfused with Ang II 10
−8
mol/L plus prazosin 10
−7
mol/L or Ang II plus the AT
2
blocker PD 123319 5×10
−7
mol/L. New protein synthesis was measured by the rate of [
3
H]phenylalanine incorporation into the LV proteins. In normal hearts, Ang II (n=8) increased the rate of [
3
H]phenylalanine incorporation by 74±27% (
P
<0.05 versus no drug). Treatment with PD123319 (n=8) did not increase protein synthesis compared with Ang II alone (32±11% versus Ang II alone,
P
=NS). In hypertrophied hearts, Ang II alone (n=6) increased the rate of [
3
H]phenylalanine incorporation only by 23±13% (
P
=NS versus no drug). In contrast, treatment with PD123319 (n=7) induced a 76±21% increase in new LV protein synthesis compared with Ang II alone (
P
<0.05). AT
2
receptor blockade in Ang II–stimulated hypertrophied hearts was associated with enhanced membrane protein kinase C translocation and reduced LV cGMP content.

Conclusions
—These data support the hypothesis that in adult hypertrophied rat hearts, inhibition of cardiac AT
2
receptors, which are upregulated in chronic LV hypertrophy, amplifies the immediate LV growth response to Ang II. This appears to be related to augmented Ang II–stimulated PKC activation and suppression of cGMP signaling.
Percutaneous Transluminal Therapy of Occluded Saphenous Vein Grafts
Authors: Rosenschein Uri , Gaul Georg , Erbel Raimund , Amann Franz , Velasguez Diego , Stoerger H. , Simon Ruediger , Gomez German , Troster Joerg , Bartorelli Antonio , Pieper Michael , Kyriakides Zenon , Laniado Shlomo , Miller Hylton I. , Cribier Alain , Fajadet Jean
Published: June 2012

Background
—Percutaneous transluminal treatment of a thrombotic vein graft yields poor results. We have previously reported our experience with transluminal percutaneous coronary ultrasound thrombolysis (CUT) in the setting of acute myocardial infarction (AMI). This report describes the first experience with ultrasound thrombolysis in thrombus-rich lesions in saphenous vein grafts (SVGs), most of which were occluded.

Methods and Results
—The patients (n=20) were mostly male (85%), aged 64±4 years old. The presenting symptom was AMI in 2 patients (10%) and unstable angina in the rest. Fifteen patients (75%) had totally occluded SVGs. The median age of clots was 6 days (range, 0 to 100 days). The ultrasound thrombolysis device has a 1.6-mm-long tip and fits into a 7F guiding catheter over a 0.014-in guidewire in a “rapid-exchange” system. CUT (41 kHz, 18 W, ≤6 minutes) led to device success in 14 (70%) of the patients and residual stenosis of 65±28%. Procedural success was obtained in 13 (65%) of the patients, with a final residual stenosis of 5±8%. There was a low rate of device-related adverse events: 1 patient (5%) had a non–Q-wave myocardial infarction, and distal embolization was noted in 1 patient (5%). Adjunct PTCA or stenting was used in all patients. There were no serious adverse events during hospitalization.

Conclusions
—Ultrasound thrombolysis in thrombus-rich lesions in SVGs offers a very promising therapeutic option.
Functional Recovery of Subepicardial Myocardial Tissue in Transmural Myocardial Infarction After Successful Reperfusion
Authors: Bogaert Jan , Maes Alex , Van de Werf Frans , Bosmans Hilde , Herregods Marie-Christine , Nuyts Johan , Desmet Walter , Mortelmans Luc , Marchal Guy , Rademakers Frank E.
Published: June 2012

Background
—The transmural extent of myocardial necrosis after an acute coronary artery occlusion can vary considerably. The contribution of residual subepicardial viable myocardium to global left ventricular function is largely unknown.

Methods and Results
—We studied 12 patients with single-vessel disease 1 week after successful reperfusion of a first transmural anterior myocardial infarction (MI). With PET, myocardial blood flow (MBF) and glucose metabolism were measured regionally, and the viability was graded as normal, mismatch, or match with severely (<50% of normal) or intermediately (50% to 80% of normal) impaired MBF. Magnetic resonance tagging was used to regionally quantify fiber strains, wall thickening, and ejection fraction in patients 1 week and 3 months after the MI and in age-matched healthy volunteers. From 1 week to 3 months, subepicardial fiber shortening improved significantly in the match region (MBF <50%, −5.1±7.0% to −9.9±8.7%; MBF of 50% to 80%, −7.1±7.6% to −14.9±7.9%). This was associated with an improvement in regional ejection fraction in the infarcted myocardium (29.6±21.8% to 43.5±15.5%,
P
<0.0001) and in normal regions (54.3±15.1% to 56.5±13.1%,
P
=0.013), contributing to an increase in global ejection fraction from 44.2±22.2% to 49.3±17.9% (
P
<0.0001).

Conclusions
—Functional recovery of viable subepicardial regions is a mechanism of late improvement in regional and global ejection fraction after a so-called transmural MI.
Activation of β
2
-Adrenergic Receptors Hastens Relaxation and Mediates Phosphorylation of Phospholamban, Troponin I, and C-Protein in Ventricular Myocardium From Patients With Terminal Heart Failure
Authors: Kaumann Alberto , Bartel Sabine , Molenaar Peter , Sanders Louise , Burrell Kylie , Vetter Donathe , Hempel Petra , Karczewski Peter , Krause Ernst-Georg
Published: June 2012

Background
—Catecholamines hasten cardiac relaxation through β-adrenergic receptors, presumably by phosphorylation of several proteins, but it is unknown which receptor subtypes are involved in human ventricle. We assessed the role of β
1
- and β
2
-adrenergic receptors in phosphorylating proteins implicated in ventricular relaxation.

