bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenoviral Constructs Encoding Phosphorylation-Competent Full-length and Truncated Forms of the Human Retinoblastoma Protein Inhibit Myocyte Proliferation and Neointima Formation
Authors: Smith Roy C. , Wills Ken N. , Antelman Douglas , Perlman Harris , Truong Lonn N. , Krasinski Kevin , Walsh Kenneth
Published: June 2012

Background
The retinoblastoma (Rb) protein is a key cell-cycle regulator that controls entry into the S phase by modulating the activity of the E2F transcription factor. We analyzed the effects of full-length phosphorylation-competent and a mutant truncated form of human Rb for their effects on vascular smooth muscle cell (VSMC) proliferation and neointima formation.

Methods and Results
A number of mutant forms, both phosphorylation competent and incompetent, of human Rb protein were evaluated for their ability to inhibit E2F activity. The results of these assays indicated that a phosphorylation competent, amino-terminal–truncated Rb protein (Rb56) was a particularly potent inhibitor of E2F-mediated transcription relative to the full-length Rb construct (Rb110). Adenoviral constructs containing Rb56 or Rb110 expressed their respective Rb forms in VSMCs, as determined by Western immunoblot analysis, and were similar in their abilities to arrest the cell cycle, as determined by assays of
3
H-thymidine incorporation and by flow cytometric analyses. When examined for their effect on neointima formation after balloon injury of the rat carotid artery, both full-length and truncated forms of Rb inhibited formation of this VSMC-derived lesion.

Conclusions
These analyses revealed that the maintenance of high levels of phosphorylation-competent human Rb, either full-length or truncated forms, in VSMCs is an effective method of modulating the extent of intimal hyperplasia that occurs after balloon-induced vascular injury.
Myocardial Stiffness Is Attributed to Alterations in Cross-Linked Collagen Rather Than Total Collagen or Phenotypes in Spontaneously Hypertensive Rats
Authors: Norton Gavin Robert , Tsotetsi Jacob , Trifunovic Boris , Hartford Craig , Candy Geoffrey Patrick , Woodiwiss Angela Jill
Published: June 2012

Background
The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined.

Methods and Results
We compared the action of hydralazine (0.07 mmol · kg
−1
· d
−1
) with that of captopril (0.22 mmol · kg
−1
· d
−1
) on the left ventricular end-diastolic (LVED) myocardial stiffness constant,
k
(g · cm
−2
) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED
k
(SHR, 27.9±1; WKY, 19.5±1.2;
P
<.01), myocardial hydroxyproline concentrations (HPRO; μg/mg dry wt) (SHR, 4.19±0.16; WKY, 3.17±0.09;
P
<.001), and collagen type I/III ratios (SHR, 7.1±0.7; WKY, 2.1±0.2;
P
<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17±3; WKY, 41±4;
P
<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED
k
, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43±4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED
k
in SHRs (20.±1.6,
P
<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18±0.18) or collagen type I/III (8±1) but did improve collagen solubility (31±2).

Conclusions
An association between alterations in LVED
k
and collagen solubility but not between changes in LVED
k
and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.
Sera From Chronic Chagasic Patients With Complex Cardiac Arrhythmias Depress Electrogenesis and Conduction in Isolated Rabbit Hearts
Authors: Farias de Oliveira Selma , Pedrosa Roberto Coury , Nascimento José Hamilton Matheus , Campos de Carvalho Antonio Carlos , Masuda Masako Oya
Published: June 2012

Background
Immune dysfunction has long been proposed as a mechanism for the etiopathogenesis of the chronic phase of Chagas’ disease. Antibodies of chagasic patients have been shown to interfere with electric and mechanical activity of embryonic myocardial cells in culture. Here, we demonstrate that antibodies derived from a group of chronic chagasic patients are able to induce disturbances in the electrogenesis and conduction in isolated adult rabbit hearts.

Methods and Results
Sera from chronic chagasic patients with complex cardiac arrhythmias (ChA+) decreased heart rate (from 131±26 to 98±37 bpm [mean±SD]; n=6;
P
<.05) in isolated rabbit hearts when perfused at a dilution of 1:100 (vol:vol) by the Langendorff method. Sera from another experimental group of four chronic chagasic patients without complex arrhythmias (ChA−) and two control groups composed of five Wolff-Parkinson-White (WPW) syndrome patients and five orthopedic surgery patients did not affect heart rate when tested under similar conditions. In addition, sera from five of six ChA+ patients and from one WPW patient induced AV conduction blockade. Effects of the sera from ChA+ patients are due to their IgG fractions. Both serum and IgG effects are blocked by atropine (10 μmol/L).

Conclusions
Antibodies of ChA+ patients decrease heart rate and induce AV conduction block in isolated adult rabbit hearts through activation of muscarinic receptors.
Paradoxical Relationship Between N-Terminal Proatrial Natriuretic Peptide and Filling Pressure in Adults With Cyanotic Congenital Heart Disease
Authors: Hopkins William E. , Hall Christian
Published: June 2012

Background
Many adults with cyanotic congenital heart disease are characterized by reduced ventricular filling pressures and decreased systemic oxygen transport. Data from animals suggest that hypoxia can induce synthesis and secretion of atrial natriuretic peptide.

