bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained Hemodynamic Efficacy of Therapy Tailored to Reduce Filling Pressures in Survivors With Advanced Heart Failure
Authors: Steimle Anthony E. , Stevenson Lynne Warner , Chelimsky-Fallick Catherine , Fonarow Gregg C. , Hamilton Michele A. , Moriguchi Jaime D. , Kartashov Alex , Tillisch Jan H.
Published: June 2012

Background
During therapy to relieve congestion in advanced heart failure, cardiac filling pressures can frequently be reduced to near-normal levels with improved cardiac output. It is not known whether the early hemodynamic improvement and drug response can be maintained long term.

Methods and Results
After referral for cardiac transplantation with initially severe hemodynamic decompensation, 25 patients survived without transplantation to undergo hemodynamic reassessment after 8±6 months of treatment tailored to early hemodynamic response. Initial changes included net diuresis, increased ACE inhibitor doses, and frequent addition of nitrates. After 8 months of therapy, early reductions were sustained for pulmonary wedge pressure (24±9 to 15±5 mm Hg early; 12±6 mm Hg late) and systemic vascular resistance (1651±369 to 1207±281 dynes·s
−1
·cm
−5
early; 1003±193 dynes·s
−1
·cm
−5
late). Acute response to doses persisted at reevaluation. Sustained reduction in filling pressures was accompanied by a progressive increase in stroke volume (42±10 to 56±13 mL early; 79±20 mL late), improved functional class, and freedom from resting symptoms. Study design did not control for amiodarone, which was initiated for arrhythmias in 12 patients and associated with greater improvement in cardiac index (1.8 to 3.2 L·min
−1
·m
−2
late on amiodarone versus 2.0 to 2.6 L·min
−1
·m
−2
,
P
<.05).

Conclusions
During chronic therapy tailored to early hemodynamic response in advanced heart failure, acute vasodilator response persists, and near-normal filling pressures can be maintained in patients who survive without transplantation. Stroke volumes at low filling pressures increase further over time. Chronic hemodynamic improvement was accompanied by symptomatic improvement, but the contributions of the monitored hemodynamic approach, increased vasodilator doses, and comprehensive outpatient management have not yet been established.
Histological Substrate of Atrial Biopsies in Patients With Lone Atrial Fibrillation
Authors: Frustaci Andrea , Chimenti Cristina , Bellocci Fulvio , Morgante Emanuela , Russo Matteo A. , Maseri Attilio
Published: June 2012

Background
Lone atrial fibrillation (LAF) is a common clinical syndrome, but its origin remains unknown.

Methods and Results
We performed endomyocardial biopsies of the right atrial septum (2 to 3 per patient; mean, 2.8) and of the two ventricles (6 per patient) in 12 patients (10 men, 2 women; mean age, 32 years) with paroxysmal LAF refractory to conventional antiarrhythmic treatment. As controls, we used endomyocardial biopsies (3 to 5 per patient; mean, 4.4) from the right atrial septum of 11 patients with Wolff-Parkinson-White syndrome (WPW) undergoing resection of the abnormal AV pathway. The weight of the biopsies ranged from 2.8 to 4.5 mg. Biopsy samples were processed for histology and electron microscopy and were read by a pathologist blinded to clinical data. All patients underwent two-dimensional Doppler echocardiography; cardiac catheterization; coronary angiography; and hormonal, virologic, and electrophysiological studies. All tests and WPW biopsies were normal, but all LAF atrial biopsy specimens (average, 2.8 per patient) showed abnormalities (
P
<.0001). The type of abnormalities varied: Two patients had a severe hypertrophy with vacuolar degeneration of the atrial myocytes and ultrastructural evidence of fibrillolysis occupying >50% of the areas assessed morphometrically (
P
=.50), 8 had lymphomononuclear infiltrates with necrosis of the adjacent myocytes (5 with fibrosis and 3 without;
P
<.003), and 2 had only nonspecific patchy fibrosis (
P
=.50). Biventricular biopsies were abnormal in only 3 patients and showed inflammatory infiltrates similar to those found in atrial biopsies.

Conclusions
Abnormal atrial histology was uniformly found in multiple biopsy specimens in all patients with LAF. It was compatible with a diagnosis of myocarditis in 66% of patients (active in 25%) and of noninflammatory localized cardiomyopathy in 17% and was represented by patchy fibrosis in 17%. The cause of the pathological changes, which were found only in atrial septal biopsies but not in biventricular biopsies, in 75% of patients remains unknown.
Is Calcium a Mediator of Infarct Size Reduction With Preconditioning in Canine Myocardium?
Authors: Przyklenk Karin , Hata Katsuya , Kloner Robert A.
Published: June 2012

Background
The cellular mechanisms by which brief episodes of ischemia protect or “precondition” the heart and limit infarct size caused by a later period of sustained coronary artery occlusion remain unresolved. We propose that calcium may be an important mediator in eliciting this cardioprotection.