Methods and Results
—Right ventricular trabeculae, obtained from freshly explanted hearts of patients with dilated cardiomyopathy (n=5) or ischemic cardiomyopathy (n=5), were paced at 60 bpm. After measurement of the contractile and relaxant effects of epinephrine (10 μmol/L) or zinterol (10 μmol/L), mediated through β
2
-adrenergic receptors, and of norepinephrine (10 μmol/L), mediated through β
1
-adrenergic receptors, tissues were freeze clamped. We assessed phosphorylation of phospholamban, troponin I, and C-protein, as well as specific phosphorylation of phospholamban at serine 16 and threonine 17. Data did not differ between the 2 disease groups and were therefore pooled. Epinephrine, zinterol, and norepinephrine increased contractile force to approximately the same extent, hastened the onset of relaxation by 15±3%, 5±2%, and 20±3%, respectively, and reduced the time to half-relaxation by 26±3%, 21±3%, and 37±3%. These effects of epinephrine, zinterol, and norepinephrine were associated with phosphorylation (pmol phosphate/mg protein) of phospholamban 14±3, 12±4, and 12±3; troponin I 40±7, 33±7, and 31±6; and C-protein 7.2±1.9, 9.3±1.4, and 7.5±2.0. Phosphorylation of phospholamban occurred at both Ser16 and Thr17 residues through both β
1
- and β
2
-adrenergic receptors.

Conclusions
—Norepinephrine and epinephrine hasten human ventricular relaxation and promote phosphorylation of implicated proteins through both β
1
- and β
2
-adrenergic receptors, thereby potentially improving diastolic function.
Pulmonary Embolism
Authors: Ribeiro Ary , Lindmarker Per , Johnsson Hans , Juhlin-Dannfelt Anders , Jorfeldt Lennart
Published: June 2012

Background
—The long-term prognosis for patients with pulmonary embolism (PE) is dependent on the underlying disease, degree of pulmonary hypertension (PH), and degree of right ventricular (RV) dysfunction. A precise description of the time course of pulmonary artery pressure (PAsP)/RV function is therefore of importance for the early identification of persistent PH/RV dysfunction in patients treated for acute PE. Other objectives were to identify variables associated with persistent PH/RV dysfunction and to analyze the 5-year survival rate for patients alive 1 month after inclusion.

Methods and Results
—Echocardiography Doppler was performed in 78 patients with acute PE at the time of diagnosis and repeatedly during the next year. A 5-year survival analysis was made. The PAsP decreased exponentially until the beginning of a stable phase, which was ≤38 days. The recovery of RV function occurred during the same time period. Risk factors for persistent PH/RV dysfunction and the 5-year mortality rate were analyzed using multiple logistic regression models. A PAsP of >50 mm Hg at the time of diagnosis of acute PE was associated with persistent PH after 1 year. The 5-year mortality rate was associated with underlying disease. Only patients with persistent PH in the stable phase required pulmonary thromboendarterectomy within 5 years.

Conclusions
—An echocardiography Doppler investigation performed 6 weeks after diagnosis of acute PE can identify patients with persistent PH/RV dysfunction and may be of value in planning the follow-up and care of these patients.
Molecular Heterogeneity in Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency Causing Pediatric Cardiomyopathy and Sudden Death
Authors: Mathur Amit , Sims Harold F. , Gopalakrishnan Deepika , Gibson Beverly , Rinaldo Piero , Vockley Jerry , Hug George , Strauss Arnold W.
Published: June 2012

Background
—Genetic defects are being increasingly recognized in the etiology of primary cardiomyopathy (CM). Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the β-oxidation spiral of fatty acid metabolism, the crucial pathway for cardiac energy production.

Methods and Results
—We studied 37 patients with CM, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis, features suggestive of fatty acid oxidation disorders. Single-stranded conformational variance was used to screen genomic DNA. DNA sequencing and mutational analysis revealed 21 different mutations on the VLCAD gene in 18 patients. Of the mutations, 80% were associated with CM. Severe CM in infancy was recognized in most patients (67%) at presentation. Hepatic dysfunction was common (33%). RNA blot analysis and VLCAD enzyme assays showed a severe reduction in VLCAD mRNA in patients with frame-shift or splice-site mutations and absent or severe reduction in enzyme activity in all.

Conclusions
—Infantile CM is the most common clinical phenotype of VLCAD deficiency. Mutations in the human VLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.
Cell Death in Acromegalic Cardiomyopathy
Authors: Frustaci Andrea , Chimenti Cristina , Setoguchi Manabu , Guerra Sabrina , Corsello Salvatore , Crea Filippo , Leri Annarosa , Kajstura Jan , Anversa Piero , Maseri Attilio
Published: June 2012

Background
—Prolonged untreated acromegaly leads to a nonspecific myopathy characterized by ventricular dysfunction and failure. However, the mechanisms responsible for the alterations of cardiac pump function remain to be defined. Because cell death is implicated in most cardiac disease processes, the possibility has been raised that myocyte apoptosis may occur in the acromegalic heart, contributing to the deterioration of ventricular hemodynamics.