Methods and Results
We measured plasma N-terminal (1-98) proatrial natriuretic peptide (proANP) in 26 cyanotic adults and 28 noncyanotic control subjects. Resting arterial oxygen saturation was significantly lower and hemoglobin concentration and hematocrit significantly greater in cyanotic patients than in control subjects (82±6 versus 96±3%, 19.7±2.2 versus 14.7±2.1 g/dL, and 59.0±8.5% versus 44.3±5.2%, respectively,
P
<.0001 in all cases). Four cyanotic patients had evidence of iron deficiency. Plasma proANP levels were elevated in cyanotic patients compared with control subjects (1828±1147 versus 689±343 pmol/L,
P
<.0001). Comparison of resting arterial oxygen saturation and proANP levels demonstrated an inverse linear relationship between the two measures (
r
=−.70,
P
<.0001). There was a significant linear relationship between both hemoglobin concentration and hematocrit and proANP levels as well (
r
=.53,
P
=.0003 and
r
=.48,
P
=.002, respectively). Cyanotic patients had lower mean right atrial pressures than the control subjects (4±3 versus 7±2 mm Hg,
P
=.005), and there were inverse logarithmic relationships between proANP levels and systemic cardiac index (
r
=−.82,
P
=.0002), systemic oxygen transport (
r
=−.68,
P
=.005), and mixed venous oxygen saturation (
r
=−.79,
P
<.0001).

Conclusions
Adults with cyanotic congenital heart disease are characterized by increased levels of plasma proANP. The increased atrial natriuretic peptide most likely results in extracellular and plasma volume depletion and reduced systemic oxygen transport. Measures designed to increase ventricular filling may improve quality of life of these patients.
Size Matters
Authors: McMillan William D. , Tamarina Natalia A. , Cipollone Maria , Johnson David A. , Parker Michele A. , Pearce William H.
Published: June 2012

Background
Despite a wealth of data detailing increased metalloproteinase (MMP)-9 expression and activity in abdominal aortic aneurysms (AAAs), no studies examine the relationship between aortic size and MMP-9 expression. Because elastolysis occurs early in AAA formation, we hypothesized that MMP-9 expression would vary with aortic diameter. The purpose of this study was to measure MMP-9 mRNA levels in AAAs of various diameters and define the relationship between AAA size and MMP-9 expression.

Methods and Results
MMP-9 mRNA levels were measured by competitive polymerase chain reaction (PCR) using gene-specific external standards with cDNA from AAAs (n=19) and normal aortas (n=4). Levels were normalized to GAPDH mRNA, determined separately via competitive PCR, to control for efficiency of reverse transcription. AAA size was measured on CT scans obtained within 6 weeks of surgery. MMP-9/GAPDH mRNA transcript levels in AAAs were expressed as mean±SEM and analyzed by ANOVA with a Tukey adjustment. There was a fourfold elevation in MMP-9/GAPDH mRNA transcript levels in 5.0- to 6.9-cm AAAs (98.06±15.19) compared with small (3.0- to 4.9-cm) AAAs (20.87±5.15,
P
<.03), large (>7-cm) AAAs (27.16±14.56,
P
<.01), or normal aortas (3.57±1.13,
P
<.003). The results did not change when they were normalized to patient height, nor were there significant differences in risk factors, age, or sex in each AAA group.

Conclusions
MMP-9 mRNA expression is significantly higher in moderate-diameter (5- to 6.9-cm) AAAs than either small (<4.0-cm) or large (>7.0-cm) AAAs. Increased MMP-9 expression may account for the propensity of AAAs >5 cm to continue to expand, in contrast to smaller aneurysms. Lower levels in AAAs >7 cm suggest that increases in other enzymes or in diameter-dependent mechanical stress on the aortic wall are responsible for their characteristic rapid expansion and high rupture rates.
Peroxynitrite Reduces Myocardial Infarct Size and Preserves Coronary Endothelium After Ischemia and Reperfusion in Cats
Authors: Nossuli Tareck O. , Hayward Reid , Scalia Rosario , Lefer Allan M.
Published: June 2012

Background
Peroxynitrite (ONOO
−
) is purported to exert cytotoxic effects at high doses. However, physiologically relevant concentrations of ONOO
−
inhibit polymorphonuclear neutrophil (PMN) adhesion to the endothelium and attenuate PMN-mediated contractile dysfunction in isolated perfused rat hearts. We are unaware of any reports in vivo showing effects of peroxynitrite in myocardial ischemia and reperfusion (MI/R). Thus, the purpose of this study was to examine the in vivo effects of a physiologically relevant concentration of ONOO
−
(1 μmol/L) in a feline model of MI/R injury.

Methods and Results
ONOO
−
(1 μmol/L) or its vehicle (0.9% NaCl at pH 8.4) was infused intraventricularly, starting 10 minutes before reperfusion in cats subjected to 90 minutes of myocardial ischemia and 4.5 hours of reperfusion. ONOO
−
-treated cats demonstrated marked attenuation of cardiac necrosis after MI/R compared with cats receiving only vehicle (
P
<.001). Moreover, vasorelaxation of ischemic-reperfused left anterior descending (LAD) coronary artery rings in response to the endothelium-dependent dilators acetylcholine and
A23187
was greater in rings isolated from ONOO
−
-treated MI/R cats compared with MI/R cats receiving only vehicle, indicating that postreperfusion coronary vascular endothelial function was preserved by ONOO
−
. ONOO
−
also significantly reduced adherence of neutrophils to the ischemic-reperfused LAD coronary endothelium. Immunohistochemical localization of P-selectin was also significantly attenuated in hearts from ONOO
−
-infused MI/R cats.