Methods and Results
To test this hypothesis, anesthetized dogs received a 15-minute intracoronary infusion of 20 mmol/L CaCl
2
or saline before undergoing 1 hour of coronary occlusion and 4 hours of reperfusion (protocol 1). Collateral blood flow during occlusion was measured with radiolabeled microspheres, area at risk of infarction (AR) was delineated by injection of blue dye, and area of necrosis (AN) was determined by tetrazolium staining. AN/AR was reduced from 20±5% in the saline-treated controls to 9±3% in CaCl
2
-treated dogs (
P
<.05). Additional animals underwent 10 minutes of preconditioning ischemia or a comparable waiting period before the 1-hour test occlusion (protocol 2). Administration of 5-(
N
,
N
-dimethyl)-amiloride (an inhibitor of calcium influx via Na
+
-H
+
and Na
+
-Ca
2+
exchange) before the preconditioning stimulus attenuated the protective effect of ischemic preconditioning: AN/AR was 12±1%, larger than the value of 4±1% observed in preconditioned dogs that received saline (
P
<.05) and comparable to the values of 12±3% and 14±3% seen in saline- and dimethylamiloride-treated controls.

Conclusions
Brief intracoronary infusion of CaCl
2
mimicked, whereas treatment with dimethylamiloride blocked, infarct size reduction with preconditioning, thereby implicating calcium as a mediator of preconditioning in this canine model.
Failure to Maintain a Low ADP Concentration Impairs Diastolic Function in Hypertrophied Rat Hearts
Authors: Tian Rong , Nascimben Luigino , Ingwall Joanne S. , Lorell Beverly H.
Published: June 2012

Background
Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling.

Methods and Results
By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb [ADP] with minimal changes in [ATP] and [inorganic phosphate] or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts.
31
P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free [ADP]. The [ADP] in the control hearts was maintained <40 μmol/L, and no change in LVEDP was observed. A linear relationship between increases in [ADP] and LVEDP was found (
r
2
=.66,
P
=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low [ADP], was decreased in LVH (
P
=.0001).

Conclusions
Increased [ADP] contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low [ADP] in LVH.
Coronary Artery Calcium in Acute Coronary Syndromes
Authors: Schmermund Axel , Baumgart Dietrich , Görge Günter , Seibel Rainer , Grönemeyer Dietrich , Ge Junbo , Haude Michael , Rumberger John , Erbel Raimund
Published: June 2012

Background
Quantification of coronary artery calcified plaques by electron-beam CT (EBCT) may predict cardiovascular events. However, whereas advanced coronary atherosclerotic plaques can be identified, mildly stenotic lipid-rich (soft) plaques may be difficult to detect. The value of EBCT in a subgroup of patients has therefore been questioned. To investigate this, we evaluated patients with acute coronary syndromes by EBCT and compared the results with coronary angiography and, in patients with an indeterminate angiogram, intracoronary ultrasound (ICUS).

Methods and Results
EBCT was performed in 118 consecutive patients (57±11 years of age) with previous myocardial infarction (n=101) or unstable angina (n=17). A standard protocol requiring a CT density >130 Hounsfield units in an area ≥1.03 mm
2
was used for the definition of coronary artery calcium. We found that 110 patients had moderate to severe coronary artery disease by coronary angiography, and 8 had either mildly stenotic plaques at a single site (4 patients, confirmed by ICUS) or nonatherosclerotic causes of the unstable coronary syndrome (4 patients). One hundred and five of the 110 patients (96%) with moderate to severe angiographic disease but only 1 of the 8 other patients (13%) had a positive EBCT. Patients with acute coronary syndromes and negative EBCTs were significantly younger than patients with positive EBCTs (46±12 versus 58±10 years,
P
<.001), and a higher percentage was actively smoking (100% of the smokers versus 46%,
P
<.05).

Conclusions
The vast majority of patients with acute coronary syndromes and at least moderate angiographic disease have identifiable coronary calcium by EBCT. Those patients with negative EBCTs have minimal or no atherosclerotic plaque formation. They are younger and tend to be active cigarette smokers.
Body-Surface Distribution of Changes in Activation-Recovery Intervals Before and After Catheter Ablation in Patients With Wolff-Parkinson-White Syndrome
Authors: Akahoshi Makoto , Hirai Makoto , Inden Yasuya , Sano Hiroaki , Shimizu Atsuya , Kondo Takahisa , Makino Mitsutaka , Horiba Mitsuru , Yoshida Yukihiko , Tsuboi Naoya , Hirayama Haruo , Ito Teruo , Hayashi Hiroshi , Saito Hidehiko
Published: June 2012

Background
T-wave abnormalities after catheter ablation in patients with manifest Wolff-Parkinson-White (WPW) syndrome have been attributed to a continuation of repolarization abnormalities induced by preexcitation (cardiac memory).

Methods and Results
To clarify changes in repolarization properties, we analyzed the activation-recovery interval (ARI) obtained from body-surface maps and the relationship between the activation time (AT) and ARI in 30 patients with WPW syndrome (group A, 18 patients with manifest left-sided accessory pathway; group B, 7 patients with manifest right-sided accessory pathway; and group C, 5 patients with concealed left-sided accessory pathway) before, 1 day after, and 1 week after ablation. The ARI significantly decreased 1 week after ablation compared with before and 1 day after ablation over the preexcited area in groups A and B. Correlation coefficients between the AT and ARI showed a significantly (
P
<.01) stronger inverse relationship before (
r
=−.58) and 1 week after (
r
=−.64) ablation than 1 day after ablation (
r
=−.46) in groups A and B. In group C, the ARI and correlation coefficients between the AT and ARI showed no significant changes.