Methods and Results
—Ten acromegalic patients with diastolic dysfunction and 4 also with systolic dysfunction were subjected to electrocardiography, Holter monitoring, 2-dimensional echocardiography, cardiac catheterization, and biventricular and coronary angiography before surgical removal of a growth hormone–secreting pituitary adenoma. Endomyocardial biopsies were obtained and analyzed quantitatively in terms of tissue scarring and myocyte and nonmyocyte apoptosis. Myocardial samples from papillary muscles of patients who underwent valve replacement for mitral stenosis were used for comparison. The presence of apoptosis in myocytes and interstitial cells was determined by confocal microscopy with the use of 2 histochemical methods, consisting of terminal deoxynucleotidyl transferase (TdT) assay and
Taq
probe in situ ligation. Acromegaly was characterized by a 495-fold and 305-fold increase in apoptosis of myocytes and nonmyocytes, respectively. The magnitude of myocyte apoptosis correlated with the extent of impairment in ejection fraction and the duration of the disease. A similar correlation was found with the magnitude of collagen accumulation, indicative of previous myocyte necrosis. Myocyte death was independent from the hormonal levels of growth hormone and insulin-like growth factor-1. Apoptosis of interstitial cells did not correlate with ejection fraction.

Conclusions
—Myocyte cell death, apoptotic and necrotic in nature, may be critical for the development of ventricular dysfunction and its progression to cardiac failure with acromegaly.
Prognostic Value of Nocturnal Cheyne-Stokes Respiration in Chronic Heart Failure
Authors: Lanfranchi Paola A. , Braghiroli Alberto , Bosimini Enzo , Mazzuero Giorgio , Colombo Roberto , Donner Claudio F. , Giannuzzi Pantaleo
Published: June 2012

Background
—Nocturnal Cheyne-Stokes respiration (CSR) occurs frequently in patients with chronic heart failure (CHF), and it may be associated with sympathetic activation. The aim of the present study was to evaluate whether CSR could affect prognosis in patients with CHF.

Methods and Results
—Sixty-two CHF patients with left ventricular ejection fraction ≤35%, in NYHA class II to III, underwent clinical evaluation, Doppler echocardiography, ergospirometry, phenylephrine test, Holter recording, and a sleep study to evaluate the occurrence of CSR, expressed as percentage of periodic breathing, and apnea/hypopnea index (AHI) (ie, the number of apneas and hypopneas per hour of recording). During a mean follow-up of 28±13 months, 15 patients died of cardiac causes. Nonsurvivors were in a higher NYHA functional class than survivors (
P
<0.001) and had a more depressed left ventricular ejection fraction (
P
<0.03), a shorter deceleration time of early filling (
P
<0.05), larger left and right atria (
P
<0.05 and
P
<0.02, respectively) and a lower peak V̇
o
2
(
P
<0.05). Nonsurvivors also spent a greater percentage of the night in periodic breathing (
P
<0.01) with a greater AHI (
P
<0.03) and showed lower values of diurnal baroreflex sensitivity (
P
<0.05) and of heart rate variability (sdNN:
P
<0.01). Multivariate analysis revealed the AHI (χ
2
, 10.4;
P
<0.01), followed by left atrial area (χ
2
, 5.7;
P
<0.01), as the only independent and additional predictors of subsequent cardiac death. Patients at very high risk for fatal outcome could be identified by an AHI ≥30/h and left atria ≥25 cm
2
.

Conclusions
—The AHI is a powerful independent predictor of poor prognosis in clinically stable patients with CHF. The presence of an AHI ≥30/h adds prognostic information compared with other clinical, echocardiographic, and autonomic data and identifies patients at very high risk for subsequent cardiac death.
Atrial Fibrillation Detection and R-Wave Synchronization by Metrix Implantable Atrial Defibrillator
Authors: Tse Hung-Fat , Lau Chu-Pak , Sra Jasbir S. , Crijns Herry J. G. M. , Edvardsson Nils , Kacet Salem , Wyse D. George
Published: June 2012

Background
—The long-term efficacy of atrial fibrillation (AF) detection and R-wave synchronization are critical safety requirements for the development of an implantable atrial defibrillator (IAD) for treatment of AF.

Methods and Results
—The long-term efficacy of the Metrix IAD for AF detection and R-wave synchronization was tested in 51 patients. The mean duration of follow-up was 259±138 days (72 to 613 days). AF detection tests were performed 2240 times during observed operation with 100% specificity and 92.3% sensitivity for differentiation between sinus rhythm and AF; 2219 episodes and their electrograms stored in the device during AF detection were analyzed. The positive predictive value of the AF detection algorithm was 97.4% (lower 95% confidence limit [CL], 94.5%) in the out-of-hospital setting. A total of 242 435 R waves were analyzed for R-wave synchronization. Of these, 49% were marked for synchronized shock delivery, 82% of sinus rhythm and 36% of AF R waves, respectively. All shock markers were properly synchronized and within the R wave (overall synchronization accuracy, 100%; lower 95% CL, 99.999%). Overall, 3719 shocks have been delivered via the IAD with no instance of unsynchronized shock delivery or any episode of proarrhythmia. The observed proarrhythmic risk was 0%, with an estimated maximum proarrhythmic risk of 0.084% per shock (95% upper CL).

Conclusions
—The Metrix IAD can appropriately detect AF with a high specificity and sensitivity and reliably synchronize within a suitable R wave for shock delivery to minimize the risk of ventricular proarrhythmia.
Tissue Expression and Immunolocalization of Tumor Necrosis Factor-α in Postinfarction Dysfunctional Myocardium
Authors: Irwin Min W. , Mak Susanna , Mann Douglas L. , Qu Rong , Penninger Josef M. , Yan Andrew , Dawood Fayez , Wen Wen-Hu , Shou Zhiping , Liu Peter
Published: June 2012

Background
—Tumor necrosis factor-α (TNF-α) is markedly elevated in advanced heart failure. It is not known whether tissue TNF-α is elevated in the common setting of myocardial infarction leading to heart failure and what the source of TNF-α is. To determine this, we studied the expression and protein localization of TNF-α and its 2 main receptors (TNF-R1/R2) in a rat model of large infarction.

