bluuebunny/crossref_metadata_2025 huggingface dataset:
Relevance of Blockade of Cardiac and Circulatory Angiotensin-Converting Enzyme for the Prevention of Volume Overload–Induced Cardiac Hypertrophy
Authors: Ruzicka Marcel , Leenen Frans H. H.
Published: June 2012

Background
Angiotensin-converting enzyme (ACE) inhibitors show major differences in their affinity for cardiac and other tissue ACEs, and their effects on tissue ACE range from minimal to nearly complete blockade. Angiotensin II taken up from the circulation or generated in the heart may mediate the cardiac hypertrophic response to increased cardiac load. Thus, differences between the ACE inhibitors regarding their effects on cardiac ACE may determine their effects on prevention or regression of cardiac hypertrophy.

Methods and Results
In the present study, we assessed the effects of ACE inhibitors with low (enalapril) and high (quinapril) affinity for cardiac tissue ACE on prevention of volume overload–induced cardiac hypertrophy in relation to their hemodynamic effects. Both blockers were equipotent for circulatory ACE as assessed from the pressure response curve to angiotensin I. Both blockers partially (and similarly) prevented the increase in left ventricular end-diastolic pressure by aortocaval shunt. However, only quinapril prevented or attenuated the development of right ventricular hypertrophy and left ventricular hypertrophy and dilation.

Conclusions
The present findings further stress the involvement of the renin-angiotensin system as a trophic stimulus in the development of cardiac hypertrophy in this model. Moreover, the low affinity of enalapril for cardiac ACE appears to lead to continuous angiotensin II generation in the heart and can thus explain the failure of enalapril to attenuate hypertrophic response of the heart induced by shunt despite decreasing cardiac volume overload.
Effect of Tachycardia Heart Failure on the Restitution of Left Ventricular Function in Closed-Chest Dogs
Authors: Prabhu Sumanth D. , Freeman Gregory L.
Published: June 2012

Background
Cardiac mechanical restitution and relaxation restitution are thought to be physiological correlates of the recovery kinetics of Ca
2+
release mechanisms and sequestration capacity of the sarcoplasmic reticulum (SR). Since congestive heart failure is characterized by abnormal intracellular Ca
2+
handling, we sought to delineate changes in mechanical and relaxation restitution produced by heart failure.

Methods and Results
Six dogs instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied under control conditions and after tachycardia heart failure (THF) produced by rapid LV pacing for 3 to 4 weeks. After priming at a basic cycle length of 375 ms, test pulses were delivered at graded extrasystolic intervals (ESIs). Mechanical response was assessed from single-beat elastance. Relaxation was assessed from the time constant of isovolumic relaxation (tau), the average rate of pressure fall during isovolumic relaxation (R
avg
), and peak negative dP/dt, the first derivative of LV pressure. Normalized mechanical and relaxation responses plotted against ESI produced monoexponential curves of mechanical and relaxation restitution. THF depressed baseline contractile and relaxation parameters compared with control (end-systolic elastance, 4.7±0.4 versus 7.1±0.5 mm Hg/mL,
P
<.005; tau, 34.8±2.2 versus 26.7±1.2 ms,
P
<.05; all values mean±SEM). THF slowed mechanical restitution and delayed development of peak contractile response, with the time constant of mechanical restitution increasing from 61.8±6.9 to 100.2±9.6 ms,
P
<.01. THF abolished the biphasic behavior of relaxation restitution, and this relation was approximated by a single monoexponential function. There was no difference in the time constants of the first phase of relaxation restitution at control and after THF (TC
R1
, normalized 1/R
avg
, 44.3±5.6 versus 42.0±8.5 ms,
P
=NS; TC
R1
, normalized (dP/dt
min
)
−1
, 42.2±6.3 versus 36.7±4.3 ms,
P
=NS).

Conclusions
These results indicate that THF alters the recovery kinetics of SR Ca
2+
release to a significantly greater extent than those of SR Ca
2+
sequestration and that the abnormal time course of Ca
2+
availability to the myofilaments is the rate-limiting step in the recovery of cardiac function after a depolarization.
Noninvasive Assessment of Left Ventricular Relaxation Using Continuous-Wave Doppler Aortic Regurgitant Velocity Curve
Authors: Yamamoto Kazuhiro , Masuyama Tohru , Doi Yasuji , Naito Johji , Mano Toshiaki , Kondo Hiroya , Nagano Reiko , Tanouchi Jun , Hori Masatsugu , Kamada Takenobu
Published: June 2012

Background
The most established parameters of left ventricular (LV) relaxation are peak negative value of the first derivative of LV pressure (−dP/dt
max
) and the time constant of isovolumic LV pressure fall. The instantaneous pressure gradient between the aorta and the LV during diastole can be calculated from the continuous-wave Doppler aortic regurgitant velocity spectrum. Because the fluctuation of aortic pressure during LV isovolumic relaxation is negligibly minor and because LV minimal pressure is negligibly low, LV pressure during the isovolumic relaxation period may be derived from the continuous-wave Doppler aortic regurgitant velocity spectrum. This study was designed to clarify whether analysis of continuous-wave Doppler aortic regurgitation recording provides accurate measures of LV relaxation over a wide range of LV function and to determine comparative values of aortic and mitral regurgitation methods in the assessment of LV relaxation.