Conclusions
These findings suggest a prolongation of the action-potential duration over the preexcited area before and just after ablation as ventricular “electrical remodeling,” a decrease in the inverse relationship between the AT and action-potential duration 1 day after ablation, and a gradual recovery of the action-potential duration over the preexcited area and inverse relationship 1 week after ablation.
The
bcl-2
Gene Product Prevents Programmed Cell Death of Ventricular Myocytes
Authors: Kirshenbaum Lorrie A. , de Moissac Danielle
Published: June 2012

Background
To formally test whether the antiapoptotic protein
bcl-2
would prevent programmed cell death in cardiac muscle cells provoked by p53, a known trigger of apoptosis in a variety of different cell types, we used replication defective adenovirus encoding either the
bcl-2
and p53 genes to deliver
bcl-2
and p53 to ventricular myocytes with high efficiency and uniformity.

Methods and Results
Vital staining of ventricular myocytes revealed a significant (7-fold,
P
<.05) increase in myocyte cell death in the presence of p53 in contrast to uninfected cells or those infected with a control virus. In addition, in the presence of p53, nucleosomal DNA fragmentation observed by Hoescht 33258 staining and terminal transferase deoxynucleotide end labeling indicated a significant increase in apoptotic cardiac nuclei compared with control cells, confirming the hypothesis that p53 alone is sufficient to trigger apoptosis of ventricular myocytes. Moreover, a significant increase in transcription of the bax promoter was seen in the presence but not in the absence of p53 compared with control cells. Expression of the antiapoptotic gene
bcl-2
in ventricular myocytes was sufficient to prevent ventricular myocyte death and apoptosis provoked by p53. Importantly, the antiapoptotic effects of
bcl-2
were independent of altered p53 expression or localization of p53 to cardiac nuclei. However, p53 dependent transcription of bax was repressed 4-fold (
P
<.05) by
bcl-2
, suggesting a tentative link between p53-mediated apoptosis and the protective properties conferred by
bcl-2
in ventricular myocytes.

Conclusions
To our knowledge, the data provide the first indication for the operation of
bcl-2
in ventricular myocytes as an antiapoptotic factor.
Ischemic Preconditioning at a Distance
Authors: Birnbaum Yochai , Hale Sharon L. , Kloner Robert A.
Published: June 2012

Background
Limitation of myocardial infarct size by an earlier brief complete occlusion of a coronary artery is defined as ischemic preconditioning. However, myocardial protection also can be achieved by partial reduction of coronary flow, rapid cardiac pacing, or brief ischemia-reperfusion of a remote region of the heart. Our study assesses the effect on myocardial infarct size of preconditioning at a distance induced by partial reduction of blood flow to a hind limb with or without increase of demand by electrical stimulation of a skeletal muscle.

Methods and Results
Anesthetized rabbits were randomized to 30 minutes of waiting period (controls), 55% to 65% reduction of femoral artery blood flow (stenosis), electrical stimulation of the gastrocnemius muscle at a rate of one per second (stimulation), or stenosis+stimulation. Thereafter, rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Each group included 8 rabbits. Risk zones were comparable among groups. However, the ratio of infarct size to risk zone was smaller in the stenosis+stimulation group (0.09±0.02) compared with the control (0.26±0.03), stenosis (0.36±0.05), and stimulation (0.30±0.05) groups (
P
=.0006). ANCOVA performed on the fraction of infarction (infarct size/left ventricular weight) and the fraction of risk zone revealed a significant group effect (
P
=.0004).

Conclusions
Remote ischemia of a skeletal muscle induced by muscle stimulation combined with restriction of blood flow preconditioned the myocardium. The combination of muscle stimulation with reduction of femoral arterial blood flow but not muscle stimulation without blood flow restriction or of flow restriction without muscle stimulation reduced myocardial infarct size considerably.
Dominant-Negative
KvLQT1
Mutations Underlie the LQT1 Form of Long QT Syndrome
Authors: Shalaby Fouad Y. , Levesque Paul C. , Yang Wen-Pin , Little Wayne A. , Conder Mary Lee , Jenkins-West Tonya , Blanar Michael A.
Published: June 2012

Background
Mutations that map to the
KvLQT1
gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the
KvLQT1
and minK proteins functionally interact to generate a current with biophysical properties similar to I
Ks
, the slowly activating delayed-rectifier cardiac potassium current. Since I
Ks
modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in
KvLQT1
reduce I
Ks
, resulting in the prolongation of cardiac action potential duration.

Methods and Results
We expressed LQTS-associated
Kv
LQT1
mutants in
Xenopus
oocytes either individually or in combination with wild-type
KvLQT1
or in combination with both wild-type
KvLQT1
and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion.

