bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporine May Affect Improvement of Cognitive Brain Function After Successful Cardiac Transplantation
Authors: Grimm Michael , Yeganehfar Wafa , Laufer Gu¨nther , Madl Christian , Kramer Ludwig , Eisenhuber Edith , Simon Paul , Kupilik Natascha , Schreiner Wolfgang , Pacher Richard , Bunzel Brigitta , Wolner Ernst , Grimm Georg
Published: June 2012

Background
The effects of cardiac transplantation on cognitive brain function are uncertain.

Methods and Results
We measured cognitive brain function and quality of life in out-of-hospital cardiac transplant candidates (n=55; ejection fraction, 19.9%; age, 54.8 years [means]). After transplantation, the patients were serially reevaluated at 4 months (n=25) and at 12 months (n=19). Brain function was measured objectively by cognitive P300 evoked potentials. Additionally, standard psychometric tests (Trail Making Test A, Mini-Mental State Examination, and Profile of Mood State test) were performed. Cognitive P300 evoked potentials were impaired in cardiac transplant candidates (359 ms, recorded at vertex) compared with 55 age- and sex-matched healthy subjects (345 ms,
P
<.01). Trail Making Test A was also abnormal (45 versus 31 seconds in 55 healthy subjects,
P
<.01). After transplantation, P300 measures were normalized at 4 months (345 ms,
P
<.05 versus before transplantation) but declined again at 12 months (352 ms,
P
=NS versus before transplantation). Stepwise multiple regression analysis revealed that cumulative cyclosporine dosage was the only predictor of individual cognitive brain function 4 months (753 mg/kg body wt,
P
<.05) and 12 months (2006 mg/kg body wt,
P
<.01) after transplantation, respectively.

Conclusions
Objective cognitive P300 auditory evoked potential measurements indicate that cognitive brain function is significantly impaired in patients suffering from stable end-stage heart failure. Successful cardiac transplantation is effective to fully normalize impaired brain function. Subsequent relative long-term decline of cognitive brain function after successful cardiac transplantation is strongly suggested to be related to cumulative cyclosporine neurotoxicity.
Spatial Resolution of Atrial Pace Mapping as Determined by Unipolar Atrial Pacing at Adjacent Sites
Authors: Man K. Ching , Chan K.K. , Kovack Paul , Goyal Rajiva , Bogun Frank , Harvey Mark , Daoud Emile , Strickberger S. Adam , Morady Fred
Published: June 2012

Background
The purpose of this study was to examine the spatial resolution of unipolar atrial pace mapping by pacing at adjacent sites within the coronary sinus and the right atrium.

Methods and Results
Unipolar pacing from each pole of a quadripolar catheter was performed in the coronary sinus (n=29) and in the right atrium (n=10). Pacing from the distal electrode was used to simulate the site of origin of an atrial tachycardia. These P waves were compared with the P waves generated by unipolar pacing from each of the three proximal electrodes. The P waves were analyzed for changes in amplitude, duration, and configuration. Pacing within the coronary sinus resulted in significant changes in amplitude and duration at distances of 17 and 21 mm from the distal pole, respectively. Similarly, pacing in the right atrium resulted in significant changes in amplitude and duration at distances of 17 and 32 mm from the distal pole, respectively. No significant changes in configuration were noted in the coronary sinus in any lead at pacing sites ≤32 mm from the distal pole. Configurational changes were noted in the right atrium at pacing sites 17 mm from the distal pole.

Conclusions
The spatial resolution of unipolar atrial pace mapping is ≈17 mm. These findings indicate that mapping techniques that depend on the accurate discrimination of P-wave morphology, such as pace mapping or concealed entrainment, are likely to be imprecise when used in the atria.
Reduction of Transient Myocardial Ischemia With Pravastatin in Addition to the Conventional Treatment in Patients With Angina Pectoris
Authors: van Boven Ad J. , Jukema J. Wouter , Zwinderman Aeilko H. , Crijns Harry J.G.M. , Lie Kong I. , Bruschke Albert V.G.
Published: June 2012

Background
Lipid-lowering therapy reduces cardiac morbidity and mortality. Less is known about its potential anti-ischemic effect.

Methods and Results
In a 2-year prospective randomized placebo-controlled study, the effect of pravastatin 40 mg on transient myocardial ischemia was assessed. Forty-eight–hour ambulatory ECGs with continuous ST-segment analysis were performed in 768 male patients with stable angina pectoris, documented coronary artery disease, and serum cholesterol between 4 and 8 mmol/L (155 and 310 mg/dL). During the trial, patients received routine antianginal treatment. In the patients randomized to pravastatin, transient myocardial ischemia was present at baseline in 28% and after treatment in 19%; in the placebo group, it was found in 20% and 23% of the patients, respectively (
P
=.021 for change in percentage between two treatment groups; odds ratio, 0.62; 95% CI, 0.41 to 0.93). Ischemic episodes decreased by 1.23±0.25 (SEM) episode with pravastatin and by 0.53±0.25 episode with placebo (
P
=.047). Under pravastatin, the duration of ischemia decreased from 80±12 minutes to 42±10 minutes (
P
=.017) and with placebo, from 60±13 minutes to 51±9 minutes (
P
=.56). The total ischemic burden decreased from 41±5 to 22±5 mm·min in the pravastatin group (
P
=.0058) and from 34±6 to 26±4 mm·min in the placebo group (
P
=.24). Adjusted for independent risk factors for the occurrence of ischemia, the effect of pravastatin on the reduction of risk for ischemia remained statistically significant (odds ratio, 0.45; 95% CI, 0.22 to 0.91;
P
=.026).