Methods and Results
In eight mongrel dogs with acute ischemic LV dysfunction, the continuous-wave Doppler aortic regurgitant velocity spectrum was recorded simultaneously with high-fidelity LV and aortic pressures, while the continuous-wave Doppler mitral regurgitant velocity spectrum was recorded simultaneously with high-fidelity left atrial and LV pressures. The aortic regurgitant velocity spectrum was provided for the determination of Doppler-derived mean rate of LV pressure fall in 20 ms after the onset of aortic regurgitation (ΔP/Δt-AR) and the time interval from the onset of aortic regurgitation to the point at (1−1/
e
)
1/2
of the maximal aortic regurgitant velocity as an estimate of the time constant. The mitral regurgitant velocity spectrum was provided for Doppler-derived mean rate of LV pressure fall in 20 ms after the point of −dP/dt
max
(ΔP/Δt-MR) and the time interval from the point of −dP/dt
max
to the point with mitral regurgitant velocity of (1/
e
)
1/2
of the mitral regurgitant velocity at the point of −dP/dt
max
as an estimate of the time constant. ΔP/Δt-AR and ΔP/Δt-MR correlated well with catheter-derived −dP/dt
max
(
r
=.92,
r
=.98,
P
<.01, respectively). The time constant derived from aortic and mitral regurgitant velocity spectra (tau-AR and tau-MR) also correlated well with catheter-derived time constant (
r
=.84,
r
=.76,
P
<.01, respectively). However, a mean difference of the catheter-derived time constant minus tau-MR was larger than tau-AR (29±30 versus 4±17 ms,
P
<.01, presented as mean±2 SD).

Conclusions
LV relaxation can be assessed from the continuous-wave Doppler aortic regurgitant velocity spectrum. The aortic regurgitation method provides an even more accurate estimate of the time constant compared with the mitral regurgitation method, particularly in the presence of LV dysfunction.
T Lymphocyte Activation in Stable Angina Pectoris and After Percutaneous Transluminal Coronary Angioplasty
Authors: Blum A. , Sclarovsky S. , Shohat B.
Published: June 2012

Background
Inflammatory reactions have an important part in atherosclerosis. Smooth muscle cells, endothelial cells, monocytes, and T lymphocytes are actively involved. The purpose of this study was to assess whether T lymphocytes are activated in patients with stable angina pectoris who are candidates for a percutaneous transluminal coronary angioplasty (PTCA) and the influence of PTCA on this process.

Methods and Results
Twenty-four patients participated in the study. All were 40- to 60-year-old men, and all but one underwent successful PTCA. Blood samples were taken 1 day before PTCA and 1 week, 1 month, and 2 months after. Two groups of patients were detected: group A, 11 patients who had high levels of soluble interleukin-2 receptor (sIL-2R) before PTCA that decreased toward normal during the follow-up period in most of them; and group B, 13 patients who did not have elevated sIL-2R levels before PTCA and in whom sIL-2R levels did not change after the procedure. Group C consisted of 15 healthy men whose sIL-2R levels were in the normal range (control subjects).

Conclusions
(1) T lymphocytes are activated in stable angina patients. (2) The level of sIL-2R can be a reliable laboratory marker for follow-up of patients after PTCA, especially those with high sIL-2R levels before the procedure.
Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans
Authors: Burke M. Nicholas , McGinn Andrew L. , Homans David C. , Christensen Betsy V. , Kubo Spencer H. , Wilson Robert F.
Published: June 2012

Background
Structural sympathetic reinnervation of the transplanted human heart is believed to occur >1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined.

Methods and Results
To test directly for functional sympathetic reinnervation, we measured left ventricular or coronary hemodynamics in 11 patients ≤4 months after transplantation, in 45 patients ≥1 year after transplantation, and in 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10 μg/kg), which causes norepinephrine release from intact sympathetic nerve terminals. Reinnervation was defined as a measure of cardiac norepinephrine release after intracoronary tyramine injection. Left ventricular pressure was measured before and at 1-minute intervals after tyramine with a micromanometer-tipped catheter (Millar Instruments). Coronary blood flow velocity (CBFV) was measured with a 3F Doppler catheter (Numed), and coronary artery cross-sectional area was calculated using quantitative coronary angiography. In both early patients and patients studied ≥4 months after transplantation without reinnervation (late denervated), there was no change in left ventricular function in response to tyramine (ΔdP/dt=31±61 and 49±54 mm Hg/s, respectively;
P
=NS). In transplant recipients with reinnervation (late reinnervated), left ventricular dP/dt rose significantly (ΔdP/dt=210±97 mm Hg/s;
P
<.05) but less than in healthy patients (ΔdP/dt=577±66 mm Hg/s;
P
<.05). In both early and late denervated patients, there was no change in CBFV in response to tyramine (CBFV=1.02±0.1 and 1.0±0.1×basal, respectively;
P
=NS). In late reinnervated patients, CBFV fell significantly (CBFV=0.94±0.1×basal;
P
<.05). In healthy patients, CBFV fell even more (CBFV=0.88±0.1×basal;
P
<.05).