Methods and Results
—Male rats were randomized to proximal left anterior descending ligation. The animals were killed on days 1, 3, 10, and 35 after ligation to examine gene expression and protein production of TNF-α and TNF-R1/R2 from the infarct, peri-infarct, and contralateral zones of infarcted heart. There was increased TNF-α mRNA production throughout the myocardium at day 1, and detectable expression persisted to day 35 after myocardial infarction. The expression of this cytokine is not confined strictly to the infarct or peri-infarct zones but is expressed by cardiac myocytes within the myocardium in the contralateral normal zone. Changes in gene expression are mirrored initially by augmented protein production within the myocytes. Levels of TNF-α protein in the infarct and peri-infarct zones rose early to 8- to 10-fold above normal levels and rose to 4- to 5-fold in the contralateral zone. Finally, expression of the TNF-R1 mRNA transcripts was upregulated at days 3 and 10 after ligation in the infarct and peri-infarct zones, suggesting that the signal transduction pathways necessary for TNF-α in the heart remain intact as TNF-α biosynthesis increases.

Conclusions
—TNF-α is present early in a model of large myocardial infarction and is sustained into the later stage within the myocardium. Expression of this cytokine is not only confined strictly to the infarct or peri-infarct zone but is expressed by cardiac myocytes within the myocardium contralateral to the infarct. Therefore TNF-α production forms a part of an important intrinsic myocardial stress response system to injury.
Adenylylcyclase Increases Responsiveness to Catecholamine Stimulation in Transgenic Mice
Authors: Gao Mei Hua , Lai N. Chin , Roth David M. , Zhou Jinyao , Zhu Jian , Anzai Toshihisa , Dalton Nancy , Hammond H. Kirk
Published: June 2012

Background
—The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the β-adrenergic receptor (βAR) is a key determinant of a cell’s response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of βAR number, increases responsiveness to catecholamine stimulation in vivo.

Methods and Results
—Transgenic mice with cardiac-directed expression of AC
VI
showed increased transgene AC expression but no change in myocardial βAR number or G-protein content. When stimulated through the βAR, cardiac function was increased, and cardiac myocytes showed increased cAMP production. In contrast, basal cAMP and cardiac function were normal, and long-term transgene expression was not associated with abnormal histological findings or deleterious changes in cardiac function.

Conclusions
—The amount of AC sets a limit on cardiac β-adrenergic signaling in vivo, and increased AC, independent of βAR number and G-protein content, provides a means to regulate cardiac responsiveness to βAR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating β-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to βAR stimulation.
Coronary Flow Reserve in Young Men With Familial Combined Hyperlipidemia
Authors: Pitkänen Olli-Pekka , Nuutila Pirjo , Raitakari Olli T. , Porkka Kimmo , Iida Hidehiro , Nuotio Ilpo , Rönnemaa Tapani , Viikari Jorma , Taskinen Marja-Riitta , Ehnholm Christian , Knuuti Juhani
Published: June 2012

Background
—Familial combined hyperlipidemia (FCHL) is a common hereditary disorder of lipoprotein metabolism estimated to cause 10% to 20% of premature coronary heart disease. We investigated whether functional abnormalities exist in coronary reactivity in asymptomatic patients with FCHL.

Methods and Results
—We studied 21 male FCHL patients (age, 34.8±5.4 years) and a matched group of 21 healthy control subjects. Myocardial blood flow (MBF) was measured at baseline and during dipyridamole-induced hyperemia with PET and
15
O-labeled water. The baseline MBF was similar in patients and control subjects (0.79±0.19 versus 0.88±0.20 mL · g
−1
· min
−1
,
P
=NS). An increase in MBF was seen in both groups after dipyridamole infusion, but MBF at maximal vasodilation was lower in FCHL patients (3.54±1.59 versus 4.54±1.17 mL · g
−1
· min
−1
,
P
=0.025). The difference in coronary flow reserve (CFR) was not statistically significant (4.7±2.2 versus 5.3±1.6,
P
=NS, patients versus control subjects). Considerable variability in CFR values was detected within the FCHL group. Patients with phenotype IIB (n=8) had lower flow during hyperemia (2.5±1.2 versus 4.2±1.5 mL · g
−1
· min
−1
,
P
<0.05) and lower CFR (3.4±2.1 versus 5.4±2.0,
P
<0.05) compared with phenotype IIA (n=13).

Conclusions
—Abnormalities in coronary flow regulation exist in young asymptomatic FCHL patients expressing phenotype IIB (characterized by abnormalities in both serum cholesterol and triglyceride concentrations). This is in line with previous observations suggesting that the metabolic abnormalities related to the pathophysiology of FCHL are associated with the phenotype IIB.
Design and Results of the Antiarrhythmics vs Implantable Defibrillators (AVID) Registry
Authors: Anderson Jeffrey L. , Hallstrom Alfred P. , Epstein Andrew E. , Pinski Sergio L. , Rosenberg Yves , Nora Matthew O. , Chilson Donald , Cannom David S. , Moore Rich
Published: June 2012

Background
—The Antiarrhythmics Versus Implantable Defibrillators (AVID) Study compared treatment with implantable cardioverter-defibrillators versus antiarrhythmic drugs in patients with life-threatening ventricular arrhythmias (VAs). AVID maintained a Registry on all patients, randomized or not, with any VA or unexplained syncope who could be considered for either of the treatment strategies. Trial-eligible arrhythmias were the categories of VF cardiac arrest, Syncopal VT, and Symptomatic VT, below.