Conclusions
These data suggest that physiologically relevant concentrations of ONOO
−
exert significant cardioprotective and vasculoprotective effects in MI/R in cats, at least partially by attenuating PMN-endothelium interactions.
Percutaneous Treatment of Abdominal Aortic Aneurysm in a Swine Model
Authors: Ruiz Carlos E. , Zhang He Ping , Butt Amjad I. , Whittaker Peter
Published: June 2012

Background
Previous studies used covered stent grafts to treat abdominal aortic aneurysms; however, such devices block flow into aortic side branches. We used uncovered stents with and without additional embolization coils to treat abdominal aortic aneurysm in a swine model and examined serial histological changes in the aneurysms over a 6-month period.

Methods and Results
We examined aneurysms in 9 control and 9 treated pigs (5 received stents alone and 4 received stents and coils). Aneurysms were surgically created with abdominal fascia. Three days later, we percutaneously placed a self-expandable uncovered stent across the aneurysm. Coils were implanted through the stent into the aneurysm lumen. An aortogram immediately after stent placement showed no significant change in aneurysm lumen; however, in pigs that had aortograms between 6 weeks and 6 months after treatment, the diameter decreased (28% to 65%) in 4 of 5 pigs, and 1 had no discernible aneurysm. Three treated pigs died, but only 1 from rupture. In contrast, 7 untreated aneurysms ruptured (2 pigs died of other causes). Histological examination revealed that the aneurysm lumen was reduced after treatment by collagen production. This healing process was accelerated in aneurysms treated with both stents and coils. In contrast, only limited amounts of new collagen were found in untreated, ruptured aneurysms. Instead, the fascia was disrupted and there was evidence of collagen degradation.

Conclusions
We found that uncovered stents reduce the likelihood of aneurysm rupture in a swine model without blocking arterial branches. The presence of coils enhanced filling of the lumen by collagen.
Simplified Electrophysiologically Directed Catheter Ablation of Recurrent Common Atrial Flutter
Authors: Shah Dipen C. , Haïssaguerre Michel , Jaïs Pierre , Fischer Bruno , Takahashi Atsushi , Hocini Meleze , Clementy Jacques
Published: June 2012

Background
Despite verification of bidirectional conduction block after radiofrequency (RF) catheter ablation in the inferior vena cava (IVC)–tricuspid annulus (TA) isthmus, recurrence of common atrial flutter is relatively common. Although complete linear reablation is usually performed, we evaluated a simplified electrophysiological strategy selectively targeting recovered conducting isthmus tissue.

Methods and Results
Twenty-one patients (18 men and 3 women, age, 54±10 years) with a recurrence of typical atrial flutter 6±7 months after an apparently successful catheter ablation in the IVC-TA isthmus prospectively underwent electrophysiologically targeted reablation during flutter. Sites with narrow electrograms or fractionated electrograms interposed between adjacent sites with double potentials considered to represent gaps were ablated without movement of the catheter. Mapping showed that 18 of 21 patients had a single gap. Successful ablation required a single application in 14 patients and, in the group as a whole, a median of one application (mean, 2±2; range, 1 to 11) with resultant bidirectional block in 13 of 16. A single narrow electrogram (duration, 48±6 ms; amplitude, 0.1±0.05 mV) was noted at the successful site in 11, whereas a fractionated electrogram (97±32 ms, 0.05±0.04 mV,
P
<.05) was noted in 9. There were four additional recurrences during a follow-up at 7±5 months; three were similarly ablated with a median of one pulse.

Conclusions
Transmural ablation lesions in the isthmus can be recognized during flutter by double potentials separated by an isoelectric interval. Postablation recurrent flutter is usually due to a single discrete recovered gap; this is represented by a single or a fractionated potential spanning the isoelectric interval of adjacent double potentials, which can be selectively targeted to minimize repeat ablation.
Exogenous and Endogenous Adenosine Inhibits Fetal Calf Serum–Induced Growth of Rat Cardiac Fibroblasts
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Mi Zaichuan , Jackson Edwin K.
Published: June 2012

Background
Because proliferation of cardiac fibroblasts participates in cardiac hypertrophy/remodeling associated with hypertension and myocardial infarction, it is important to elucidate factors regulating cardiac fibroblast proliferation. Adenosine, a nucleoside abundantly produced by cardiac cells, is antimitogenic vis-à-vis vascular smooth muscle cells; however, the effect of adenosine on cardiac fibroblast proliferation is unknown. The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast–derived) adenosine on cardiac fibroblast proliferation.

Methods and Results
Growth-arrested cardiac fibroblasts were stimulated with 2.5% FCS in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels, including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; adenosine deaminase inhibitor); (2) dipyridamole (adenosine transport blocker); and (3) iodotubericidin (adenosine kinase inhibitor). All of these agents inhibited, in a concentration-dependent manner, FCS-induced cardiac fibroblast proliferation as assessed by DNA synthesis ([
3
H]thymidine incorporation) and cell counting. EHNA, dipyridamole, and iodotubericidin increased extracellular levels of adenosine by 2.3- to 5.6-fold when added separately to cardiac fibroblasts, and EHNA+iodotubericidin or EHNA+iodotubericidin+dipyridamole increased extracellular adenosine levels by >690-fold. Both KF17837 (selective A
2
antagonist) and DPSPX (nonselective A
2
antagonist) but not DPCPX (selective A
1
antagonist) blocked the antimitogenic effects of 2-chloroadenosine, EHNA, and dipyridamole on DNA synthesis, suggesting the involvement of A
2A
and/or A
2B
but excluding the participation of A
1
receptors. The lack of effect of
CGS21680
(selective A
2A
agonist) excluded involvement of A
2A
receptors and suggested a major role for A
2B
receptors. This conclusion was confirmed by the rank order potencies of four adenosine analogues.