Conclusions
In men with documented coronary artery disease and optimal antianginal therapy, pravastatin reduces transient myocardial ischemia.
(
Circulation.
1996;94:1503-1505.)
Determination of Angiographic (TIMI Grade) Blood Flow by Intracoronary Doppler Flow Velocity During Acute Myocardial Infarction
Authors: Kern Morton J. , Moore Joseph A. , Aguirre Frank V. , Bach Richard G. , Caracciolo Eugene A. , Wolford Thomas , Khoury Alexander F. , Mechem Carol , Donohue Thomas J.
Published: June 2012

Background
This study compared angiographically graded coronary blood flow with intracoronary Doppler flow velocity in patients during percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction. Different TIMI angiographic flow grades (flow grades based on results of the Thrombolysis In Myocardial Infarction trial) have been associated with different clinical results after reperfusion for acute myocardial infarction. However, intracoronary blood flow velocity has not been compared with the angiographic method of determining flow grade in patients.

Methods and Results
Coronary flow velocity (measured by use of a Doppler guidewire) during primary or rescue PTCA in 41 acute myocardial infarction patients was compared with TIMI grade and cineframes-to-opacification count. Before PTCA, 34 patients had TIMI grade 0 or 1, 5 had TIMI grade 2, and 2 had TIMI grade 3 flow in the infarct artery. Flow velocity was similar among patients with TIMI grades 0, 1, or 2 but was lower than in those with TIMI grade 3 flow (9.4±5.4 versus 16.0±5.4 cm/s for TIMI grades ≤2 versus TIMI grade 3, respectively;
P
<.05). After PTCA, 1 patient had TIMI grade 1, 5 had TIMI 2, and 35 had TIMI 3 flow. Poststenotic flow velocity increased from 6.6±6.1 to 20.0±11.1 cm/s (
P
<.01). TIMI grade 3 flow increased to 21.8±10.9 cm/s (
P
<.05 versus before PTCA). Although post-PTCA flow velocity correlated with angiographic cineframes-to-opacification count (
r
=.45;
P
<.02) for TIMI grade 3, there was a large overlap with TIMI grades ≤2 that had low flow velocity (<20 cm/s). Nine of 11 clinical events (unstable angina and coronary artery bypass graft surgery) occurred in patients with low coronary flow velocity.

Conclusions
Determination of flow velocity after reperfusion may enhance patient characterization and provide the physiological rationale for clinical variations after reperfusion therapy.
Inverse Relation of Dietary Protein Markers With Blood Pressure
Authors: Stamler J. , Elliott P. , Kesteloot H. , Nichols R. , Claeys G. , Dyer A.R. , Stamler R.
Published: June 2012

Background
The purpose of this study was to assess relations to blood pressure (BP) in individuals of markers of dietary protein in their 24-hour urine collections.

Methods and Results
INTERSALT (INTERnational study of SALT and blood pressure) was a cross-sectional study of 10 020 men and women aged 20 to 59 years in 52 population-based samples in 32 countries worldwide, with quality-controlled standardized procedures and assessment of multiple possible confounders. Three measurements of dietary protein in 24-hour urine of each individual participant were studied: total nitrogen and urea as indexes of total protein intake, and sulfate as an index of sulfur-containing dietary amino acids. Repeat examination was performed in a random 8% of participants to assess reliability and to correct for regression-dilution bias. Significant independent inverse relationships were found between BP (systolic and diastolic) and both 24-hour urinary total nitrogen and urea nitrogen, with adjustment for age, sex, alcohol intake, body mass, and 24-hour urinary sodium, potassium, calcium, and magnesium. With adjustment for regression-dilution bias, it was estimated that systolic and diastolic BP were on average 3.0 and 2.5 mm Hg lower, respectively, for persons with dietary total protein intake 30% above the overall mean than for those whose dietary protein intake was 30% below the overall mean (12.94 versus 6.96 g/d urinary total nitrogen, equivalent to 81 versus 44 g/d dietary protein, respectively). For the association of these markers with diastolic BP, results were similar for younger (20- to 39-year-old) and older (40- to 59-year-old) persons and for women and men. For their relation to systolic BP, regression coefficients were larger both for those aged 40 to 59 years than for those aged 20 to 39 years and for women than for men. Nonsignificant inverse relations were recorded for urinary sulfate and BP.

Conclusions
These INTERSALT findings lend support to the hypothesis that higher dietary protein intake has favorable influences on BP.
Apoptosis of Cardiac Myocytes During Cardiac Allograft Rejection
Authors: Szabolcs Matthias , Michler Robert E. , Yang Xiaochun , Aji Walif , Roy Dilip , Athan Eleni , Sciacca Robert R. , Minanov Oktavjian P. , Cannon Paul J.
Published: June 2012

Background
Apoptosis is a distinct form of programmed cell death characterized by activation of endonucleases that cleave nuclear DNA, condensation and fragmentation of nuclear chromatin, blebbing of intact membranes, and cell shrinkage and fragmentation. The mechanisms responsible are unclear, but nitric oxide (NO) generated by inducible NO synthase (iNOS) has been demonstrated to induce apoptosis in macrophages in vitro. This study investigated whether apoptosis occurs during cardiac allograft rejection and examined the relationship of apoptosis to iNOS expression.