Methods and Results
—Of 5989 patients screened, 4595 were registered and 1016 were randomized. Mortality follow-up through 1996 was obtained on the 4219 Registry patients enrolled before 1997 through the National Death Index. Crude mortality rates (mean±SD, follow-up, 16.9±11.5 months) were: VF cardiac arrest, 17.0% (n=1399, 238 deaths); Syncopal VT, 21.2% (n=598, 127 deaths); Symptomatic VT, 15.8% (n=1065, 168 deaths); Stable (asymptomatic) VT, 19.7% (n=497, 98 deaths); VT/VF with transient/correctable cause, 17.8% (n=270, 48 deaths); and Unexplained syncope, 12.3% (n=390, 48 deaths).

Conclusions
—Patients with seemingly lower-risk or unknown-risk VAs (asymptomatic VT, and VT/VF associated with a transient factor) have a (high) mortality similar to that of higher-risk, AVID-eligible VAs. The similar (and poor) prognosis of most patients with VT/VF suggests the need for reevaluation of a priori risk grouping and raises the question of the appropriate arrhythmia therapy for a broad range of patients.
Mortality and Morbidity of Aortic Regurgitation in Clinical Practice
Authors: Dujardin Karl S. , Enriquez-Sarano Maurice , Schaff Hartzell V. , Bailey Kent R. , Seward James B. , Tajik A. Jamil
Published: June 2012

Background
—The outcome of aortic regurgitation conservatively followed in clinical practice is poorly defined.

Methods and Results
—Long-term outcome of 246 patients with severe or moderately severe aortic regurgitation diagnosed by color Doppler echocardiography was analyzed. With conservative management, mortality rate was higher than expected (at 10 years, 34±5%,
P
<0.001) and morbidity was high (10-year rates of 47±6% for heart failure and 62±4% for aortic valve surgery). At 10 years, 75±3% of patients had died or had surgery and 83±3% had had cardiovascular events. In multivariate analysis, predictors of survival were age (
P
<0.001), functional class (
P
<0.001), comorbidity index (
P
=0.033), atrial fibrillation (
P
=0.002), and left ventricular end-systolic diameter corrected for body surface area (
P
=0.025). Ejection fraction was also an independent predictor of overall survival, including postoperative follow-up of surgically treated patients (
P
<0.001). High risk during conservative treatment, with mortality rate in excess of that expected, was noted among patients with severe, even transient, symptoms (24.6% yearly,
P
<0.001) but also in those with mild (class II) symptoms (6.3% yearly,
P
=0.02) and in asymptomatic patients with left ventricular ejection fraction <55% (5.8% yearly,
P
=0.03) or with end-systolic diameter normalized to body surface area ≥25 mm/m
2
(7.8% yearly,
P
=0.004). Surgery performed during follow-up was independently associated with reduced cardiovascular mortality (adjusted hazard ratio, 0.54;
P
=0.048).

Conclusions
—Patients diagnosed with severe aortic regurgitation in clinical practice incur excess mortality and high morbidity, underscoring the serious prognosis of the disease. Surgery, which reduces cardiac mortality rates, should be considered promptly in high-risk patients.
Thermal Heterogeneity Within Human Atherosclerotic Coronary Arteries Detected In Vivo
Authors: Stefanadis Christodoulos , Diamantopoulos Leonidas , Vlachopoulos Charalambos , Tsiamis Eleftherios , Dernellis John , Toutouzas Konstantinos , Stefanadi Elli , Toutouzas Pavlos
Published: June 2012

Background
—Activated macrophages play an important role in the pathogenesis of acute ischemic syndromes. It has been postulated that detection of heat released by activated inflammatory cells of atherosclerotic plaques may predict plaque rupture and thrombosis. Previous ex vivo studies have shown that there is thermal heterogeneity in human carotid atherosclerotic plaques.

Methods and Results
—To measure the temperature of human arteries in vivo, we developed a catheter-based technique. Ninety patients (45 with normal coronary arteries, 15 with stable angina [SA], 15 with unstable angina [UA], and 15 with acute myocardial infarction [AMI]) were studied. The thermistor of the thermography catheter has a temperature accuracy of 0.05°C, a time constant of 300 ms, and a spatial resolution of 0.5 mm. Temperature was constant within the arteries of the control subjects, whereas most atherosclerotic plaques showed higher temperature compared with healthy vessel wall. Temperature differences between atherosclerotic plaque and healthy vessel wall increased progressively from SA to AMI patients (difference of plaque temperature from background temperature, 0.106±0.110°C in SA, 0.683±0.347°C in UA, and 1.472±0.691°C in AMI). Heterogeneity within the plaque was shown in 20%, 40%, and 67% of the patients with SA, UA, and AMI, respectively, whereas no heterogeneity was shown in the control subjects.

Conclusions
—Thermal heterogeneity within human atherosclerotic coronary arteries was shown in vivo by use of a special thermography catheter. This heterogeneity is larger in UA and AMI, suggesting that it may be related to the pathogenesis.
Antiphospholipid Antibodies From Antiphospholipid Syndrome Patients Activate Endothelial Cells In Vitro and In Vivo
Authors: Pierangeli Silvia S. , Colden-Stanfield Margaret , Liu Xiaowei , Barker John H. , Anderson Gary L. , Harris E. Nigel
Published: June 2012

Background
—Antiphospholipid (aPL) antibodies are associated with thrombosis in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. Although aPL antibodies have been shown to inhibit protein C activation and activate endothelial cells (ECs) in vitro, no study has examined whether these antibodies activate ECs in vivo. Therefore, human affinity-purified aPL (ap aPL) antibodies from APS patients were tested in a mouse model of microcirculation using the cremaster muscle that allows direct microscopic examination of thrombus formation and adhesion of white blood cells (WBCs) to ECs as an indication of EC activation in vivo. Adhesion molecule expression on human umbilical vein endothelial cells (HUVECs) after aPL exposure was performed to confirm EC activation in vitro.