Conclusions
Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
Association Between Ease of Suppression of Ventricular Arrhythmia and Survival
Authors: Goldstein Sidney , Brooks Maria Mori , Ledingham Robert , Kennedy Harold L. , Epstein Andrew E. , Pawitan Yudi , Bigger J. Thomas
Published: June 2012

Background
We tested the hypothesis that patients whose ventricular arrhythmias are easy to suppress have a lower rate of arrhythmic death, defined as arrhythmic death and nonfatal cardiac arrest, the primary end point in the Cardiac Arrhythmia Suppression Trials (CAST-I and CAST-II), than patients whose ventricular arrhythmias are hard to suppress. In addition, we evaluated the association between ease of suppression of ventricular arrhythmias and mortality of all causes.

Methods and Results
CAST-I investigated the effect on arrhythmic death of ventricular premature depolarization (VPD) suppression achieved by three drugs, encainide, flecainide, and moricizine, at two different dose levels; CAST-II investigated the same effect, using moricizine alone at three dose levels. If suppression was achieved, patients were randomized to the effective active drug or corresponding placebo. To examine the independence of easily suppressed ventricular arrhythmias as a predictor of arrhythmic death, we adjusted statistically for other variables that were related both to ease of suppression and arrhythmic death. Patients with ventricular arrhythmias (n=1778) that were easy to suppress had fewer arrhythmic deaths during follow-up than those with ventricular arrhythmias that were hard to suppress (n=1173) (relative risk, .59;
P
=.003). Patients whose VPDs were easily suppressed were older and had a lower frequency of prior history of heart failure and myocardial infarction. They also had a higher incidence of anterior myocardial infarction, VPD frequency, and average ejection fraction. After adjusting for these variables, we found that easily suppressed ventricular arrhythmias were still significant predictors of arrhythmic death (relative risk, .66;
P
=.013).

Conclusions
This study shows that the ease of VPD suppression identifies a subgroup of postmyocardial infarction patients who have low risk of arrhythmic death.
Early and 1-Year Clinical Outcome of Patients’ Evolving Non–Q-Wave Versus Q-Wave Myocardial Infarction After Thrombolysis
Authors: Aguirre Frank V. , Younis Liwa T. , Chaitman Bernard R. , Ross Allan M. , McMahon Robert P. , Kern Morton J. , Berger Peter B. , Sopko George , Rogers William J. , Shaw Leslee , Knatterud Genell , Braunwald Eugene
Published: June 2012

Background
There are few data comparing clinical outcome and potential indications for routine post–myocardial infarction cardiac catheterization and revascularization of patients who sustain a non–Q-wave versus Q-wave infarct after thrombolytic therapy.

Methods and Results
A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non–Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%;
P
<.001) and anterior wall infarcts (53.8% versus 43.7%;
P
<.001) were more frequent in the Q-wave versus the non–Q-wave group. During recombinant tissue-type plasminogen activator (rTPA) infusion, a greater percentage of non–Q-wave patients (37.3% versus 23.5%;
P
=.001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) (
P
=.02), complete infarct-related artery reperfusion (TIMI 3 flow grade) (
P
<.001), and the percentage of patients with a predischarge resting left ventricular ejection fraction >55% (
P
<.001) were greater in the non–Q-wave group. New congestive heart failure during hospitalization developed more frequently in Q-wave patients (18.9% versus 11.6%;
P
<.001). After 42 days, the occurrences of reinfarction (
P
=.76), death (
P
=.76), and combined death or reinfarction (
P
=.43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non–Q-wave versus Q-wave infarct type, respectively (
P
=.25).

Conclusions
Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non–Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non–Q wave or Q wave.
Acute Hemodynamic Improvement by Thermal Vasodilation in Congestive Heart Failure
Authors: Tei Chuwa , Horikiri Yutaka , Park Jong-Chun , Jeong Jin-Won , Chang Kyoung-Sig , Toyama Yoshihumi , Tanaka Nobuyuki
Published: June 2012

Background
A warm-water bath (WWB) or sauna bath (SB) has generally been considered inappropriate for patients with severe congestive heart failure (CHF). However, a comprehensive investigation of the hemodynamic effects of thermal vasodilation in CHF has not been previously undertaken.

Methods and Results
To investigate the acute hemodynamic effects of thermal vasodilation in CHF, we studied 34 patients with chronic CHF (mean age, 58±14 years). Clinical stages were New York Heart Association functional class II in 2, III in 19, and IV in 13 patients. Mean ejection fraction was 25±9%. After a Swan-Ganz catheter was inserted via the right jugular vein, the patient had a WWB for 10 minutes at 41°C or an SB for 15 minutes at 60°C. Blood pressure, ECG, echo-Doppler, expiration gas, and intracardiac pressures were recorded before, during, and 30 minutes after each bath. Oxygen consumption increased mildly, pulmonary arterial blood temperature increased by 1.2°C, and heart rate increased by 20 to 25 beats per minute on average at the end of WWB or SB. Systolic blood pressure showed no significant change. Diastolic blood pressure decreased significantly during SB (
P
<.01). Cardiac and stroke indexes increased and systemic vascular resistances decreased significantly during and after WWB and SB (
P
<.01). Mean pulmonary artery, mean pulmonary capillary wedge, and mean right atrial pressures increased significantly during WWB (
P
<.05) but decreased significantly during SB (
P
<.05). These pressures decreased significantly from the control level after each bath (
P
<.01). Mitral regurgitation associated with CHF decreased during and 30 minutes after each bath. Cardiac dimensions decreased and left ventricular ejection fraction increased significantly after WWB and SB. In an additional study, plasma norepinephrine increased significantly during SB in healthy control subjects and in patients with CHF and returned to control levels by 30 minutes after SB.