Conclusions
In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I
Ks
current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.
Long-term Instability of Fasting Plasma Glucose, a Novel Predictor of Cardiovascular Mortality in Elderly Patients With Non–Insulin-Dependent Diabetes Mellitus
Authors: Muggeo M. , Verlato G. , Bonora E. , Zoppini G. , Corbellini M. , de Marco R.
Published: June 2012

Background
We recently reported that long-term fasting plasma glucose (FPG) instability predicts all-cause mortality in elderly patients with non–insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to evaluate whether glucose instability, as represented by the coefficient of variation of FPG concentrations (CV-FPG) measured during a 3-year period, can predict specific causes of death in the subsequent 5 years.

Methods and Results
Five hundred sixty-six elderly patients with NIDDM were followed up for 5 years to assess mortality and causes of death. All FPG determinations of the 3 years preceding the follow-up available in the clinical records were collected and analyzed. Patients were grouped in tertiles of mean FPG, CV-FPG, and the slope of FPG. These parameters of glucose control, as well as sex, age, duration of diabetes, insulin treatment, cigarette smoking, hypertension, and total cholesterol, were included in a multivariate analysis of mortality. During the follow-up, 63 men and 128 women died. Diabetes- and malignancy-related mortality were not independently associated with any parameter of glucose control, whereas cardiovascular-related mortality was independently associated with CV-FPG (
P
=.007) but not with the mean or the slope of FPG. In particular, the relative risk of cardiovascular mortality in subjects in tertile III versus tertile I of CV-FPG was 2.40 (95% CI, 1.28 to 4.53).

Conclusions
These results indicate that FPG instability is a predictor of cardiovascular-related mortality in elderly patients with NIDDM and suggest that glucose stability might be a goal in the management of these patients.
Distribution and Categorization of Echocardiographic Measurements in Relation to Reference Limits
Authors: Vasan Ramachandran S. , Larson Martin G. , Levy Daniel , Evans Jane C. , Benjamin Emelia J.
Published: June 2012

Background
Despite widespread categorization of echocardiographic measurements, there are no standardized guidelines for partitioning values exceeding reference limits.

Methods and Results
We used regression analyses to develop sex- and height-specific reference limits for cardiac M-mode measurements (left ventricular [LV] mass, LV wall thickness, and LV and left atrial dimensions) in a healthy reference sample (n=1099) from the Framingham Heart Study. We then examined the distribution of measurements in a broad sample (n=4957) and classified the measurements according to increasing deviation from the height- and sex-specific reference limits and the 95th, 98th, and 99th percentile values for the broad sample (categories 0 through 4, respectively). To validate the categorization scheme, we used multivariable proportional-hazards regression to assess the relations of LV mass and LV wall thickness categories to risk of cardiovascular events and the relations of left atrial size to risk of atrial fibrillation. During a mean follow-up period of 7.7 years, 587 subjects developed new cardiovascular disease events, and 166 subjects developed new-onset atrial fibrillation. After adjustment for known risk factors, there was a 1.2- and 1.3-fold risk of cardiovascular disease events per category of LV wall thickness and LV mass, respectively, and a 1.6-fold risk of atrial fibrillation per category of left atrial size.

Conclusions
Using a large community-based study sample, we propose a classification scheme that provides a standardized and validated framework for partitioning echocardiographic measurements. If adopted, the categorization scheme should promote uniformity in describing measurements among echocardiographic laboratories and enhance the comprehensibility of measurements to clinicians.
Coronary Sinus Pacing Prevents Induction of Atrial Fibrillation
Authors: Papageorgiou Panos , Anselme Frédéric , Kirchhof Charles J. H. J. , Monahan Kevin , Rasmussen Carl A. F. , Epstein Laurence M. , Josephson Mark E.
Published: June 2012

Background
Atrial fibrillation (AF) is due to reentry, and its incidence has been shown to decrease after dual-site atrial or biatrial pacing. We investigated whether a simpler pacing approach via the distal coronary sinus (CSd) could eliminate AF inducibility by high right atrial (HRA) extrastimuli (APDs). We based our hypothesis on our previous observation that AF inducibility by HRA APDs was associated with conduction delays to the posterior triangle of Koch, whereas AF was never induced with CSd APDs, which were associated with minimal intra-atrial conduction delays.

Methods and Results
Programmed electrical stimulation was performed from the high right atrium and CSd, and bipolar recordings were obtained from the high right atrium, His bundle, posterior triangle of Koch, and coronary sinus. In 13 patients (age, 44±18 years), AF was reproducibly induced with a critically timed HRA APD (220±22 ms) delivered during HRA pacing. AF was not induced in any of the patients when HRA APDs were delivered during CSd pacing at the same critical coupling intervals. Coronary sinus APDs delivered during HRA pacing also were not associated with AF induction. The APD coupling interval measured at the posterior triangle of Koch during CSd pacing was significantly prolonged compared with the one measured during HRA pacing and AF induction (381±58 versus 263±37 ms;
P
<.0001).

Conclusions
We propose that CSd pacing suppresses the propensity of HRA APDs to induce AF by limiting their prematurity at the posterior triangle of Koch and not allowing local conduction delay and local reentry to occur.
Amelioration of Ischemia- and Reperfusion-Induced Myocardial Injury by 17β-Estradiol
Authors: Node Koichi , Kitakaze Masafumi , Kosaka Hiroaki , Minamino Tetsuo , Funaya Hiroharu , Hori Masatsugu
Published: June 2012

Background
17β-Estradiol increases the production of nitric oxide (NO) and prostacyclin and opens Ca
2+
-activated K
+
(K
Ca
) channels. Whether these effects of 17β-estradiol reduce infarct size and the incidence of ventricular arrhythmia was investigated in dogs subjected to myocardial ischemia and reperfusion.