Methods and Results
—All 6 ap aPL antibodies significantly increased the expression of VCAM-1 (2.3- to 4.4-fold), with one of the antibodies also increasing the expression of E-selectin (1.6-fold) on HUVECs in vitro. In the in vivo experiments, each ap aPL antibody except for 1 preparation increased WBC sticking (mean number of WBCs ranged from 22.7 to 50.6) compared with control (14.4), which correlated with enhanced thrombus formation (mean thrombus size ranged from 1098 to 6476 versus 594 μm
2
for control).

Conclusions
—Activation of ECs by aPL antibodies in vivo may create a prothrombotic state on ECs, which may be the first pathophysiological event of thrombosis in APS.
Quantification of Extracellular and Intracellular Adenosine Production
Authors: Deussen Andreas , Stappert Margit , Schäfer Stefan , Kelm Malte
Published: June 2012

Background
—Inhibitors of adenosine membrane transport cause vasodilation and enhance the plasma adenosine concentration. However, it is unclear why the plasma adenosine concentration rises rather than falls when membrane transport is inhibited. We tested the hypothesis that the cytosolic adenosine concentration exceeds the interstitial concentration under well-oxygenated conditions.

Methods and Results
—In isolated, isovolumically working guinea pig hearts (n=50), the release rate of adenosine and accumulation of
S
-adenosylhomocysteine (after 20 minutes of 200 μmol/L homocysteine), a measure of the free cytosolic adenosine concentration, were determined in the absence and presence of specific and powerful blockers of adenosine membrane transport (nitrobenzylthioinosine 1 μmol/L), adenosine deaminase (erythro-9-hydroxy-nonyl-adenine 5 μmol/L), and adenosine kinase (iodotubericidine 10 μmol/L). Data analysis with a distributed multicompartment model revealed a total cardiac adenosine production rate of 2294 pmol · min
−1
· g
−1
, of which 8% was produced in the extracellular region. Because of a high rate of intracellular metabolism, however, 70.3% of extracellularly produced adenosine was taken up into cellular regions, an effect that was effectively eliminated by membrane transport block. The resulting ≈2.8-fold increase of the interstitial adenosine concentration evoked near-maximal coronary dilation.

Conclusions
—We rejected the hypothesis that the cytosolic adenosine concentration exceeds the interstitial. Rather, there is significant extracellular production, and the parenchymal cell represents a sink, not a source, for adenosine under well-oxygenated conditions.
Infective Endocarditis in Hypertrophic Cardiomyopathy
Authors: Spirito Paolo , Rapezzi Claudio , Bellone Pietro , Betocchi Sandro , Autore Camillo , Conte Maria Rosa , Bezante Gian Paolo , Bruzzi Paolo
Published: June 2012

Background
—The literature on infective endocarditis in hypertrophic cardiomyopathy (HCM) is virtually confined to case reports. Consequently, the risk of endocarditis in HCM remains undefined.

Methods and Results
—We assessed the occurrence of endocarditis in 810 HCM patients evaluated between 1970 and 1997. Endocarditis was diagnosed in 10 patients, 2 of whom were excluded from analysis of prevalence and incidence because they were referred for acute endocarditis. At first evaluation, echocardiographic features consistent with prior endocarditis were identified in 3 of 808 patients, a prevalence of 3.7 per 1000 patients (95% CI, 0.8 to 11). Of 681 patients who were followed, 5 developed endocarditis, an incidence of 1.4 per 1000 person-years (95% CI, 0.5 to 3.2); outflow obstruction was present in each of these 5 patients and was associated with the risk of endocarditis (
P
=0.006). In the 224 obstructive patients, incidence of endocarditis was 3.8 per 1000 person-years (95% CI, 1.6 to 8.9) and probability of endocarditis 4.3% at 10 years. Left atrial size was also associated with the risk of endocarditis (
P
=0.007). In patients with both obstruction and atrial dilatation (≥50 mm), incidence of endocarditis increased to 9.2 per 1000 person-years (95% CI, 2.5 to 23.5). Analysis of all 10 patients with endocarditis identified outflow obstruction in each and atrial dilatation in 7.

Conclusions
—Endocarditis in HCM is virtually confined to patients with outflow obstruction and is more common in those with both obstruction and atrial dilatation. These results indicate that antibiotic prophylaxis is required only in patients with obstructive HCM.
Inhibition of Intimal Thickening After Balloon Angioplasty in Porcine Coronary Arteries by Targeting Regulators of the Cell Cycle
Authors: Gallo Richard , Padurean Adrian , Jayaraman Thottala , Marx Steven , Roque Merce , Adelman Steven , Chesebro James , Fallon John , Fuster Valentin , Marks Andrew , Badimon Juan José
Published: June 2012

Background
—Although percutaneous transluminal coronary angioplasty (PTCA) is a highly effective procedure to reduce the severity of stenotic coronary atherosclerotic disease, its long-term success is significantly limited by the high rate of restenosis. Several cellular and molecular mechanisms have been implicated in the development of restenosis post-PTCA, including vascular smooth muscle cell (VSMC) activation, migration, and proliferation. Recently, our group demonstrated that rapamycin, an immunosuppressant agent with antiproliferative properties, inhibits both rat and human VSMC proliferation and migration in vitro. In the present study, we investigated (1) whether rapamycin administration could reduce neointimal thickening in a porcine model of restenosis post-PTCA and (2) the mechanism by which rapamycin inhibits VSMCs in vivo.