Conclusions
Hemodynamics improve after WWB or SB in patients with chronic CHF. This is attributable to the reduction in cardiac preload and afterload. Thus, thermal vasodilation can be applied with little risk if appropriately performed and may provide a new nonpharmacological therapy for CHF.
Long-term Effects of Varying Intensities and Formats of Physical Activity on Participation Rates, Fitness, and Lipoproteins in Men and Women Aged 50 to 65 Years
Authors: King Abby C. , Haskell William L. , Young Deborah R. , Oka Roberta K. , Stefanick Marcia L.
Published: June 2012

Background
Although exercise parameters such as intensity and format have been shown to influence exercise participation rates and physiological outcomes in the short term, few data are available evaluating their longer-term effects. The study objective was to determine the 2-year effects of differing intensities and formats of endurance exercise on exercise participation rates, fitness, and plasma HDL cholesterol levels among healthy older adults.

Methods and Results
Higher-intensity, group-based exercise training; higher-intensity, home-based exercise; and lower-intensity, home-based exercise were compared in a 2-year randomized trial. Participants were 149 men and 120 postmenopausal women 50 to 65 years of age who were sedentary and free of cardiovascular disease. Recruitment was achieved through a random digit-dial community telephone survey and media promotion. All exercise occurred in community settings. For higher-intensity exercise training, three 40-minute endurance training sessions per week were prescribed at 73% to 88% of peak treadmill heart rate. For lower-intensity exercise, five 30-minute endurance training sessions per week were prescribed at 60% to 73% of peak treadmill heart rate. Treadmill exercise performance, lipoprotein levels and other heart disease risk factors, and exercise adherence were evaluated at baseline and across the 2-year period. Treadmill exercise test performance improved for all three training conditions during year 1 and was successfully maintained during year 2, particularly for subjects in the higher-intensity, home-based condition. Subjects in that condition also showed the greatest year 2 exercise adherence rates (
P
<.003). Although no significant increases in HDL cholesterol were observed during year 1, by the end of year 2 subjects in the two home-based training conditions showed small but significant HDL cholesterol increases over baseline (
P
<.01). The increases were particularly pronounced for subjects in the lower-intensity condition, whose exercise prescription required more frequent exercise sessions per week. For all exercise conditions, increases in HDL cholesterol were associated with decreases in waist-to-hip ratio in both men and women (
P
<.04).

Conclusions
While older adults can benefit from initiating a regular regimen of moderate-intensity exercise in terms of improved fitness levels and small improvements in HDL cholesterol levels, the time frame needed to achieve HDL cholesterol change (2 years) may be longer than that reported previously for younger populations. Frequency of participation may be particularly important for achieving such changes. Supervised home-based exercise regimens represent a safe, attractive alternative for achieving sustained participation.
17β-Estradiol Inhibits Ca
2+
Influx and Ca
2+
Release Induced by Thromboxane A
2
in Porcine Coronary Artery
Authors: Han Shu-Zhong , Karaki Hideaki , Ouchi Yasuyoshi , Akishita Masahira , Orimo Hajime
Published: June 2012

Background
We wished to investigate the possible mechanism of the protective effect of estrogen replacement on coronary atherosclerosis observed in postmenopausal women.

Methods and Results
Cytosolic Ca
2+
concentration ([Ca
2+
]
i
) and contraction were measured simultaneously in fura 2–loaded porcine coronary arterial strips stimulated by the thromboxane A
2
analogue U46619 and high-K
+
depolarization in the presence and absence of 17β-estradiol. Pretreatment with 17β-estradiol (30 nmol/L to 30 μmol/L) inhibited the sustained elevation of [Ca
2+
]
i
and the sustained contraction induced by 300 nmol/L U46619. Higher concentrations of 17β-estradiol (1 to 100 μmol/L) also inhibited the U46619-induced transient increase in [Ca
2+
]
i
and contraction in the absence of extracellular Ca
2+
. In the strips precontracted by 90 mmol/L K
+
, 17β-estradiol (30 μmol/L) inhibited the increases in [Ca
2+
]
i
and contraction to resting levels. In contrast, 30 μmol/L 17β-estradiol only partially inhibited the U46619-induced sustained contraction, despite complete inhibition of the sustained increase in [Ca
2+
]
i
. Verapamil (10 μmol/L) also strongly inhibited the sustained increase in [Ca
2+
]
i
induced by 300 nmol/L U46619, with a partial inhibition of the U46619-induced sustained contraction. A subsequent addition of 30 μmol/L 17β-estradiol did not show an additional inhibitory effect on either the [Ca
2+
]
i
or the tension after the addition of verapamil. 17β-Estradiol (10 μmol/L) also inhibited the increase in [Ca
2+
]
i
and the contraction induced by cumulative addition of Ca
2+
in the strips pretreated with 90 mmol/L K
+
. However, 17β-estradiol did not change the slope of the [Ca
2+
]
i
-tension curves. 17β-Estradiol (10 μmol/L) had no effect on the levels of cAMP and cGMP in the coronary strips.