Methods and Results
Infarct size was measured in open-chest dogs after 90 minutes’ occlusion of the left anterior descending coronary artery and a subsequent 6 hours of reperfusion. Infusion of 17β-estradiol into the coronary artery was initiated 10 minutes before coronary occlusion and continued until after 1 hour of reperfusion, with the exception of the occlusion period. The difference in NO concentration between coronary venous and arterial blood 10 minutes after the onset of reperfusion was significantly greater in dogs treated with 17β-estradiol (10 ng · kg
−1
· min
−1
) than in control animals. Infarct size (13.1±3.0% versus 43.7±5.4% of the area at risk) and the incidence of ventricular arrhythmia during ischemia and reperfusion periods were significantly reduced in the 17β-estradiol group. Both
N

G

-nitro-
l
-arginine methyl ester (an inhibitor of NO synthase) and iberiotoxin (a blocker of K
Ca
channels) reduced both the infarct size-limiting effect (infarct size, 29.3±3.0% and 31.7±2.1%, respectively) and the antiarrhythmic effect of 17β-estradiol; indomethacin (an inhibitor of cyclooxygenase) did not attenuate the beneficial effects of 17β-estradiol.

Conclusions
17β-Estradiol reduced both myocardial infarct size and the occurrence of ischemia- and reperfusion-induced ventricular arrhythmias, which appear to be mediated by NO and the opening of K
Ca
channels in canine hearts.
Insights From Three-Dimensional Echocardiography Into the Mechanism of Functional Mitral Regurgitation
Authors: Otsuji Yutaka , Handschumacher Mark D. , Schwammenthal Ehud , Jiang Leng , Song Jae-Kwan , Guerrero J. Luis , Vlahakes Gus J. , Levine Robert A.
Published: June 2012

Background
Recent advances in three-dimensional (3D) echocardiography allow us to address uniquely 3D scientific questions, such as the mechanism of functional mitral regurgitation (MR) in patients with left ventricular (LV) dysfunction and its relation to the 3D geometry of mitral leaflet attachments. Competing hypotheses include global LV dysfunction with inadequate leaflet closing force versus geometric distortion of the mitral apparatus by LV dilatation, which increases leaflet tethering and restricts closure. Because geometric changes generally accompany dysfunction, these possibilities have been difficult to separate.

Methods and Results
We created a model of global LV dysfunction by esmolol and phenylephrine infusion in six dogs, initially with LV expansion limited by increasing pericardial restraint and then with the pericardium opened. The mid-systolic 3D relations of the papillary muscle (PM) tips and mitral valve were reconstructed. Despite severe LV dysfunction (ejection fraction, 18±6%), only trace MR developed when pericardial restraint limited LV dilatation; with the pericardium opened, moderate MR accompanied LV dilatation (end-systolic volume, 44±5 mL versus 12±5 mL control,
P
<.001). Mitral regurgitant volume and orifice area did not correlate with LV ejection fraction and dP/dt (global function) but did correlate with changes in the tethering distance from the PMs to the anterior annulus derived from the 3D reconstructions, especially PM shifts in the posterior and mediolateral directions, as well as with annular area (
P
<.0005). By multiple regression, only changes in the PM-to-annulus distance independently predicted MR volume and orifice area (
R
2
=.82 to .85,
P
=2×10
−7
to 6×10
−8
).

Conclusions
LV dysfunction without dilatation fails to produce important MR. Functional MR relates strongly to changes in the 3D geometry of the mitral valve attachments at the PM and annular levels, with practical implications for approaches that would restore a more favorable configuration.
Myocardial Phosphocreatine-to-ATP Ratio Is a Predictor of Mortality in Patients With Dilated Cardiomyopathy
Authors: Neubauer Stefan , Horn Michael , Cramer Monika , Harre Kerstin , Newell John B. , Peters Werner , Pabst Thomas , Ertl Georg , Hahn Dietbert , Ingwall Joanne S. , Kochsiek Kurt
Published: June 2012

Background
In patients with heart failure due to dilated cardiomyopathy, cardiac energy metabolism is impaired, as indicated by a reduction of the myocardial phosphocreatine-to-ATP ratio, measured noninvasively by
31
P-MR spectroscopy. The purpose of this study was to test whether the phosphocreatine-to-ATP ratio also offers prognostic information in terms of mortality prediction as well as how this index compares with well-known mortality predictors such as left ventricular ejection fraction (LVEF) or New York Heart Association (NYHA) class.