Methods and Results
Heterotopic abdominal transplantation from Lewis to Wistar-Furth rats was used as a model of cardiac allograft rejection; Lewis-to-Lewis grafts served as controls. Apoptosis was identified by DNA ladders after electrophoresis on agarose gels and by in situ labeling of DNA fragments; cell types were determined by immunohistochemistry. The number of apoptotic cardiac myocytes increased sharply from day 3 (0.31/mm
2
ventricular tissue) to day 5 (1.27/mm
2
) after transplantation. At day 5, allografts showed a significant increase (
P
<.01) in apoptotic cardiac myocytes, macrophages, and endothelial cells compared with syngeneic grafts. The expression of iNOS mRNA, protein, and enzyme activity paralleled in time and extent the apoptosis of cardiac myocytes. iNOS immunostaining of infiltrating macrophages and cardiac muscle fibers increased significantly in the allografts at days 3 to 5 and was accompanied by immunostaining of both cell types for nitrotyrosine, which is indicative of peroxynitrite formation.

Conclusions
Apoptosis of myocardial cells occurs during cardiac allograft rejection. Apoptosis during rejection parallels the expression of iNOS, which suggests that apoptosis may be triggered by NO and peroxynitrite.
Occurrence and Properties of the Hyperpolarization-Activated Current I
f
in Ventricular Myocytes From Normotensive and Hypertensive Rats During Aging
Authors: Cerbai Elisabetta , Barbieri Mario , Mugelli Alessandro
Published: June 2012

Background
Cellular electrophysiological alterations may contribute to arrhythmogenesis in cardiac hypertrophy. An I
f
-like current occurs in left ventricular myocytes (LVMs) isolated from the hypertrophied heart of old spontaneously hypertensive rats (SHR). Factors that influence I
f

occurrence during development of cardiac hypertrophy were studied by determining its presence, amplitude, characteristics, and β-adrenoceptor modulation.

Methods and Results
Patch-clamped LVMs from young (2 to 3 months old) or old (18 to 24 months old) normotensive Wistar-Kyoto rats (WKY) and SHR were used. A diastolic depolarization phase was present in old SHR. An I
f
-like current occurred in >90% of LVMs from old SHR and WKY and in ≈15% of LVMs from young rats (
P
<.05). Activation curves of I
f
were similar in old rats, with the midpoint at −92.9±2.9 mV in WKY (n=42) and −88.1±1.5 mV in SHR (n=25); maximal specific conductance was 54.4±1.7 in SHR and 20.1±0.5 picosiemens/picofarad in WKY (
P
<.05). In WKY, I
f
amplitude was linearly related to membrane capacitance, an index of cell size (
r
=.53,
P
<.001). This relation was absent in SHR, in which a significant positive correlation was found between the heart weight to body weight ratio and I
f
density. In both old WKY and old SHR, 0.1 μmol/L (−)-isoproterenol increased I
f
amplitude by shifting its activation curve toward more positive potentials.

Conclusions
In LVMs from both WKY and SHR, the occurrence of I
f
increases with aging. Density appears linearly related to the severity of cardiac hypertrophy and increases with β-adrenoceptor stimulation, which suggests that I
f
may contribute to an increased propensity of the hypertrophied heart for arrhythmias.
Genetic Polymorphism of Methylenetetrahydrofolate Reductase and Myocardial Infarction
Authors: Schmitz Christian , Lindpaintner Klaus , Verhoef Petra , Gaziano J. Michael , Buring Julie
Published: June 2012

Background
Elevated total plasma homocyst(e)ine (tHcy; the composite of homocysteine-derived moieties in their oxidized and reduced forms) levels are a risk factor for coronary heart disease, stroke, and venous thrombosis. tHcy plasma levels are influenced by folate, vitamins B
6
and B
12
, as well as by hereditary factors. A point mutation (
C677T
) in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine remethylation, has been reported to render the enzyme thermolabile and less active and has been associated with elevated tHcy in homozygous carriers (+/+ genotype) as well as with increased risk of premature cardiovascular disease.

Methods and Results
We investigated whether this mutation influences risk for myocardial infarction (MI) and plasma levels of tHcy and whether this effect may be modified by dietary folate intake in 190 MI cases and 188 control subjects from the Boston Area Health Study. Genotype frequencies were 37.8% for −/−, 47.8% for +/−, and 14.4% for +/+ in the control group and 50.0% for −/−, 34.7% for +/−, and 15.3% for +/+ in the case group. The relative risk for MI associated with the +/+ genotype (compared with +/− and −/−) was 1.1 (95% CI, 0.6 to 1.9;
P
=.8). Stratification by folate intake values above and below the median did not significantly alter these results. Plasma tHcy levels were 9.9±2.7 μmol/L in −/− individuals, 10.6±3.8 μmol/L in +/− individuals, and 9.1±2.3 μmol/L in +/+ individuals (
P
trend
=NS; determined in 68 cases and 59 control subjects).

Conclusions
Our data show that homozygosity for the C677T mutation in this largely white, middle-class US population is not associated with increased risk for MI, irrespective of folate intake. This suggests that this mutation does not represent a useful marker for increased cardiovascular risk in this and in similar populations.
Heart Transplantation in Chagas' Disease
Authors: de Carvalho Valeria B. , Sousa Eduardo F.L. , Vila Jose´ Henrique A. , da Silva Jose´ Pedro , Caiado Marcio R. , de R. Araujo Sergio R. , Macruz Radi , Zerbini E.J.
Published: June 2012

Background
Heart transplantation (HT) as a therapeutic option for end-stage chronic Chagas' heart disease (CCHD) is controversial. Reactivation of
Trypanosoma cruzi
infection and recurrence of the disease in the allograft are likely to occur. Furthermore, active myocarditis has been reported to predispose patients to an increased incidence and severity of rejection.