Conclusions
17β-Estradiol inhibits the contraction of coronary vascular smooth muscle mainly by inhibiting Ca
2+
influx without changing Ca
2+
sensitivity of contractile elements. The Ca
2+
channel blocker–like action of 17β-estradiol may explain at least a part of the antiatherosclerotic effect of estrogen.
Reversal of Chronic Ventricular Dilation in Patients With End-Stage Cardiomyopathy by Prolonged Mechanical Unloading
Authors: Levin Howard R. , Oz Mehmet C. , Chen Jonathan M. , Packer Milton , Rose Eric A. , Burkhoff Daniel
Published: June 2012

Background
Ventricular dilation, indexed by marked shifts toward larger volumes of the end-diastolic pressure-volume relation (EDPVR), has been considered to represent an irreversible aspect of ventricular remodeling in end-stage heart failure. However, we hypothesized that such dilation could be reversed with sufficient hemodynamic unloading, such as can be provided by a left ventricular assist device (LVAD).

Methods and Results
The EDPVRs of hearts from seven patients with end-stage idiopathic cardiomyopathy and comparable baseline hemodynamics were measured ex vivo at the time of cardiac transplantation; these were compared with EDPVRs from three normal human hearts that were technically unsuitable for transplantation. Four of the patients received optimal medical therapy; three of the patients, who deteriorated on optimal therapy, underwent LVAD support for ≈4 months. Compared with the normal hearts, EDPVRs of hearts from medically treated patients were shifted toward markedly larger volumes. In contrast, EDPVRs of hearts from LVAD patients were similar to those of normal hearts.

Conclusions
Chronic hemodynamic unloading of sufficient magnitude and duration can result in reversal of chamber enlargement and normalization of cardiac structure as indexed by the EDPVR, both important aspects of remodeling, even in the most advanced stages of heart failure.
Long-term Outcome of Transient, Uncomplicated In-Laboratory Coronary Artery Closure
Authors: Abdelmeguid Alaa E. , Whitlow Patrick L. , Sapp Shelly K. , Ellis Stephen G. , Topol Eric J.
Published: June 2012

Background
Successful reversal of abrupt vessel closure without resultant major ischemic complications (death, Q-wave myocardial infarction, or coronary artery bypass graft surgery) is achieved in nearly half of all cases of abrupt vessel closure. The long-term outcome of these patients has not been previously addressed, and it is not clear whether they have a different prognosis than that of patients who have a successful procedure not associated with transient vessel closure.

Methods and Results
We examined 4863 consecutive patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) or directional coronary atherectomy (DCA). Eighty-eight patients had an uncomplicated, successfully reversed transient in-laboratory vessel closure (group 2) and were compared with 4775 patients who had a successful procedure not associated with transient in-laboratory closure (group 1). Clinical follow-up was available in 4839 patients (99.5%), with a mean duration of 41±23 months (range, 1 to 104 months). Survival analysis showed that successfully treated, uncomplicated transient vessel closure per se does not have an adverse effect on long-term prognosis (death, myocardial infarction, or coronary interventions). However, when the procedure (PTCA or DCA) was associated with an increase in creatine kinase–MB (CK-MB), there was a significant adverse effect on long-term outcome. By multivariate logistic regression, an increase in postprocedure CK-MB was the most significant correlate for cardiac death (risk ratio, 1.25;
P
<.0001). An increase in CK-MB was also the most important correlate for major ischemic complications (death, infarction, or coronary interventions) on follow-up (risk ratio, 1.08;
P
=.0005).

Conclusions
Transient, uncomplicated in-laboratory vessel closure per se does not have an adverse long-term effect. However, a concomitant elevation of postprocedure cardiac enzymes has an important and significant adverse effect on long-term outcome. This study suggests that periprocedural creatine kinase isoenzyme determination in patients experiencing in-laboratory coronary closure has important prognostic implications.
Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells
Authors: Mori Katsumi , Hara Yukio , Saito Toshihiro , Masuda Yoshiaki , Nakaya Haruaki
Published: June 2012

Background
It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor–mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor–operated K
+
current (I
K.ACh
), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.

Methods and Results
Effects of three class III antiarrhythmic drugs,
d,l
-sotalol, E-4031, and MS-551, on the carbachol (1 μmol/L)–induced action potential shortening and outward K
+
current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria,
d,l
-sotalol (100 μmol/L), E-4031 (3 μmol/L), and MS-551 (30 μmol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, I
K.ACh
was activated by extracellular application of carbachol (1 μmol/L) or adenosine (10 μmol/L) or by intracellular loading of GTPγS (100 μmol/L). Sotalol (3 to 1000 μmol/L), E-4031 (1 to 100 μmol/L), and MS-551 (1 to 100 μmol/L) inhibited the carbachol-induced I
K.ACh
in a concentration-dependent manner, and their IC
50
(half-maximal inhibition) values were 35.5, 7.8, and 11.4 μmol/L, respectively. However, the GTPγS-induced and adenosine-induced I
K.ACh
were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.