Methods and Results
Thirty-nine patients with dilated cardiomyopathy were followed up for 928±85 days (2.5 years). At study entry, LVEF and NYHA class were determined, and the cardiac phosphocreatine-to-ATP ratio was measured by localized
31
P-MR spectroscopy of the anterior myocardium. During the study period, total mortality was 26%. Patients were divided into two groups, one with a normal phosphocreatine-to-ATP ratio (>1.60; mean±SE, 1.98±0.07; n=19; healthy volunteers: 1.94±0.11, n=30) and one with a reduced phosphocreatine-to-ATP ratio (<1.60; 1.30±0.05; n=20). At reevaluation (mean, 2.5 years), 8 of 20 patients with reduced phosphocreatine-to-ATP ratios had died, all of cardiovascular causes (total and cardiovascular mortality, 40%). Of the 19 patients with normal phosphocreatine-to-ATP ratios, 2 had died (total mortality, 11%), one of cardiovascular causes (cardiovascular mortality, 5%). Kaplan-Meier analysis showed significantly reduced total (
P
=.036) and cardiovascular (
P
=.016) mortality for patients with normal versus patients with low phosphocreatine-to-ATP ratios. A Cox model for multivariate analysis showed that the phosphocreatine-to-ATP ratio and NYHA class offered significant independent prognostic information on cardiovascular mortality.

Conclusions
The myocardial phosphocreatine-to-ATP ratio, measured noninvasively with
31
P-MR spectroscopy, is a predictor of both total and cardiovascular mortality in patients with dilated cardiomyopathy.
Lung Function and Exercise Gas Exchange in Chronic Heart Failure
Authors: Wasserman Karlman , Zhang Yong-Yu , Gitt Anselm , Belardinelli Romualdo , Koike Akira , Lubarsky Laura , Agostoni Pier G.
Published: June 2012

Background
The ventilatory response to exercise in patients with chronic heart failure (HF) is greater than normal for a given metabolic rate. The objective of the present study was to determine the mechanism(s) for the high ventilatory output in patients with chronic HF.

Methods and Results
Centers in Germany, Italy, Japan, and the United States participated in this study. Each center contributed studies on patients and normal subjects of similar age and sex. One hundred thirty patients with chronic HF and 52 healthy subjects participated. Spirometric and breath-by-breath gas exchange measurements were made during rest and increasing cycle exercise. Arterial blood was sampled for measurement of pH, Pa
co
2
, Pa
o
2
, and lactate during exercise in 85 patients. Resting forced expiratory volume in 1 second (FEV
1
) and vital capacity (VC) were proportionately reduced at all levels of impairment. Patients with more severe HF had greater tachypnea and a smaller tidal volume (V
t
) at a given exercise expired volume per unit time (V̇
e
). This was associated with an expiratory flow pattern characteristic of lung restriction. V̇
e
and V̇
co
2
as a function of V̇
o
2
were increased during exercise in HF patients. The increases were greater the lower the peak V̇
o
2
per kilogram of body weight. The ratio of V
d
(physiological dead space) to V
t
and the difference between arterial and end tidal P
co
2
at peak V̇
o
2
also increased inversely with peak V̇
o
2
/kg. In contrast, the difference between alveolar and arterial P
o
2
and PaCO
2
were both normal, on average, at peak V̇
o
2
regardless of the level of impairment. The more severe the exercise limitation, the higher the lactate and the lower the HCO
3
−
at a given V̇
o
2
, although pH was tightly regulated.

Conclusions
The increase in V̇
e
in chronic HF patients is caused by an increase in V
d
/V
t
due to high ventilation/perfusion mismatching, an increase in V̇
co
2
relative to V̇
o
2
resulting from HCO
3
−
buffering of lactic acid, and a decrease in Pa
co
2
due to tight regulation of arterial pH. With regard to the excessive V̇
e
in HF patients, the increases in V
d
/V
t
and V̇
co
2
relative to V̇
o
2
are more important as the patient becomes more exercise limited. Regional hypoperfusion but not hypoventilation typifies lung gas exchange in HF. This and other mechanisms might account for the restrictive changes leading to exercise tachypnea in HF patients.
Regulation by Differential Development of Th1 and Th2 Cells in Peripheral Tolerance to Cardiac Allograft Induced by Blocking ICAM-1/LFA-1 Adhesion
Authors: Isobe Mitsuaki , Suzuki Jun-ichi , Yamazaki Satoshi , Yazaki Yoshikazu , Horie Shiro , Okubo Yoshio , Maemura Koji , Yazaki Yoshio , Sekiguchi Morie
Published: June 2012

Background
Specific immune tolerance to cardiac allografts is induced by anti–ICAM-1 and anti–LFA-1 MAbs. Although the expression of the Th1 cytokines IL-2 and IFN-γ is shown to increase in association with acute rejection, the roles of cytokines in the induction of peripheral tolerance by anti–ICAM-1 and anti–LFA-1 MAbs are not yet known.

Methods and Results
BALB/c hearts were transplanted into C3H/He mice. The MAbs to ICAM-1 and LFA-1 were injected for 3 days after transplantation in some recipients, and others were treated with FK506. IL-2 concentration in the supernatant of splenocytes from MAb-treated mice that were mix-cultured with donor splenocytes was lower than in normal controls. The expression of Th1 cytokines, detected by Northern blot assay, was enhanced in grafts or spleens of nontreated mice, whereas Th2 cytokines were expressed in the spleens of MAb-treated mice. No cytokine expression was enhanced in mice treated with FK506. Also, the induction of tolerance was prevented by the administration of rIL-2 in vivo in 5 of 7 mice, which were rendered tolerant.