Methods and Results
We prospectively investigated the long-term follow-up of 10 patients with CCHD who underwent HT. Immunosuppression was based on cyclosporine A and azathioprine.
T cruzi
reactivation was prevented with benzonidazole. Besides allograft rejection surveillance,
T cruzi
infection was monitored through blood tests, myocardial biopsies, and serological tests. Over a mean follow-up period of 34±38 months (range, 73 to 124 months), 7 patients are alive and in NYHA functional class I. Life expectancy was 78% for the second year and 65% for 10 years. Rejection was less frequent in chagasic than in age- and sex-matched control patients (mean±SD, 1.60±1.26 versus 5.70±1.89 episodes per patient, respectively;
P
=.0001); decreased severity of rejection was also observed (
P
=.006).
T cruzi
parasitemias detected on three occasions were successfully treated with benzonidazole. There were no signs of recurrence of the disease in the allograft.

Conclusions
These results suggest an important role of HT in the treatment of CCHD. There was a low frequency of
T cruzi
infection reactivation and no signs of recurrence of the disease in the allograft. The surprisingly decreased rejection incidence and severity require further studies for elucidation.
Coronary Angioplasty in Diabetic Patients
Authors: Kip Kevin E. , Faxon David P. , Detre Katherine M. , Yeh Wanlin , Kelsey Sheryl F. , Currier Jesse W.
Published: June 2012

Background
Patients with diabetes mellitus are at increased risk of cardiovascular disease. To date, the baseline status and subsequent outcomes of diabetic coronary angioplasty (percutaneous transluminal coronary angioplasty, or PTCA) patients with advanced atherosclerotic disease and with procedures performed across North America have not been well characterized.

Methods and Results
Data on baseline clinical and angiographic characteristics and short- and long-term outcomes of 281 diabetic and 1833 nondiabetic PTCA patients in the multicenter National Heart, Lung, and Blood Institute 1985-1986 PTCA Registry were analyzed. Diabetic patients were older, were more likely to be female, and had more comorbid baseline conditions, triple-vessel disease, and atherosclerotic lesions. Angiographic success and completeness of revascularization did not differ significantly, yet diabetic patients experienced more in-hospital death (women) and nonfatal myocardial infarction. Nine-year mortality was twice as high in diabetic patients (35.9% versus 17.9%). Similarly, 9-year rates of nonfatal myocardial infarction (29.0% versus 18.5%), bypass surgery (36.7% versus 27.4%), and repeat PTCA (43.7% versus 36.5%) were higher in diabetics than in nondiabetics. In multivariate analysis, diabetes remained a significant predictor of decreased 9-year survival and other untoward events.

Conclusions
Compared with nondiabetic PTCA patients, diabetic patients have more extensive and diffuse atherosclerotic disease. Despite similar probability of angiographic success, diabetic patients are more likely to suffer in-hospital death (women) and nonfatal myocardial infarction. Long-term survival and freedom from myocardial infarction and coronary revascularization is also reduced in diabetic PTCA patients. Whether PTCA or coronary bypass surgery is more suitable for these patients is currently under investigation.
Simultaneous Coronary Pressure and Flow Velocity Measurements in Humans
Authors: de Bruyne Bernard , Bartunek Jozef , Sys Stanislas U. , Pijls Nico H.J. , Heyndrickx Guy R. , Wijns William
Published: June 2012

Background
To assess coronary lesion severity in the catheterization laboratory, several guide wire–based methods have been proposed. The purpose of the present study was to compare the feasibility and the reproducibility of coronary flow velocity reserve (CFVR), instantaneous hyperemic diastolic velocity-pressure slope index (IHDVPS), and pressure-derived myocardial fractional flow reserve (FFR
myo
).

Methods and Results
From distal coronary pressure and flow velocity signals (0.014-in guide wires), CFVR, IHDVPS, and FFR
myo
were computed in 15 stenoses (13 patients) under the four following pairs of conditions: (1) twice under baseline conditions; (2) during atrial pacing at 80 and 110 bpm; (3) before and during intravenous infusion of nitroprusside; and (4) before and during intravenous infusion of dobutamine. A total of 104 measurements were obtained. Both CFVR and FFR
myo
could be calculated in all cases. IHDVPS could be calculated in only 79% of cases. The mean value of CFVR did not change between the two baseline measurements and during infusion of nitroprusside but decreased from 1.85±0.41 to 1.66±0.45 (
P
<.05) during atrial pacing and from 1.90±0.50 to 1.41±0.28 (
P
<.05) during dobutamine infusion. The mean values of IHDVPS and FFR
myo
remained similar, whichever the changes in hemodynamic conditions. The coefficient of variation between two consecutive measurements was significantly lower for FFR
myo
(4.2%) than for CFVR (17.7%) and for IHDVPS (24.7%).

Conclusions
CFVR is easy to measure but sensitive to hemodynamic changes. IHDVPS can be measured only in <80% of cases and is highly variable even without changes in hemodynamic conditions. FFR
myo
is easy to measure and almost independent of hemodynamic changes.
Mechanism of Spontaneous Termination of Functional Reentry in Isolated Canine Right Atrium
Authors: Ikeda Takanori , Uchida Takumi , Hough Dustan , Lee John J. , Fishbein Michael C. , Mandel William J. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2012

Background
According to the spiral wave hypothesis of reentry, the core of functional reentry remains excitable but not excited. We sought to determine whether the core remains excitable and whether excitation of the core by an outside wave front leads to termination of the reentry in the atrium.