Methods and Results
—PTCA was performed on a porcine model at a balloon/vessel ratio of 1.7±0.2. Coronary arteries were analyzed for neointimal formation 4 weeks after PTCA. Intramuscular administration of rapamycin started 3 days before PTCA at a dose of 0.5 mg/kg and continued for 14 days at a dose of 0.25 mg/kg. Cyclin-dependent kinase inhibitor (CDKI) p27
kip1
protein levels and pRb phosphorylation within the vessel wall were determined by immunoblot analysis. PTCA in the control group was associated with the development of significant luminal stenosis 4 weeks after the coronary intervention. Luminal narrowing was a consequence of significant neointimal formation in the injured areas. Rapamycin administration was associated with a significant inhibition in coronary stenosis (63±3.4% versus 36±4.5%;
P
<0.001), resulting in a concomitant increase in luminal area (1.74±0.1 mm
2
versus 3.3±0.4 mm
2
;
P
<0.001) after PTCA. Inhibition of proliferation was associated with markedly increased concentrations of the p27
kip1
levels and inhibition of pRb phosphorylation within the vessel wall.

Conclusions
—Rapamycin administration significantly reduced the arterial proliferative response after PTCA in the pig by increasing the level of the CDKI p27
kip1
and inhibition of the pRb phosphorylation within the vessel wall. Therefore, pharmacological interventions that elevate CDKI in the vessel wall and target cyclin-dependent kinase activity may have a therapeutic role in the treatment of restenosis after angioplasty in humans.
Role of Endothelin in Deterioration of Heart Failure Due to Cardiomyopathy in Hamsters
Authors: Yamauchi-Kohno Rikako , Miyauchi Takashi , Hoshino Tomoko , Kobayashi Tsutomu , Aihara Hajime , Sakai Satoshi , Yabana Hideo , Goto Katsutoshi , Sugishita Yasuro , Murata Sakae
Published: June 2012

Background
—We previously reported that chronic endothelin (ET) receptor blockade ameliorated the survival rate and cardiac hemodynamics in rats with chronic heart failure (CHF) due to myocardial infarction. However, it remains unclear whether ET-1 is involved in the pathophysiology of cardiomyopathy, which is one of the major causes of CHF. Accordingly, we investigated the production of ET-1 in the heart and the effect of chronic ET
A
receptor blockade on survival rate and cardiac function in the Bio 14.6 hamster, which is an idiopathic model of CHF caused by cardiomyopathy.

Methods and Results
—We used 52-week-old Bio 14.6 cardiomyopathic hamsters and age-matched F1b normal hamsters. The expression of preproET-1 mRNA and the ET-1 level in the hearts were markedly higher in the cardiomyopathic hamsters than in the normal hamsters. The cardiomyopathic hamsters showed severe CHF, illustrated by lower left ventricular (LV) +dP/dt/P
max
and right ventricular (RV) +dP/dt/P
max
and by higher LV end-diastolic pressure (EDP), RVEDP, and central venous pressure compared with the normal hamsters. Long-term (9 weeks) treatment with an ET
A
antagonist (TA-0201, 1.3 mg · kg
−1
· d
−1
) markedly increased survival of cardiomyopathic hamsters (untreated, 16%; TA-0201–treated, 65.2%;
P
<0.001). After 6 weeks of treatment, LV +dP/dt/P
max
and RV +dP/dt/P
max
were significantly higher and LVEDP and RVEDP were lower in the TA-0201–treated group than in the untreated group, suggesting that chronic TA-0201 treatment effectively prevented deterioration of cardiac dysfunction.

Conclusions
—In the cardiomyopathic hamsters with CHF, the production of ET-1 in the heart was markedly increased, and chronic ET
A
receptor blockade greatly ameliorated survival and cardiac dysfunction. These results suggest that ET-1 plays an important role in the deterioration of CHF caused by cardiomyopathy, and ET
A
antagonists may exert therapeutic effects in CHF due to cardiomyopathy.
Monocyte Chemoattractant Protein-1 but Not Tumor Necrosis Factor-α Is Correlated With Monocyte Infiltration in Mouse Lipid Lesions
Authors: Reckless Jill , Rubin Edward M. , Verstuyft Judy B. , Metcalfe James C. , Grainger David J.
Published: June 2012

Background
—Apolipoprotein (apo)(a) transgenic mice and C57BL/6 mice fed a high fat diet develop similar-sized lipid lesions, but lesions in apo(a) mice are devoid of macrophages. We used this observation to identify which proinflammatory proteins might be involved in mediating monocyte recruitment during atherogenesis.

Methods and Results
—Macrophage-deficient apo(a) transgenic mouse lesions contained similar levels of several different proinflammatory proteins, both adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) and cytokines (tumor necrosis factor-α [TNF-α] and macrophage inflammatory protein-1α [MIP-1α]), similar to the macrophage-rich lesions of C57BL/6 mice.

Conclusions
—From this we conclude that ICAM-1, VCAM-1, TNF-α, and MIP-1α may all be necessary for vascular monocyte recruitment in vivo, but they cannot be sufficient. Monocyte chemoattractant protein-1 (MCP-1) protein was undetectable in the vessel wall taken from apo(a) transgenic mice fed a high fat diet compared with high expression in mice with lipid lesions (C57BL/6 and apoE knockout mice). Therefore elevated expression of MCP-1 but not TNF-α, MIP-1α, ICAM-1, or VCAM-1 is correlated with vascular macrophage accumulation. To test the hypothesis that monocyte infiltration during atherogenesis is MCP-1 dependent, it will be necessary to develop specific pharmacological inhibitors of MCP-1 activity.
Rising Tide of Cardiovascular Disease in American Indians
Authors: Howard Barbara V. , Lee Elisa T. , Cowan Linda D. , Devereux Richard B. , Galloway James M. , Go Oscar T. , Howard William James , Rhoades Everett R. , Robbins David C. , Sievers Maurice L. , Welty Thomas K.
Published: June 2012

Background
—Although cardiovascular disease (CVD) used to be rare among American Indians, Indian Health Service data suggest that CVD mortality rates vary greatly among American Indian communities and appear to be increasing. The Strong Heart Study was initiated to investigate CVD and its risk factors in American Indians in 13 communities in Arizona, Oklahoma, and South/North Dakota.