Conclusions
These data provide evidence that impairment of IL-2 production is critically involved in this tolerance induction and suggest that predominance of Th2 over Th1 cells is essential for tolerance induction by antiadhesion therapy.
Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure
Authors: Spinale Francis G. , Mukherjee Rupak , Iannini Julie P. , Whitebread Steve , Hebbar Latha , Clair Mark J. , Melton D. Mark , Cox Montgomery H. , Thomas Patrick B. , Marc de Gasparo
Published: June 2012

Background
The goal of this study was to determine the effects of ACE inhibition alone, AT
1
angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT
1
Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process.

Methods and Results
Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg · kg
−1
· d
−1
) and rapid pacing (n=9), (3) concomitant AT
1
Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT
1
Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg · kg
−1
· d
−1
) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2±0.6 versus 58.6±1.2 μm/s,
P
<.05) and remained reduced with AT
1
Ang II receptor blockade and rapid pacing (28.0±0.5 μm/s,
P
<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9±0.7 and 42.3±0.8 μm/s, respectively,
P
<.05). Myocyte β-adrenergic response was reduced by >50% in both the rapid pacing group and the AT
1
Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca
2+
channel density and the relative abundance of sarcoplasmic reticulum Ca
2+
ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT
1
Ang II blockade group.

Conclusions
The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT
1
Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.
Incidence of and Risk Factors for Atrial Fibrillation in Older Adults
Authors: Psaty Bruce M. , Manolio Teri A. , Kuller Lewis H. , Kronmal Richard A. , Cushman Mary , Fried Linda P. , White Richard , Furberg Curt D. , Rautaharju Pentti M.
Published: June 2012

Background
This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.

Methods and Results
In this cohort study, 5201 adults ≥65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of β-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.

Conclusions
The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.
Efficacy of Mibefradil Compared With Amlodipine in Suppressing Exercise-Induced and Daily Silent Ischemia
Authors: Tzivoni Dan , Kadr Honer , Braat Simon , Rutsch Wolfgang , Ramires José Antonio , Kobrin Isaac
Published: June 2012

Background
Mibefradil is a new benzimidazolyl-substituted tetraline-derivative calcium antagonist. Its vasodilatory activity combined with an ability to lower heart rate without negative inotropic effects as well as its long duration of action make it a promising anti-ischemic agent.

Methods and Results
Three hundred nine patients with coronary artery disease, stable angina pectoris, and positive exercise tests were randomized to receive mibefradil (50, 100, or 150 mg), amlodipine (10 mg), or placebo. The anti-ischemic effects of mibefradil on exercise test and silent ischemia parameters were assessed. At doses of 100 and 150 mg, mibefradil increased exercise duration (by 55.5 and 51.0 seconds, respectively;
P
<.001 for both), increased time to onset of angina (by 98.3 and 82.7 seconds, respectively;
P
<.001), and increased time to 1-mm ST depression (by 81.7 and 94.3 seconds, respectively;
P
<.001). By comparison, a 10 mg/d dose of amlodipine significantly improved only time to onset of angina (treatment effect: 38.5 seconds,
P
=.036). Mibefradil 100 mg and 150 mg decreased the number of episodes of silent ischemia (treatment effects: −3.1 and −3.6, respectively;
P
<.001) and the duration of silent ischemia (treatment effects: −9.2 minutes,
P
=.048, and −14.6 minutes,
P
=.002, respectively). The decrease in the number of episodes of silent ischemia was also statistically significant in the group receiving 10 mg of amlodipine (−1.5;
P
=.036).

Conclusions
Once-daily doses of 100 and 150 mg mibefradil were effective in improving exercise tolerance and reducing ischemic episodes during ambulatory monitoring in patients with coronary artery disease.
Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease
Authors: Kluijtmans Leo A. J. , Kastelein John J. P. , Lindemans Jan , Boers Godfried H. J. , Heil Sandra G. , Bruschke Albert V. G. , Jukema J. Wouter , van den Heuvel Lambert P. W. J. , Trijbels Frans J. M. , Boerma Geert J. M. , Verheugt Freek W. A. , Willems Frank , Blom Henk J.
Published: June 2012

Background
Hyperhomocysteinemia, an independent and graded risk factor for coronary artery disease (CAD), may result from both environmental and hereditary factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the methyl donor in the remethylation of homocysteine to methionine. A 677C→T mutation in the MTHFR gene has been associated with elevated homocysteine concentrations in homozygous (+/+) individuals.

Methods and Results
We assessed the frequency of this common mutation in 735 CAD patients from the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering coronary-regression trial, and in 1250 population-based control subjects. Furthermore, the association between the mutation and serum homocysteine concentrations was studied. The frequency of the homozygous (+/+) mutation was 9.5% among patients versus 8.5% among control subjects, resulting in an odds ratio of 1.21 (95% confidence interval [CI], 0.87 to 1.68), relative to the (−/−) genotype. Homocysteine concentrations were significantly elevated in both (+/+) and (+/−) individuals compared with (−/−) individuals (median homocysteine levels, 15.4, 13.4, and 12.6 μmol/L, for (+/+), (+/−), and (−/−) individuals, respectively). For a summary estimation of the risk of the (+/+) genotype for CAD, we performed a meta-analysis on 8 different case-control studies on thermolabile MTHFR in CAD. In the meta-analysis, the homozygous (+/+) genotype was present in 299 of 2476 patients (12.1%) and in 257 (10.4%) of 2481 control subjects, resulting in a significant odds ratio of 1.22 (95% CI, 1.01 to 1.47) relative to the (−/−) genotype.