Methods and Results
In nine isolated canine right endocardial atrial tissues (3.8 by 3.2 cm wide), reentry was induced by a premature point stimulus (S
2
). The isochronal activation maps and dynamics of the activation patterns were visualized with the use of 509 bipolar electrodes (1.6-mm resolution). The S
2
applied after 8 regular beats induced reentry with a mean cycle length of 162±20 ms (15 episodes). Reentry had a large excitable gap (93±26 ms) as determined by early capture with twice the level of threshold stimuli. The central area (core) around which the wave fronts rotated had a mean surface area of 12±3 mm
2
. The electrograms located in the core of the reentry registered no or very low amplitude potentials. In 13 of 15 episodes, reentry terminated when an outside new wave front merged with the original wave front and excited the core. Core excitation caused disruption of the original wave front, and the newly formed wave front(s) vanished at the tissue border within 77±18 ms. In 2 episodes, reentry terminated abruptly when an outside new wave front propagating in a direction opposite to the reentrant wave front collided with the leading edge of the reentrant wave front.

Conclusions
Functional reentry in the atrium is compatible with a spiral wave of excitation with an excitable but nonexcited core and a large excitable gap. Reentry may be terminated either by direct excitation of the core that displaces the wave front to the tissue border or by collision with an outside new wave front.
Regional Differences in Electrophysiological Properties of Epicardium, Midmyocardium, and Endocardium
Authors: Anyukhovsky Evgeny P. , Sosunov Eugene A. , Rosen Michael R.
Published: June 2012

Background
Microelectrode studies have described a population of cells within the midmyocardium (M cells) displaying a steep rate dependence of action potential duration (APD) and high V̇
max
compared with endocardial (Endo) and epicardial (Epi) cells.

Methods and Results
We studied repolarization in different myocardial layers in vitro and in situ. In addition to confirming the results of earlier studies, we found that after abrupt lengthening of the cycle length (CL), APDs in M cells reached a new steady state faster than in Epi or Endo cells: the time to achieve 90% of the difference in APD (t
90
) was 13.3±0.7 minutes in Endo cells, 12.8±1.1 minutes in Epi cells, and 2.6±0.4 minutes in M cells (
P
<.05 compared with Epi or Endo) when CL changed from 400 to 1000 ms. In situ, we registered activation-recovery intervals (ARIs) in bipolar electrograms obtained from different myocardial layers in conditions of AV block and His-bundle pacing. At all CLs from 300 to 2000 ms, ARIs were equal in all myocardial layers from Epi to Endo cells. Steady-state ARIs coincided with APD of M cells registered in vitro in the physiological range of CL from 300 to 700 ms. When CL was changed from 300 to 1000 ms, the ARI followed the rapid time course typical of M cells (t
90
=2.6±0.5, 2.2±0.4, 2.5±0.4, 2.6±0.5, and 2.3±0.4 minutes for Epi; 3-, 5-, and 7-mm sub-Epi; and Endo cells, respectively).

Conclusions
In contrast to in vitro results, there is no significant difference in repolarization among myocardial layers in the intact normal canine heart.
Comparison of High-Dose With Low-Dose Aspirin in Patients With Mechanical Heart Valve Replacement Treated With Oral Anticoagulant
Authors: Altman Rau´l , Rouvier Jorge , Gurfinkel Enrique , Scazziota Alejandra , Turpie Alexander G.G.
Published: June 2012

Background
There are no reported studies on the safety and efficacy of low-dose aspirin with low-intensity oral anticoagulation in patients with heart valve replacement. In this study, we compared the use of 100 mg/d aspirin with 650 mg/d aspirin in the prevention of systemic embolism and vascular death in patients with heart valve replacement who were being treated with oral anticoagulants with a target international normalized ratio (INR) of 2.0 to 3.0.

Methods and Results
Four hundred nine of 416 consecutive patients who had cardiac valve replacement were randomized in open allocation into one of two groups; both groups were treated with oral anticoagulant therapy with a target INR of 2.0 to 3.0. Two hundred seven patients who received 100 mg/d aspirin for an average of 24.1 months were compared with 202 patients who received 650 mg/d aspirin for an average of 21.7 months in a randomized-treatment, open-allocation study. There were no significant differences in systemic embolism, vascular death, or total death rates between the low- and high-dose aspirin treatment groups (0.5 and 1.1, 1.2 and 0.5, and 4.6 and 2.5 per 100 patients/y, respectively). The total number of hemorrhagic events was 13.4 per 100 patients/y in the high-dose aspirin group and 7.9 per 100 patients/y in the low-dose aspirin group (
P
=.035), but the rate of bleeding was influenced by dipyridamole in the 650-mg aspirin group.

Conclusions
In patients with mechanical heart valve replacements, low-dose aspirin (100 mg/d) in conjunction with oral anticoagulants at an INR of 2.0 to 3.0 is as effective as the use of high-dose aspirin (650 mg/d) in the prevention of systemic embolism.
Reperfusion Causes Significant Activation of Heat Shock Transcription Factor 1 in Ischemic Rat Heart
Authors: Nishizawa Junichiro , Nakai Akira , Higashi Toshio , Tanabe Masako , Nomoto Shinichi , Matsuda Katsuhiko , Ban Toshihiko , Nagata Kazuhiro
Published: June 2012

Background
The myocardial protective role of heat shock protein (HSP) has been demonstrated, and there has been increasing interest in stress response in the heart. We examined the DNA-binding activity of heat shock transcription factor (HSF), by which the transcription of heat shock genes is mainly regulated, during heat shock or ischemia/reperfusion in isolated rat heart.