Conclusions
Sotalol may inhibit I
K.ACh
by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K
+
channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on I
K.ACh
.
β-Adrenergic Blocking Property of
dl
-Sotalol Maintains Class III Efficacy in Guinea Pig Ventricular Muscle After Isoproterenol
Authors: Groh William J. , Gibson Kevin J. , McAnulty John H. , Maylie James G.
Published: June 2012

Background
Catecholamines antagonize the efficacy of several class III antiarrhythmic agents. To determine the role of the intrinsic β-adrenergic blocking property of
dl
-sotalol in maintaining class III efficacy during a high-catecholamine state, we compared the electrophysiological properties of
dl
-sotalol with those of
d
-sotalol, which is devoid of significant β-adrenergic blocking effect, before and after isoproterenol infusion.

Methods and Results
Action potential duration at 90% repolarization (APD
90
) was prolonged in isolated guinea pig papillary muscles perfused with
d
-sotalol and
dl
-sotalol 10
−4
mol/L over stimulation cycle lengths from 200 to 2000 ms. The increases in APD
90
for
d
-sotalol and
dl
-sotalol over control were 10.9±2.5 to 23.7±4.8 ms and 27.9±4.0 to 39.0±5.6 ms, respectively. APD
90
shortened to less than control in papillary muscles treated with
d
-sotalol but not
dl
-sotalol on addition of isoproterenol 10
−6
mol/L: −31.2±3.5 to −18.3±4.8 ms and 10.5±3.6 to 33.3±7.8 ms, respectively,
P
<.003. Single guinea pig ventricular myocytes were studied by the whole-cell patch clamp method. Time-dependent (I
out
) and total (I
tot
) outward current in response to a 300-ms pulse to 20 mV and tail current (I
tail
) to −35 mV were measured after Ca
2+
channel block and Na
+
channel inactivation. I
out
, I
tail
, and I
tot
were reduced in myocytes perfused with
d
-sotalol and
dl
-sotalol 10
−4
mol/L: I
out
, −36.1±4.1%, −40.5±3.3%; I
tail
, −59.3±4.6%, −62.2±11.1%; I
tot
, −27.3±4.3%, −50.0±11.8%. I
out
and I
tot
increased to a greater degree in myocytes treated with
d
-sotalol than
dl
-sotalol on addition of isoproterenol 10
−6
mol/L: I
out
, 100.3±20.6%, 11.3±7.6%,
P
=.002; I
tot
, 86.8±39.2%, −41.1±20.9%,
P
=.01. I
tail
tended to increase more in myocytes treated with
d
-sotalol than
dl
-sotalol on addition of isoproterenol, but the difference was not significant (−9.1±13.5%, −28.0±9.0%).

Conclusions
The β-adrenergic blocking property of
dl
-sotalol maintains APD prolongation and repolarizing outward current block during isoproterenol infusion in guinea pig ventricular muscle. Extrapolation of these data to a clinical setting may explain the efficacy of
dl
-sotalol in diminishing ventricular arrhythmia recurrence.
The Relation of Parental Cardiovascular Disease to Risk Factors in Children and Young Adults
Authors: Bao Weihang , Srinivasan Sathanur R. , Wattigney Wendy A. , Berenson Gerald S.
Published: June 2012

Background
Although cardiovascular risk factors relate to family history of cardiovascular disease, it is not clear how the relation changes from children to young adults.

Methods and Results
As part of a community study for cardiovascular health, parental history of diseases was obtained from 8276 offspring 5 to 31 years old, 36% black and 64% white. Between 5- to 10-year-old children and 25- to 31-year-old young adults, prevalence of parental heart attack increased from 5% to 25%. More prevalent in blacks than in whites, parental stroke increased from 2% to 9% in whites versus 3% to 19% in blacks; parental diabetes rose from 7% to 19% in whites versus 9% to 33% in blacks; and parental hypertension increased from 26% to 59% in whites versus 40% to 72% in blacks. Offspring with parental heart attack history were significantly overweight after 10 years of age and showed elevated levels of total cholesterol, VLDL cholesterol, LDL cholesterol, insulin, and glucose after 17 years of age, irrespective of weight. Offspring of diabetic parents were significantly overweight, irrespective of age. They showed significant increases in levels of insulin, glucose, triglycerides, total cholesterol, VLDL cholesterol, and LDL cholesterol after age 24 years, independent of weight. Offspring of hypertensive parents displayed overweight regardless of age, higher levels of blood pressure after age 10 years, and elevations of triglycerides and VLDL cholesterol after age 24 years irrespective of weight. Analyzed by race and sex in young adults, parental heart attack related strongly to LDL cholesterol in the white offspring, especially white males, and to insulin in the black offspring. Parental diabetes showed a stronger association with overweight and glucose in black females. Also noted was the relation between parental hypertension and overweight in black females.

Conclusions
Parental history is an important surrogate measure for cardiovascular risk in the offspring. However, parental history information alone is not sufficient to designate younger children for selective screening for high cholesterol, because of the young age of parents.
Pharmacokinetics and Regional Electrophysiological Effects of Intracoronary Amiodarone Administration
Authors: Nanas John N. , Mason Jay W.
Published: June 2012

Background
The reason for the delay in onset of the electrophysiological effects and antiarrhythmic efficacy of amiodarone is not clear. The relation between the development of the electrophysiological effects of amiodarone and its myocardial concentration is unknown. We therefore examined the time course of development of electrophysiological effects during intracoronary infusion of amiodarone and related these changes to myocardial concentrations.