Methods and Results
—A total of 4549 participants (1846 men and 2703 women 45 to 74 years old) who were seen at the baseline (1989 to 1991) examination were subjected to surveillance (average 4.2 years, 1991 to 1995), and 88% of those remaining alive underwent a second examination (1993 to 1995). The medical records of all participants were exhaustively reviewed to ascertain nonfatal cardiovascular events that occurred since the baseline examination or to definitively determine cause of death. CVD morbidity and mortality rates were higher in men than in women and were similar in the 3 geographic areas. Coronary heart disease (CHD) incidence rates among American Indian men and women were almost 2-fold higher than those in the Atherosclerosis Risk in Communities Study. Significant independent predictors of CVD in women were diabetes, age, obesity (inverse), LDL cholesterol, albuminuria, triglycerides, and hypertension. In men, diabetes, age, LDL cholesterol, albuminuria, and hypertension were independent predictors of CVD.

Conclusions
—At present, CHD rates in American Indians exceed rates in other US populations and may more often be fatal. Unlike other ethnic groups, American Indians appear to have an increasing incidence of CHD, possibly related to the high prevalence of diabetes. In the general US population, the rising prevalence of obesity and diabetes may reverse the decline in CVD death rates. Therefore, aggressive programs to control diabetes and its risk factors are needed.
Clinical Experience With a Novel Multielectrode Basket Catheter in Right Atrial Tachycardias
Authors: Schmitt Claus , Zrenner Bernhard , Schneider Michael , Karch Martin , Ndrepepa Gjin , Deisenhofer Isabel , Weyerbrock Sonja , Schreieck Jürgen , Schömig Albert
Published: June 2012

Background
—The complexity of atrial tachycardias (ATs) makes the electroanatomic characterization of the arrhythmogenic substrate difficult with conventional mapping techniques. The aim of our study was to evaluate possible advantages of a novel multielectrode basket catheter (MBC) in patients with AT.

Methods and Results
—In 31 patients with AT, an MBC composed of 64 electrodes was deployed in the right atrium (RA). The possibility of deployment, spatial relations between MBC and RA, MBC recording and pacing capabilities, mapping performance, and MBC-guided ablation were assessed. MBC deployment was possible in all 31 patients. The MBC was left in the RA for 175±44 minutes. Stable bipolar electrograms were recorded in 88±4% of electrodes. Pacing from bipoles was possible in 64±5% of electrode pairs. The earliest activity intervals, in relation to P-wave onset, measured from the MBC and standard roving catheters were 41±9 and 46±6 ms, respectively (
P
=0.21). Radiofrequency ablation was successful in 15 (94%) of 16 patients in whom it was attempted, including 2 patients with polymorphic right atrial tachycardia (RAT), 2 with RAT–atrial flutter combination, 1 with macroreentrant AT, and 1 with focal origin of atrial fibrillation.

Conclusions
—These data demonstrate that MBC can be used safely in patients with right atrial arrhythmias. The simultaneous multielectrode mapping aids in the rapid identification of sites of origin of the AT and facilitates radiofrequency ablation procedures. The technique is especially effective for complex atrial arrhythmias.
Prevention of Sudden Cardiac Death by Dietary Pure ω-3 Polyunsaturated Fatty Acids in Dogs
Authors: Billman George E. , Kang Jing X. , Leaf Alexander
Published: June 2012

Background
—Rat diets high in fish oil have been shown to be protective against ischemia-induced fatal ventricular arrhythmias. Increasing evidence suggests that this may also apply to humans. To confirm the evidence in animals, we tested a concentrate of the free fish-oil fatty acids and found them to be antiarrhythmic. In this study, we tested the pure free fatty acids of the 2 major dietary ω-3 polyunsaturated fatty acids in fish oil: cis-5,8,11,14,17-eicosapentaenoic acid (C20:5ω-3) and cis-4,7,10,13,16,19-docosahexaenoic acid (C22:6ω-3), and the parent ω-3 fatty acid in some vegetable oils, cis-9,12,15-α-linolenic acid (C18:3ω-3), administered intravenously on albumin or a phospholipid emulsion.

Methods and Results
—The tests were performed in a dog model of cardiac sudden death. Dogs were prepared with a large anterior wall myocardial infarction produced surgically and an inflatable cuff placed around the left circumflex coronary artery. With the dogs running on a treadmill 1 month after the surgery, occlusion of the left circumflex artery regularly produced ventricular fibrillation in the control tests done 1 week before and after the test, with the ω-3 fatty acids administered intravenously as their pure free fatty acid. With infusion of the eicosapentaenoic acid, 5 of 7 dogs were protected from fatal ventricular arrhythmias (
P
<0.02). With docosahexaenoic acid, 6 of 8 dogs were protected, and with α-linolenic acid, 6 of 8 dogs were also protected (
P
<0.004 for each). The before and after control studies performed on the same animal all resulted in fatal ventricular arrhythmias, from which they were defibrillated.

Conclusions
—These results indicate that purified ω-3 fatty acids can prevent ischemia-induced ventricular fibrillation in this dog model of sudden cardiac death.