Methods and Results
Rat hearts were isolated and perfused with Krebs-Henseleit buffer by the Langendorff method. Whole-cell extracts were prepared for gel mobility shift assay using oligonucleotides containing the heat shock element, which is present upstream of all heat shock genes. Induction of mRNAs for HSP70, HSP90, and GRP78 (glucose-regulated protein) was examined by Northern blot analysis. Although the activation of HSF during global ischemia was weak and rapidly attenuated, postischemic reperfusion induced a significant activation of HSF. In addition, although HSP70 mRNA was hardly induced during ischemia, its burst induction was detected during postischemic reperfusion. Supershift assays using specific antisera for HSF1 and HSF2 revealed that ischemia/reperfusion as well as heat shock induced the activation of HSF1 in hearts. Although the expression of HSP70 mRNA during heat shock was more vigorous than the expression during ischemia/reperfusion, the induction of HSP90 mRNA in postischemic reperfusion was significantly greater than that in heat shock.

Conclusions
Our findings demonstrated that reperfusion causes a significant activation of HSF1 in ischemia-reperfused heart. The striking contrast between the induction of HSP70 mRNA and that of HSP90 mRNA suggests the presence of regulatory mechanisms other than HSF.
In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide
Authors: Laursen Jørn Bech , Mu¨lsch Alexander , Boesgaard Søren , Mordvintcev Petr , Trautner Simon , Gruhn Nicolai , Nielsen-Kudsk Jens Erik , Busse Rudi , Aldershvile Jan
Published: June 2012

Background
In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats.

Methods and Results
Five groups (n=6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC)
2
and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly (
P
<.05) increased in all tissues in nitrate-tolerant rats in an NTG dose–dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats.

Conclusions
The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.
Increased Cardiac Adrenergic Drive Precedes Generalized Sympathetic Activation in Human Heart Failure
Authors: Rundqvist Bengt , Elam Mikael , Bergmann-Sverrisdottir Yrsa , Eisenhofer Graeme , Friberg Peter
Published: June 2012

Background
Previous studies with radiotracer methods have indicated increases in cardiac norepinephrine (NE) and renal NE spillover in patients with severe congestive heart failure (CHF). However, data on the regional sympathetic profile in early stages of CHF are limited. In this study, sympathetic function in the heart, kidneys, and skeletal muscle was evaluated in patients with mild-to-moderate CHF and compared with that in patients with severe CHF and healthy subjects.

Methods and Results
Total body and regional NE spillover from the heart and kidney was assessed with isotope dilution with steady state infusions of [
3
H]NE. Sympathetic nerve traffic to the skeletal muscle vascular bed (MSA) was recorded intraneurally. Cardiac NE spillover in patients with mild-to-moderate CHF (n=21) was increased threefold versus that in healthy subjects (n=12,
P
<.05), whereas total body and renal NE spillover and MSA did not differ from those in healthy subjects. In the severe CHF group (n=12), cardiac NE spillover was increased fourfold (
P
<.05), and total body and renal NE spillover and MSA were high compared with both mild-to-moderate CHF subjects and healthy subjects (
P
<.05 for both). Fractional extraction of [
3
H]NE across the heart was reduced by ≈40% in both CHF groups versus control subjects (
P
<.05).

Conclusions
These results indicate a selective increase in cardiac adrenergic drive (increased amounts of transmitter available at neuroeffector junctions) in patients with mild-to-moderate CHF. This increase appears to precede the augmented sympathetic outflow to the kidneys and skeletal muscle found in advanced CHF.
Evidence for Altered Balance Between Matrix Metalloproteinases and Their Inhibitors in Human Aortic Diseases
Authors: Knox James B. , Sukhova Galina K. , Whittemore Anthony D. , Libby Peter
Published: June 2012

Background
Although abdominal aortic aneurysms (AAAs) exhibit increased expression of matrix metalloproteinases (MMPs), the functional balance between MMPs and their tissue inhibitors (TIMPs) remains uncertain. This report compares the proteolytic activity in normal aorta, aorto-occlusive disease (AOD), and AAA by use of a novel in situ zymographic technique.

Methods and Results
Infrarenal aortic specimens were obtained from 25 patients undergoing surgery for AOD or AAA and were compared with normal aortic tissue (n=7) obtained from cadavers. Immunohistochemical staining was performed for collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), TIMP-1, and TIMP-2. Net proteolytic activity was determined with in situ zymography whereby aortic sections were incubated on fluorescently labeled substrate. Proteolytic activity was detected under epifluorescent examination. Compared with normal aortic tissue, AOD and AAA tissue demonstrated marked increases in MMP-1 and MMP-3 immunoreactivity, predominantly in the neointima, and modest increases in TIMP-1. MMP-2 was increased in the diseased aortas, and TIMP-2 was abundant in normal, AOD, and AAA samples. Zymography revealed proteolytic activity in AOD and AAA tissues with active digestion of casein and gelatin substrate, particularly on the luminal portion of the specimens. Normal specimens exhibited no lytic activity. Comparison of AOD and AAA specimens revealed no difference in MMP/TIMP immunoreactivity or net proteolytic activity.