Conclusions
Cardiac fibroblasts synthesize adenosine, and exogenous and cardiac fibroblast–derived adenosine inhibits cardiac fibroblast proliferation via activation of A
2B
receptors. Cardiac fibroblast–derived adenosine may regulate cardiac hypertrophy and/or remodeling by modulating cardiac fibroblast proliferation.
Risk and Predictors for Pregnancy-Related Complications in Women With Heart Disease
Authors: SM Samuel C. Siu , Sermer Mathew , Harrison David A. , Grigoriadis Elizabeth , Liu Grace , Sorensen Sheryll , BS Jeffrey F. Smallhorn , Farine Dan , Amankwah Kofi S. , Spears John C. , Colman Jack M.
Published: June 2012

Background
The physiological changes of pregnancy can result in cardiovascular complications in the mother, which in turn may have fetal implications. Prior studies have focused on specific cardiac lesions or identified univariate predictors. There is a need to refine the risk stratification of women with heart disease so they can receive appropriate obstetrical counseling and care.

Methods and Results
We examined the outcomes of 221 women with heart disease who underwent 276 pregnancies and received their obstetrical care at three Toronto hospitals from 1986 through 1994. Those who underwent therapeutic abortions were excluded. Among the study participants, there were 24 miscarriages and 252 completed pregnancies (pregnancies not ending in miscarriage). Maternal heart failure, arrhythmia, or stroke occurred in 45 completed pregnancies (18%). There were no maternal deaths. Poor maternal functional class or cyanosis, myocardial dysfunction, left heart obstruction, prior arrhythmia, and prior cardiac events were predictive of maternal cardiac complications. These predictors were incorporated into a point score that can be used to estimate the probability of a cardiac complication in the mother. The rate of cardiac complications for a patient with 0, 1, and >1 of the above factors was 3%, 30%, and 66%, respectively. Neonatal complications occurred in 42 completed pregnancies (17%). Neonatal events included death (2), respiratory distress syndrome (16), intraventricular hemorrhage (2), premature birth (35), and small-for-gestational-age birth weight (14). Poor maternal functional class or cyanosis was predictive of neonatal events.

Conclusions
Despite low maternal and neonatal mortality, pregnancy in women with heart disease is associated with significant cardiac and neonatal morbidity. The probability of maternal cardiac or neonatal events can be predicted from baseline characteristics of the mother.
Assessment of Myocardial Viability With
99m
Tc-Sestamibi Tomography Before Coronary Bypass Graft Surgery
Authors: Dakik Habib Abbas , Howell Jimmy F. , Lawrie Gerald M. , Espada Rafael , Weilbaecher Donald G. , He Zuo-Xiang , Mahmarian John J. , Verani Mario S.
Published: June 2012

Background
Assessment of myocardial viability by
99m
Tc-sestamibi remains controversial. Accordingly, we investigated the use of sestamibi as a marker of myocardial viability, defined by histopathology, and for predicting improvement of myocardial function after coronary artery bypass graft surgery (CABG).

Methods and Results
99m
Tc-sestamibi perfusion tomography and radionuclide angiography were performed within 2 days before CABG in 21 patients with ≥75% stenosis of the left anterior descending coronary artery and resting anterior wall dyssynergy. During CABG, transmural myocardial biopsies were obtained from the dyssynergic anterior wall and from normal myocardial segments to determine the extent of viable myocardium by histopathology. Improvement of regional left ventricular function was evaluated by radionuclide angiography at 6 to 8 weeks after CABG. There was a good correlation (
r
=.85,
P
<.001) between the quantified sestamibi activity and the extent of viable myocardium determined morphometrically. Among 21 biopsied dyssynergic myocardial segments, 11 improved their function after CABG and 10 failed to improve. Biopsied segments with improved postoperative function had significantly higher sestamibi activity (81±5% versus 49±16%,
P
<.0001) and significantly lower extent of interstitial fibrosis (7±4% versus 31±21%,
P
=.0002) than segments that failed to improve. A 55% threshold of
99m
Tc-sestamibi activity had positive and negative predictive values of 79% and 100%, respectively, for recovery of function after CABG in the biopsied segments.

Conclusions
Myocardial
99m
Tc-sestamibi activity correlates well with the extent of viable myocardium and predicts improvement in regional function after CABG. This lends support to the use of sestamibi as a myocardial viability agent.
Prevention of Fatty Streak Formation of 17β-Estradiol Is Not Mediated by the Production of Nitric Oxide in Apolipoprotein E– Deficient Mice
Authors: Elhage R. , Bayard F. , Richard V. , Holvoet P. , Duverger N. , Fiévet C. , Arnal J.-F.
Published: June 2012

Background
Estrogens have atheroprotective properties, the mechanisms of which remain obscure. Estrogens have recently been reported to increase endothelial NO synthase expression in castrated animals and to prevent the degradation of NO by decreasing superoxide anion production in cultured endothelial cells. In both cases, increased NO bioavailability would promote vasodilation, inhibit proliferation of the adjacent vascular smooth muscle, reduce platelet aggregation, and inhibit monocyte adhesion to the endothelium and the inflammatory reaction induced by cytokines, all key contributors in the development of atherosclerosis.