Methods and Results
Amiodarone (0.139 mg/min) or normal saline was infused for 10 hours into the proximal left anterior descending coronary artery of 24 open-chest dogs. Nineteen animals received intracoronary amiodarone and 5 received normal saline (control group). Ten of the 19 that received amiodarone underwent electrophysiological study (amio-EPS group). Sixteen of the 19, including 7 from the amio-EPS group, underwent pharmacological study (PS group). In the amio-EPS group during pacing at a cycle length of 300 ms, changes in conduction velocities in drug-exposed myocardium referenced to nonexposed myocardium at 1 hour of infusion were −3.7% in the longitudinal direction (
P
=NS) and −7.2% in the transverse direction (
P
<.05); at 3 hours, −12.9% (
P
<.05) and −9.1% (
P
<.05); and at 9 hours, −32.9% (
P
<.02) and −31.7% (
P
<.01). These changes were dependent on amiodarone concentration (
R
2
=.83). There was also an obvious rate-dependent effect that was more pronounced for transverse conduction velocities. This effect was also dependent on amiodarone concentration. In the PS group, amiodarone levels in the drug-exposed myocardium increased from a mean of 5.95 μg/g at 15 minutes of infusion to 188.88 μg/g at the 10th hour. This increase was time dependent (
R
2
=.91). In the nonexposed myocardium, amiodarone levels were always low and increased minimally over time from a mean of 2.68 to 14.45 μg/g. This increase was also time dependent (
R
2
=.97).

Conclusions
Selective intracoronary amiodarone infusion resulted in selective drug accumulation and concomitant time-dependent reduction of myocardial conduction velocity. There was a significant correlation between the extent of reduction of conduction velocity and myocardial amiodarone concentration but not coronary arterial or systemic concentration. Repolarization was not significantly altered.
Unstable Triplet Repeat Diseases
Authors: Monckton Darren G. , Caskey C. Thomas
Published: June 2012

Abstract
Seven inherited human disorders are now associated with the intragenic expansion of triplet repeat DNA sequences. These repeats demonstrate extreme instability in both germline and somatic tissue, accounting for the unusual genetic inheritance patterns and symptom variability associated with these diseases.
Clinical Follow-up of Patients Undergoing Percutaneous Mitral Balloon Valvotomy
Authors: Palacios Igor F. , Tuzcu Murat E. , Weyman Arthur E. , Newell John B. , Block Peter C.
Published: June 2012

Background
This study is the clinical follow-up (20±12 months; range, 6 to 49 months) of 327 patients who had percutaneous mitral balloon valvotomy (PMV) at the Massachusetts General Hospital.

Methods and Results
There were seven in-hospital deaths. Patients were divided into two groups according to their echocardiographic score; 211 patients had echocardiographic scores ≤8 and 116, echocardiographic scores >8. Patients with echocardiographic scores >8 were older (64±11 versus 48±14 years,
P
<.01), and more had atrial fibrillation (65% versus 40%,
P
<.01), calcium under fluoroscopy (81% versus 29%,
P
<.01), and previous surgical commissurotomy (30% versus 16%,
P
<.01) than patients with echocardiographic scores ≤8. With PMV, mitral valve area increased from 1.0±0.3 to 2.2±0.8 cm
2
in patients with echocardiographic scores ≤8 and from 0.8±1 to 1.7±0.7 cm
2
in those with echocardiographic scores >8. Rates of survival (98±2% versus 72±11%), survival with freedom from mitral valve replacement (91±4% versus 55±13%), and survival with freedom from combined events (79±10% versus 39±18%) at follow-up were greater in patients with echocardiographic scores ≤8 (
P
<.00005). Cox regression analysis identified the echocardiographic score as the most important unfavorable intermediate long-term follow-up prediction factor after PMV.

Conclusions
The excellent intermediate long-term clinical follow-up of patients with echocardiographic score ≤8 and no calcified mitral valves suggests that PMV may be the treatment of choice in this group of patients.
Reproducible Induction of Early Afterdepolarizations and Torsade de Pointes Arrhythmias by
d
-Sotalol and Pacing in Dogs With Chronic Atrioventricular Block
Authors: Vos Marc A. , Verduyn S. Cora , Gorgels Anton P.M. , Lipcsei Gyorgyi C. , Wellens Hein J.J.
Published: June 2012

Abstract
It has been well established that antiarrhythmic drugs can also have proarrhythmic effects such as torsade de pointes (TdP) arrhythmias. It was the purpose of this study to create an animal model with a high incidence of reproducible TdP that occurs under clinically relevant circumstances. Experiments were performed in anesthetized dogs that had been in chronic atrioventricular block for 9±6 weeks. TdP inducibility was attempted using different pacing modes before and after the administration of 2 mg/kg
d
-sotalol. In some experiments, endocardial monophasic action potentials were recorded.
d
-Sotalol increased the cycle length of the idioventricular rhythm (1475±460 to 1730±570 ms,
P
<.01) and the QT time (390±65 to 480±85 ms,
P
<.01). In 10% of the experiments, spontaneous TdP occurred after
d
-sotalol. The incidence of pacing-dependent TdP was 52% (
P
<.01). In the inducible group, the cycle length of idioventricular rhythm and QT time were significantly longer despite equal percentage increases in these parameters after
d
-sotalol in both groups. The pacing modes consisting of more than one frequency change had a higher TdP induction rate (
P
<.05). Reproducibility of TdP induction (three times or more using the same pacing train) remained present for approximately 60 minutes after d-sotalol and was greater than 90% within the same animal over weeks. TdP induction was related to the presence of early afterdepolarizations on the monophasic action potential recordings: five of six in the inducible group versus two of six in the nonresponders. Inducibility could be further increased to 89% when a second bolus of
d
-sotalol was administered to noninducible dogs. On the other hand, decreasing QT time by faster basic pacing or administration of isoproterenol, or MgSO
4
prevented TdP induction. This effect of MgSO
4
coincided with the disappearance of early afterdepolarizations. Our animal model shows a high incidence of reproducible acquired TdP arrhythmias, allowing study of the mechanism and treatment of TdP. TdP induction was related to the combination of a slow ventricular rate, the prolongation of QT time, a sudden induced rate change that often required two or more cycle length changes, and the presence of early afterdepolarizations.
Valve Repair Improves the Outcome of Surgery for Mitral Regurgitation
Authors: Enriquez-Sarano Maurice , Schaff Hartzell V. , Orszulak Thomas A. , Tajik A. Jamil , Bailey Kent R. , Frye Robert L.
Published: June 2012