Conclusions
MMP expression is markedly increased in AOD and AAA samples, and an imbalance between MMPs and their inhibitors results in similar proteolytic activity. The eventual formation of aneurysmal or occlusive lesions appears not to result from an ongoing difference in the proteolytic pattern.
Unfavorable Effect of Smoking on the Elastic Properties of the Human Aorta
Authors: Stefanadis Christodoulos , Tsiamis Eleftherios , Vlachopoulos Charalambos , Stratos Costas , Toutouzas Konstantinos , Pitsavos Christos , Marakas Stelios , Boudoulas Harisios , Toutouzas Pavlos
Published: June 2012

Background
Smoking is a major risk factor for cardiovascular morbidity and mortality. Because previous studies have shown that smoking affects vasomotor response, we hypothesized that smoking may also acutely alter aortic elastic properties.

Methods and Results
We studied 40 male current and long-term smokers who underwent diagnostic cardiac catheterization for chest-pain evaluation. Twenty subjects (age, 48±2 years, mean±SEM) were randomly assigned to smoking and 20 (age, 47±2 years) to sham smoking studies. Aortic elastic properties were studied with the determination of the aortic pressure-diameter relation before smoking, every minute for the first 5 minutes after the initiation of smoking or sham smoking, and every 5 minutes for the following 15 minutes. Instantaneous diameter of the thoracic aorta was measured with a special ultrasonic dimension catheter developed in our laboratory and previously validated. Instantaneous aortic pressure was measured at the same site as was diameter with a Millar micromanometer. Smoking was associated with significant changes in the aortic pressure-diameter relation that denote deterioration of the elastic properties and were maintained during the whole study period: the slope of the pressure-diameter loop became steeper (baseline, 35.43±1.38; minute 1, 45.26±1.65; peak at minute 10, 46.36±1.69 mm Hg/mm;
P
<.001) and aortic distensibility decreased (baseline, 2.08±0.12; minute 1, 1.60±0.08; nadir at minute 5, 1.54±0.07×10
−6
cm
2
·dyne
−1
;
P
<.001). In contrast, no changes in aortic elasticity indexes were observed with sham smoking.

Conclusions
Smoking is associated with an acute deterioration of aortic elastic properties. This effect of smoking may contribute to the unfavorable consequences of smoking on the cardiovascular system.
Small, Dense Low-Density Lipoprotein Particles as a Predictor of the Risk of Ischemic Heart Disease in Men
Authors: Lamarche Benoiˆt , Tchernof Andre´ , Moorjani Sital , Cantin Bernard , Dagenais Gilles R. , Lupien Paul J. , Despre´s Jean-Pierre
Published: June 2012

Background
Case-control studies have reported that patients with ischemic heart disease (IHD) have a higher proportion of small, dense LDL particles than do healthy control subjects. The extent to which the risk attributed to small LDL particles may be independent of concomitant variations in plasma lipoprotein-lipid concentrations remains to be clearly determined, however, particularly through prospective studies.

Methods and Results
Baseline characteristics were obtained in 2103 men initially free of IHD, among whom 114 developed IHD during a 5-year follow-up period. These 114 case patients were matched with healthy control subjects for age, body mass index, smoking habits, and alcohol intake. LDL peak particle diameter (PPD) was measured a posteriori in 103 case-control pairs by nondenaturing gradient gel electrophoresis of whole plasma. Conditional logistic regression analysis of the case-control status revealed that men in the first tertile of the control LDL-PPD distribution (LDL-PPD≤25.64 nm) had a 3.6-fold increase in the risk of IHD (95% CI, 1.5 to 8.8) compared with those in the third tertile (LDL-PPD>26.05 nm). Statistical adjustment for concomitant variations in LDL cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B concentrations had virtually no impact on the relationship between small LDL particles and the risk of IHD.

Conclusions
These results represent the first prospective evidence suggesting that the presence of small, dense LDL particles may be associated with an increased risk of subsequently developing IHD in men. Results also suggest that the risk attributed to small LDL particles may be partly independent of the concomitant variation in plasma lipoprotein-lipid concentrations.
Hypertension, Serum Angiotensinogen, and Molecular Variants of the Angiotensinogen Gene Among Nigerians
Authors: Rotimi Charles , Cooper Richard , Ogunbiyi Olufemi , Morrison Linda , Ladipo Modupe , Tewksbury Duane , Ward Ryk
Published: June 2012

Background
We evaluated the association among the M235T and T174M variants of the angiotensinogen (AGT) gene, plasma AGT, and hypertension status in a sample of Nigerians.

Methods and Results
Participants were selected from the extremes of the blood pressure distribution obtained from the population survey of 2509 men and women aged 25 to 74 years. Cases (hypertensive subjects) were individuals who had high blood pressure or were taking antihypertensive medication, and control subjects were individuals with low blood pressure who had never taken antihypertensive medication. We found a significant association between the M235T variant and plasma AGT level. Hypertensive subjects had higher plasma AGT levels compared with control subjects. The allele frequencies of the two variants were similar in the hypertensive patients and the control subjects.