Methods and Results
In the present work, the respective roles of 17β-estradiol and NO in the development of the atherosclerotic process were investigated in castrated apolipoprotein E–deficient (apo E KO) mice, which spontaneously develop fatty streak lesions within 3 months.
N
ω
-Nitro-
l
-arginine methyl ester (L-NAME), an NO synthase inhibitor, 50 mg · kg
−1
· d
−1
, increased arterial blood pressure and decreased cerebellum cGMP content, demonstrating the blockade of NO production, but did not influence the atherogenic process in castrated apo E KO mice.

Conclusions
17β-Estradiol decreased the size of the aortic lesions approximately threefold, and the magnitude of this vasculoprotective effect was not altered by L-NAME. Moreover, L-NAME increased circulating malonyldialdehyde (MDA)-modified LDL, which was not altered by 17β-estradiol, leading to a complete dissociation between circulating MDA-modified LDL and parietal lesions.
Synergistic Effects of ACE Inhibition and Ang II Antagonism on Blood Pressure, Cardiac Weight, and Renin in Spontaneously Hypertensive Rats
Authors: Ménard Joël , Campbell Duncan J. , Azizi Michel , Gonzales Marie-Françoise
Published: June 2012

Background
Blockade of type 1 angiotensin (Ang) II receptors combined with ACE inhibition may amplify the efficacy of the renin-angiotensin system blockade because ACE inhibitors do not completely and permanently suppress Ang II production.

Methods and Results
Enalapril or losartan (1, 3, 10, and 30 mg/kg) or their combination was administered for 2 to 4 weeks to spontaneously hypertensive rats. The combination of low doses of each agent induced greater reductions in blood pressure (BP) and left ventricular weight/body weight (LVW/BW) ratio than monotherapy with the same or higher doses. When approximately equipotent regimens of enalapril, losartan, and their combination, as judged by BP fall, were compared, there were similar increases in plasma and renal renin and in plasma Ang-(1-7) and Ang I and similar reductions in plasma angiotensinogen. Enalapril alone reduced plasma Ang II levels, and losartan alone increased Ang II levels. The combination of enalapril with losartan prevented or reduced the increase in Ang II levels observed with losartan alone.

Conclusions
These findings show that the synergistic interaction between the effects of low doses of enalapril and losartan on BP and LVW/BW ratio is due to more effective inhibition of the renin-angiotensin system by their combination than by either agent alone. When both drugs are given together, the ACE inhibitor–induced fall in plasma Ang II results in modulation of the Ang II antagonist–induced reactive rise in Ang II, thereby lowering the plasma Ang II concentration, which competes with the antagonist for the Ang II receptors.
Mechanisms for Absence of Inverse Relationship Between Coupling Intervals of Premature Impulses Initiating Reentrant Ventricular Tachycardia and Intervals Between Premature and First Tachycardia Impulses
Authors: Cabo Candido , Deruyter Bernard , Coromilas James , Wit Andrew L.
Published: June 2012

Background
During initiation of tachycardias by programmed stimulation (PES), an inverse relationship between the coupling interval of the premature impulse (V
1
V
2
) and the interval between the premature impulse and the first impulse of tachycardia (V
2
T
1
) has been proposed to be a specific indicator of reentry. However, an inverse relationship has not always been observed during initiation of clinical reentrant ventricular tachycardias (VTs).

Methods and Results
Reentrant VT was initiated by PES in twelve 4-day-old infarcted dog hearts. The relationship between V
1
V
2
and V
2
T
1
was always direct. Mapping of the epicardial border zone (EBZ) indicated that initiation of VT was secondary to functional orthodromic block of V
2
, propagation of V
2
around the line of block, and antidromic propagation through the original location of the block. In 7 dogs, the line of orthodromic block and the pathway of orthodromic propagation were similar for different V
1
V
2
coupling intervals. Orthodromic conduction time around the line to its distal side was longer at shorter V
1
V
2
intervals, but a shorter antidromic delay in the area of unidirectional block for shorter V
1
V
2
intervals, possibly reflecting small changes in the conduction pathway involving deeper layers of the EBZ, resulted in shorter V
2
T
1
intervals. In the other 5 dogs, the orthodromic conduction pathway of V
2
around the line of block changed markedly, with a shorter pathway for shorter V
1
V
2
intervals resulting in shorter V
2
T
1
intervals.

Conclusions
An inverse relationship between V
1
V
2
and V
2
T
1
is not a specific indicator of functional reentry.
Mechanism of Benefit of Negative Inotropes in Obstructive Hypertrophic Cardiomyopathy
Authors: Sherrid Mark V. , Pearle Gretchen , Gunsburg David Z.
Published: June 2012

Background
—Drugs with negative inotropic effect are widely used to decrease obstruction in hypertrophic cardiomyopathy (HCM). However, the mechanism of therapeutic benefit has not been studied.