Background
Mitral valve repair has been suggested as providing a better postoperative outcome than valve replacement for mitral regurgitation, but this impression has been obscured by differences in baseline characteristics and has not been confirmed in multivariate analyses.

Methods and Results
The outcomes in 195 patients with valve repair and 214 with replacement for organic mitral regurgitation were compared using multivariate analysis. All patients had preoperative echocardiographic assessment of left ventricular function. Before surgery, patients with valve repair were less symptomatic than those with replacement (42% in New York Heart Association functional class I or II versus 24%, respectively;
P
=.001), had less atrial fibrillation (41% versus 53%;
P
=.017), and had a better ejection fraction (63±9% versus 60±12%,
P
=.016). After valve repair, compared with valve replacement, overall survival at 10 years was 68±6% versus 52±4% (
P
=.0004), overall operative mortality was 2.6% versus 10.3% (
P
=.002), operative mortality in patients under age 75 was 1.3% versus 5.7% (
P
=.036), and late survival (in operative survivors) at 10 years was 69±6% versus 58±5% (
P
=.018). Late survival after valve repair was not different from expected survival. After surgery, ejection fraction decreased significantly in both groups but was higher after valve repair (
P
=.001). Multivariate analysis indicated an independent beneficial effect of valve repair on overall survival (hazard ratio, 0.39;
P
=.00001), operative mortality (odds ratio, 0.27;
P
=.026), late survival (hazard ratio, 0.44;
P
=.001), and postoperative ejection fraction (
P
=.001).

Conclusions
Valve repair significantly improves postoperative outcome in patients with mitral regurgitation and should be the preferred mode of surgical correction. The low operative mortality is an incentive for early surgery before ventricular dysfunction occurs.
Sex Differences in Perioperative and Long-term Cardiac Event–Free Survival in Vascular Surgery Patients
Authors: Hendel Robert C. , Chen Ming Hui , L’Italien Gilbert J. , Newell John B. , Paul Sumita D. , Eagle Kim A. , Leppo Jeffrey A.
Published: June 2012

Background
Little information is available regarding the occurrence of perioperative and late cardiac events in women with vascular disease. The current study was performed to examine whether sex-specific differences exist in these outcomes in a large population of vascular surgery patients and to determine the value of clinical and dipyridamole thallium variables in predicting myocardial infarction and cardiac death.

Methods and Results
Preoperative dipyridamole thallium imaging was performed in 567 vascular surgery patients, including 380 men and 187 women. The incidence of nonfatal myocardial infarction and cardiac death was noted during the perioperative period and during a follow-up period of 50±5 months. Fixed and reversible thallium perfusion abnormalities were more common in men than in women (
P
<.001 and
P
=.004, respectively). Perioperative cardiac event rates were similar in men and women, 8.4% and 7.5%, respectively (
P
=.07). A transient thallium defect was associated with an increased risk of cardiac events by 3.9-fold in men (CI, 1.5 to 10.2) and 5.5-fold in women (CI, 1.4 to 22). Various clinical factors also were predictive of events but demonstrated substantial sex differences. For example, dipyridamole-induced ST-segment depression was strongly associated with perioperative events in men but not in women. There were 22 nonfatal myocardial infarctions and 29 cardiac deaths in men during the follow-up period, with comparable event rates noted for women. Cardiac event–free survival rates also were similar for men and women (
P
=.40). Multivariate analysis demonstrated that a history of heart failure was an important prognostic variable for both sexes, as was a fixed thallium defect. Significant sex differences in the predictive value of other clinical factors for late cardiac events was apparent.

Conclusions
The present study demonstrates that (1) thallium perfusion defects are more common in men; (2) transient thallium defects are associated with perioperative myocardial infarction and cardiac death in both sexes; (3) long-term survival rates after vascular surgery are similar between men and women; (4) a fixed perfusion defect is predictive of late cardiac events in women, with a trend noted in men; and (5) sex-specific differences were noted with regard to the prognostic value of various clinical risk factors. Therefore, dipyridamole thallium plays a significant role in the assessment of perioperative and long-term prognosis for both male and female vascular surgery patients. On the basis of these observations, modifications in risk stratification based on sex may be appropriate for men and women with vascular disease.