Conclusions
The consistent relationships observed between the M235T variant and the protein product and between plasma level of the protein and hypertension status in different ethnic groups provide some evidence for a biochemical mechanism linking DNA variation in the renin-angiotensin system with the hypertension phenotype.
Effects of Exercise During Long-term Support With a Left Ventricular Assist Device
Authors: Jaski Brian E. , Kim Joseph , Maly Richard S. , Branch Kelley R. , Adamson Robert , Favrot Laurence K. , Smith Sidney C. , Dembitsky Walter P.
Published: June 2012

Background
Long-term implantation of a left ventricular assist device (LVAD) may be a future alternative treatment for end-stage heart failure. The objective of the present study was to determine the hemodynamic effects of supine bicycle exercise and functional capacity during upright treadmill exercise in 10 patients after LVAD implantation placed for refractory heart failure as a bridge to cardiac transplantation.

Methods and Results
With supine bicycle exercise, 46±25 days after device placement, heart and LVAD rates increased in parallel from 87±12 to 117±14 bpm and 82±18 to 107±21 bpm, respectively. Peak O
2
consumption was 8.2±1.7 mL O
2
·kg
−1
·min
−1
. Fick systemic blood flow rose from 5.0±1.2 to 7.8±2.5 L/min. Right atrial and pulmonary capillary wedge pressures increased from 6±4 and 5±3 mm Hg to 12±5 and 13±8 mm Hg, respectively. End-diastolic left ventricular dimension increased from 3.9±1.3 to 4.8±1.6 cm; however, right ventricular dimension decreased from 3.2±1.0 to 2.3±0.9 cm. With upright treadmill exercise, peak O
2
consumption was 14.1±2.9 mL O
2
·kg
−1
·min
−1
.

Conclusions
This study indicates that exercise during long-term LVAD support is safe and is not limited by right heart decompensation. It also justifies a larger study to examine how exercise after LVAD implantation compares with that after cardiac transplantation.
Serial Assessment of the Cardiovascular System in Normal Pregnancy
Authors: Poppas Athena , Shroff Sanjeev G. , Korcarz Claudia E. , Hibbard Judith U. , Berger David S. , Lindheimer Marshall D. , Lang Roberto M.
Published: June 2012

Background
Temporal changes in systemic arterial compliance and wave propagation properties (pulsatile arterial load) and their role in ventricular–systemic arterial coupling during gestation have not been explored. Noninvasive methods combined with recently developed mathematical modeling techniques were used to characterize vascular and left ventricular (LV) mechanical adaptations during normal gestation.

Methods and Results
Fourteen healthy women were studied at each trimester of pregnancy and again postpartum. Experimental measurements included instantaneous aortic pressure (subclavian pulse tracings) and flow (aortic Doppler velocities) and echocardiographic imaging of the LV. A small increase in LV muscle mass and end-diastolic chamber dimension occurred by late gestation, with no significant alterations in myocardial contractility. Cardiac output increased and the steady component of arterial load (total vascular resistance) decreased during pregnancy. Several changes in pulsatile arterial load were noted: Global arterial compliance increased (≈30%) during the first trimester and remained elevated thereafter. The magnitude of peripheral wave reflections at the aorta was reduced. The mathematical model-based analysis revealed that peripheral wave reflections at the aorta were delayed and that both conduit and peripheral vessels contributed to the increased arterial compliance. Finally, coordinated changes in the pulsatile arterial load and LV properties were responsible for maintaining the efficiency of LV-to–arterial system energy transfer.

Conclusions
The rapid time course of compliance changes and the involvement of both conduit and peripheral vessels are consistent with reduced vascular tone as being the main underlying mechanism. The pulsatile arterial load alterations during normal pregnancy are adaptive in that they help to accommodate the increased intravascular volume while maintaining the efficiency of ventricular-arterial coupling and diastolic perfusion pressure.
Quantitative Assessment of Alterations in Regional Left Ventricular Contractility With Color-Coded Tissue Doppler Echocardiography
Authors: Gorcsan John , Strum David P. , Mandarino William A. , Gulati Vijay K. , Pinsky Michael R.
Published: June 2012

Background
Tissue Doppler imaging (TDI) is a novel method of color-coding myocardial velocity on-line. The objective of the present study was to evaluate endocardial velocity with TDI as a method of objectively quantifying alterations in regional contractility over a wide range induced by inotropic modulation.

Methods and Results
Myocardial length crystals were used to simultaneously assess regional left ventricular (LV) function, and high-fidelity pressure and conductance catheters were used to assess global LV contractility by pressure-volume relations in nine open-chest dogs. Mid-LV M-mode and two-dimensional color TDI images were recorded during control and inotropic modulation stages with dobutamine and esmolol. Predicted significant increases in TDI indices occurred with dobutamine: peak systolic velocity of 4.41±1.07 to 6.67±1.07 cm/s*, systolic time-velocity integral (TVI) of 0.43±0.12 to 0.62±0.10 cm*, and diastolic TVI of 0.49±0.11 to 0.71±0.17 cm*. Opposing significant decreases occurred with esmolol: peak systolic velocity of 4.46±0.94 to 2.31±0.81 cm/s*, systolic TVI of 0.47±0.12 to 0.19±0.11 cm*, and diastolic TVI of 0.55±0.11 to 0.33±0.11 cm* (*all
P
<.001 versus control). Changes in TDI peak systolic velocity were correlated with changes in fractional shortening (
r
=.88) and shortening velocity (
r
=.87) by sonomicrometry. Changes in TDI peak velocity from multiple mid-LV sites also correlated significantly with maximal elastance (
r
=.85±.04) from pressure-volume relations.

Conclusions
TDI measures reflect directional and incremental alterations in regional and global LV contractility and have the potential to quantify regional LV function.