Methods and Results
—We used M-mode, two-dimensional, and pulsed Doppler echocardiography to study 11 patients with obstructive HCM before and after medical elimination of left ventricular outflow tract obstruction. We measured 148 digitized pulsed Doppler tracings recorded in the left ventricular cavity 2.5 cm apical of the mitral valve. Successful treatment slowed average acceleration of left ventricular ejection by 34% (
P
=.001). Mean time to peak velocity in the left ventricle was prolonged 31% (
P
=.001). Mean time to an ejection velocity of 60 cm/s was prolonged 91% (
P
=.001). Before treatment, left ventricular ejection velocity peaked in the first half of systole; after successful treatment, it peaked in the second half (
P
=.001). In contrast, after treatment, we found no change in peak left ventricular ejection velocity. We also found no change in the distance between the mitral coaptation point and the septum, as measured in two planes, indicating no treatment-induced alteration of this anatomic relationship.

Conclusions
—Medical treatment eliminates mitral-septal contact and obstruction by decreasing left ventricular ejection acceleration. By slowing acceleration, treatment reduces the hydrodynamic force on the protruding mitral leaflet and delays mitral-septal contact. This, in turn, results in a lower final pressure gradient.
Association of High-Altitude Pulmonary Edema With the Major Histocompatibility Complex
Authors: Hanaoka Masayuki , Kubo Keishi , Yamazaki Yoshitaka , Miyahara Takashige , Matsuzawa Yukinori , Kobayashi Toshio , Sekiguchi Morie , Ota Masao , Watanabe Hideto
Published: June 2012

Background
—A constitutional susceptibility has been suggested in the development of high-altitude pulmonary edema (HAPE) because HAPE generally affects healthy young people, some of whom suffer recurrent episodes. We examined whether immunogenetic susceptibility is present in HAPE-susceptible subjects.

Methods and Results
—The frequencies of human leukocyte antigen (HLA) alleles in 28 male and 2 female subjects with a history of HAPE were compared with those in 100 healthy volunteers. We assayed the HLA-A, -B, -C, -DR, and -DQ antigens serologically. The pulmonary hemodynamics on admission to the hospital and the ventilatory response to hypoxia and hypercapnia were retrospectively examined in 10 of the HAPE-susceptible subjects. HLA-DR6 was positive in 14 (46.7%) of the subjects with HAPE but only 16.0% of the control subjects (
P
=.0005), and HLA-DQ4 was positive in 12 (40.0%) of the subjects with HAPE but only 10.0% of the control subjects (
P
=.0001). HLA-DR6 or HLA-DQ4 was positive in 8 (100%) of the subjects with recurrent HAPE. The pulmonary arterial pressure on admission of the HLA-DR6–positive subjects with HAPE was significantly higher than that of the HLA-DR6–negative subjects with HAPE.

Conclusions
—There were significant associations of HAPE with HLA-DR6 and HLA-DQ4 and of pulmonary hypertension with HLA-DR6. An immunogenetic susceptibility, which is associated with HLA class II alleles located within the major histocompatibility complex, may underlie the development of HAPE, at least in some of its forms.
Elevated Circulating Levels of C-C Chemokines in Patients With Congestive Heart Failure
Authors: Aukrust Pål , Ueland Thor , Müller Fredrik , Andreassen Arne K. , Nordøy Ingvild , Aas Halfdan , Kjekshus John , Simonsen Svein , Frøland Stig S. , Gullestad Lars
Published: June 2012

Background
—Immunologic and inflammatory responses appear to play a pathogenic role in the development of congestive heart failure (CHF). Activation and migration of leukocytes to areas of inflammation are important factors in these immunologic responses. Because the C-C chemokines are potent chemoattractants of monocytes and lymphocytes and can modulate other functions of these cells (eg, generation of reactive oxygen species), we measured circulating levels of three C-C chemokines in CHF.

Methods and Results
—Levels of macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and RANTES (
r
egulated on
a
ctivation
n
ormally
T
-cell
e
xpressed and
s
ecreted) were measured by enzyme immunoassays in 44 patients with CHF and 21 healthy control subjects. CHF patients had significantly elevated levels of all chemokines with the highest levels in New York Heart Association class IV, and MCP-1 and MIP-1α levels were significantly inversely correlated with left ventricular ejection fraction. Elevated C-C chemokine levels were found independent of the cause of the heart failure, but MCP-1 levels were particularly raised in patients with coronary artery disease. Studies on cells isolated from peripheral blood suggested that platelets, CD3+ lymphocytes, and in particular, monocytes, might contribute to the elevated C-C chemokine levels in CHF. The increased MCP-1 levels in CHF were correlated with increased monocyte activity reflected in an enhancing effect of serum from CHF patients on O
2
−
generation in monocytes, which was inhibited by neutralizing antibodies against MCP-1.

Conclusions
—This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.
Regional Myocardial Blood Flow Redistribution as a Cause of Postprandial Angina Pectoris
Authors: Baliga Ragavendra R. , Rosen Stuart D. , Camici Paolo G. , Kooner Jaspal S.
Published: June 2012

Background
—Postprandial angina pectoris has been recognized for more than two centuries and can be identified in up to 10% of patients with chronic ischemic heart disease. Redistribution of myocardial blood flow, from a region supplied by a severely stenotic coronary artery to those supplied by less diseased or normal vessels, is a potential mechanism of postprandial angina.