Conclusions
Both the homozygous (+/+) and heterozygous (+/−) genotype result in elevated homocysteine concentrations. From our meta-analysis, we conclude that the homozygous (+/+) genotype is a modest but significant risk factor for CAD.
Augmented Peripheral Chemosensitivity as a Potential Input to Baroreflex Impairment and Autonomic Imbalance in Chronic Heart Failure
Authors: Ponikowski Piotr , Chua Tuan Peng , Piepoli Massimo , Ondusova Daniela , Webb-Peploe Katharine , Harrington Derek , Anker Stefan D. , Volterrani Maurizio , Colombo Roberto , Mazzuero Giorgio , Giordano Amerigo , Coats Andrew J. S.
Published: June 2012

Background
The precise mechanisms responsible for the sympathetic overactivity and blunted baroreflex control in chronic heart failure (CHF) remain obscure. Augmented peripheral chemosensitivity has recently been demonstrated in CHF. We evaluated the relation between peripheral chemoreflex sensitivity and autonomic activity in patients with CHF.

Methods and Results
We studied in 26 stable patients with CHF the peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalations of pure nitrogen), autonomic balance (spectral analysis of heart rate variability [HRV]), and baroreflex sensitivity (bolus phenylephrine method and α index). To determine whether transient inactivation of peripheral chemoreceptors might influence autonomic balance, 12 patients underwent a second study during which they breathed 100% O
2
. Peripheral chemosensitivity correlated inversely with HRV power within the low-frequency band (0.04 to 0.15 Hz) (
r
=−.52,
P
=.006) and inversely with baroreflex sensitivity (
r
=−.60,
P
=.005). When the patients were divided into two groups according to the chemosensitivity of age-matched normal controls (above and below mean+2 SDs of chemosensitivity of control subjects), those above the normal range revealed more impaired autonomic balance, ie, lower baroreflex sensitivity (1.4±1.3 versus 5.0±1.5 ms/mm Hg,
P
<.0001) and depressed values of low-frequency power (2.5±1.8 versus 4.1±0.8 ln ms
2
,
P
<.005) compared with those with normal chemosensitivity. Transient hyperoxia did not alter heart rate or systolic pressure but resulted in an increase in HRV and an improvement in baroreflex sensitivity.

Conclusions
A link between increased peripheral chemosensitivity and impaired autonomic control, including baroreflex inhibition, is demonstrated. The clinical importance of this phenomenon warrants further investigation.
Prediction of Transition to Chronic Atrial Fibrillation in Patients With Paroxysmal Atrial Fibrillation by Signal- Averaged Electrocardiography
Authors: Abe Yasushi , Fukunami Masatake , Yamada Takahisa , Ohmori Masaharu , Shimonagata Tsuyoshi , Kumagai Kazuaki , Kim Jiyoong , Sanada Shoji , Hori Masatsugu , Hoki Noritake
Published: June 2012

Background
It is well known that paroxysmal atrial fibrillation (PAF) often precedes the establishment of chronic atrial fibrillation (CAF). However, there have been no definite methods to predict the transition from PAF to CAF. The purpose of this report was to determine prospectively whether P-wave–triggered signal-averaged ECG (P-SAE) is useful for the prediction of the transition to CAF in patients with PAF.

Methods and Results
One hundred twenty-two consecutive patients with PAF were prospectively followed after P-SAE, echocardiography, and 24-hour Holter monitoring at study entry. The duration (Ad) and root-mean-square voltage for the last 30 ms (LP30) of the filtered P wave were measured in P-SAE. The abnormality of P-SAE for the prediction of transition to CAF was defined as Ad ≥145 ms and LP30 <3.0 μV. Twenty-three (19%; group 1) of the patients had the abnormality of P-SAE, whereas the others (group 2) did not. During the follow-up period (mean, 26±12 months), 10 patients (43%) in group 1 acquired CAF, whereas the transition to CAF was observed in only 4 patients (4%) in group 2. Kaplan-Meier analysis revealed that the transition to CAF was significantly observed more often in group 1 than in group 2 (log-rank test,
P
<.0001). The Cox proportional hazards regression model identified that the variables most significantly associated with the transition to CAF were Ad (χ
2
=8.6,
P
=.003) and LP30 (χ
2
=5.1,
P
=.02), although significant differences in the left atrial dimension (40.8±5.3 versus 37.3±5.5 mm,
P
<.01) and the number of atrial premature contractions (3641±4524 versus 1489±2895 beats/d,
P
<.05) were observed between groups 1 and 2.

Conclusions
These results indicate that P-SAE could be useful to identify patients at risk for the transition from PAF to CAF.