Methods and Results
—To test this hypothesis, we have determined the effects of a standard liquid meal on whole heart and regional myocardial blood flow, measured by means of dynamic positron emission tomography (PET) with
15
O-labeled water in 14 patients with a reproducible history of postprandial angina and 7 matched control subjects. The standard liquid meal precipitated angina pectoris in all patients. Baseline whole heart blood flow was similar and increased normally after the meal in patients (0.97±0.14 to 1.14±0.25 mL · min
−1
· g
−1
,
P
<.04) as in control subjects (0.92±0.12 to 1.02±0.13 mL · min
−1
· g
−1
,
P
<.02). In contrast, the coefficient of variation of blood flow increased significantly after the standard liquid meal in patients (34±9%,
P
<.05 versus baseline) but not in control subjects (17±7%,
P
=NS versus baseline). In patients, analysis of regional myocardial blood flow demonstrated decreased myocardial blood flow in territories supplied by stenotic arteries (1.01±0.35 to 0.76±0.27 mL · min
−1
· g
−1
,
P
<.03), but there was an increase in blood flow in territories supplied by normal arteries (0.89±0.16 to 1.34±0.25 mL · min
−1
· g
−1
,
P
<.001) after the meal.

Conclusions
—The standard liquid meal induced angina pectoris in patients with coronary artery disease. Although whole heart blood flow increased appropriately for the greater cardiac work, there was a redistribution of regional blood flow from territories supplied by severely stenosed coronary arteries to those supplied by less diseased or normal arteries. This redistribution may be the cause of myocardial ischemia in postprandial angina.
Effects of Cardiac Versus Circulatory Angiotensin-Converting Enzyme Inhibition on Left Ventricular Diastolic Function and Coronary Blood Flow in Hypertrophic Obstructive Cardiomyopathy
Authors: Kyriakidis Michael , Triposkiadis Filippos , Dernellis John , Androulakis Aristides E. , Mellas Panagiotis , Kelepeshis Glafkos A. , Gialafos John E.
Published: June 2012

Background
—Left ventricular (LV) diastolic function and coronary flow are impaired in hypertrophic obstructive cardiomyopathy (HOCM). This study was designed to evaluate the impact of cardiac and circulatory ACE inhibition on such derangements.

Methods and Results
—Twenty patients with HOCM underwent cardiac ACE inhibition with intracoronary (IC) enalaprilat (0.05 mg/min infused into the left anterior descending coronary artery for 15 minutes) followed by circulatory ACE inhibition with 25 mg sublingual (SL) captopril. Contrast ventriculography, pressure, and coronary flow measurements were performed at baseline, after IC enalaprilat infusion, and 45 minutes after SL captopril. Heart rate was not affected by the respective interventions (75±11 versus 76±13 versus 75±10 bpm;
P
=NS), whereas mean aortic pressure dropped slightly after IC enalaprilat and significantly after SL captopril (90±8 versus 85±10 versus 74±9 mm Hg;
P
<.05). Compared with baseline, IC enalaprilat resulted in a decrease in LV end-diastolic pressure (17.6±5.9 versus 14.4±4.9 mm Hg;
P
<.05), time constant of isovolumic LV pressure relaxation (τ
G
) (69±9 versus 52±10 ms;
P
<.05), and outflow gradient (45.2±6.9 versus 24.4±3.7 mm Hg;
P
<.05) and in an increase in coronary blood flow (107±10 versus 127±12 mL/min;
P
<.05) and coronary flow reserve (2.2±0.4 versus 2.6±0.3;
P
<.05). After SL captopril, τ
G
was prolonged (60±13 ms;
P
<.05 versus IC enalaprilat), and LV outflow gradient, coronary blood flow, and coronary flow reserve values returned to baseline (45.5±5.3 mm Hg, 107±12 mL/min, and 2.2±0.5, respectively;
P
=NS versus baseline).

Conclusions
—Activation of the cardiac renin-angiotensin system contributes to LV diastolic dysfunction as well as to the decreased coronary blood flow and coronary flow reserve in HOCM. Cardiac ACE inhibition restores and circulatory ACE inhibition aggravates the above derangements.
Procedural Results and Late Clinical Outcomes After Placement of Three or More Stents in Single Coronary Lesions
Authors: Kornowski Ran , Mehran Roxana , Hong Mun K. , Satler Lowell F. , Pichard Augusto D. , Kent Kenneth M. , Mintz Gary S. , Waksman Ron , Laird John R. , Lansky Alexandra J. , Bucher Theresa A. , Popma Jeffrey J. , Leon Martin B.
Published: June 2012

Background
—Previous reports have suggested higher procedural and long-term complications among patients treated with multiple stents for diffuse lesions and/or long dissections.

Methods and Results
—To evaluate procedural success, major complications, and clinical outcomes (≥1 year) in a consecutive series of patients treated with multiple (≥3) contiguous stents in single lesions, we evaluated in-hospital and long-term (1-year) clinical outcomes in 117 consecutive patients treated with ≥3 coronary stents compared with a concurrent series of patients treated with 1 or 2 stents (n=1673) between January 1, 1994, and December 31, 1995. Multiple stents were implanted more often in larger vessels, in the right coronary artery or saphenous vein grafts, and for unfavorable lesion characteristics, including long (>20 mm), calcified, ulcerated, thrombotic, and/or flow-obstructing lesions. Overall procedural success was obtained in 97.4% of patients and was similar whether 1 or 2 versus ≥3 stents were used. Non–Q-wave MI (CK-MB ≥5 times normal) was more frequent after ≥3 stents (22.8% versus 13.4%,
P
=.005). Target lesion revascularization (TLR) was 14.6% for 1 or 2 stents and 13.3% for ≥3 stents (
P
=.70). There was no difference in death (2.2% versus 0.9%,
P
=.34) or Q-wave MI (1.4% versus 0.9%,
P
=.64) between the two groups (1 or 2 stents versus ≥3 stents, respectively), and overall cardiac event–free survival was similar during follow-up (
P
=.70).

Conclusions
—Patients treated with multiple (≥3) contiguous stents compared with 1 or 2 stents have (1) similar in-hospital procedural success and major complications despite having more unfavorable lesion characteristics, (2) a higher rate of procedural non–Q-wave MI, and (3) similar TLR and overall major cardiac event rates during 1 year of follow-up.
Angiotensin-Converting Enzyme Inhibitors
Authors: Brown Nancy J. , Vaughan Douglas E.
Published: June 2012

Abstract
—ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT
1
receptor antagonists.
Relationship Between Plasma LDL Concentrations During Treatment With Pravastatin and Recurrent Coronary Events in the Cholesterol and Recurrent Events Trial
Authors: Sacks Frank M. , Moyé Lemuel A. , Davis Barry R. , Cole Thomas G. , Rouleau Jean L. , Nash David T. , Pfeffer Marc A. , Braunwald Eugene
Published: June 2012

Background
—Although LDL lowering has been shown to reduce recurrent coronary events in patients with coronary heart disease, little direct information is available on the extent of LDL lowering required to achieve this outcome.

Methods and Results
—The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction (MI) who had average concentrations of total cholesterol <240 mg/dL (baseline mean, 209 mg/dL) and LDL cholesterol (LDL) 115 to 174 mg/dL (mean, 139 mg/dL). Pravastatin reduced coronary death or recurrent MI by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant, although nonlinear, predictor of the coronary event rate (
P
=.007), whereas the extent of LDL reduction was not significant, whether expressed as an absolute amount (
P
=.97) or a percentage (
P
=.76). The coronary event rate declined as LDL decreased during follow-up from 174 to ≈125 mg/dL, but no further decline was seen in the LDL range from 125 to 71 mg/dL. In multivariate analysis, triglyceride but not HDL concentrations during follow-up were weakly but significantly associated with the coronary event rate.

Conclusions
—The LDL concentrations achieved during treatment with pravastatin or placebo were associated with reduction in coronary events down to an LDL concentration of ≈125 mg/dL. LDL concentrations <125 mg/dL during treatment were not associated with further benefit. Absolute or percentage reduction in LDL had little relationship to coronary events.
Increased Matrix Metalloproteinase Activity and Selective Upregulation in LV Myocardium From Patients With End-Stage Dilated Cardiomyopathy
Authors: Thomas Chadwick V. , Coker Mytsi L. , Zellner James L. , Handy John R. , Crumbley A. Jackson , Spinale Francis G.
Published: June 2012

Background
—One of the hallmarks of dilated cardiomyopathy (DCM) is left ventricular (LV) remodeling. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. Additionally, a family of inhibitors called tissue inhibitors of MMPs (TIMPs) has been shown to exist and to tightly regulate MMP activity. However, the types of MMPs and TIMPs expressed within the normal and DCM LV myocardium and the relation to MMP activity remain unexplored.

Methods and Results
—Relative LV myocardial MMP activity was determined in the normal (n=8) and idiopathic DCM (n=7) human LV myocardium by substrate zymography. Relative LV myocardial abundance of interstitial collagenase (MMP-1), stromelysin (MMP-3), 72 kD gelatinase (MMP-2), 92 kD gelatinase (MMP-9), TIMP-1, and TIMP-2 were measured with quantitative immunoblotting. LV myocardial MMP zymographic activity increased with DCM compared with normal (984±149 versus 413±64 pixels,
P
<.05). With DCM, LV myocardial abundance of MMP-1 decreased to 16±6% (
P
<.05), MMP-3 increased to 563±212% (
P
<.05), MMP-9 increased to 422±64% (
P
<.05), and MMP-2 was unchanged when compared with normal. LV myocardial abundance of TIMP-1 and TIMP-2 increased by >500% with DCM. A high-molecular-weight immunoreactive band for both TIMP-1 and TIMP-2, suggesting a TIMP/MMP complex, was increased >600% with DCM.

Conclusions
—This study demonstrated increased LV myocardial MMP activity and evidence for independent regulatory mechanisms of MMP and TIMP expression with DCM. These findings suggest that selective inhibition of MMP species within the LV myocardium may provide a novel therapeutic target in patients with DCM.
Variation in the Region of the Angiotensin-Converting Enzyme Gene Influences Interindividual Differences in Blood Pressure Levels in Young White Males
Authors: Fornage Myriam , Amos Christopher I. , Kardia Sharon , Sing Charles F. , Turner Stephen T. , Boerwinkle Eric
Published: June 2012

Background
—The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance.

Methods and Results
—Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components–based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I–converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (
ACE
) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (
P
=0.04), and 16% (
P
=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [
P
=0.005], and 32% [
P
<0.005], respectively). In sex-specific analyses, genetic variation in the region of the
ACE
gene significantly influenced interindividual blood pressure variation in males (37% for SBP [
P
=0.03], 38% for DBP [
P
=0.04], and 53% for MAP [
P
<0.005]) but not in females.

Conclusions
—Although it is possible that variation in a gene near the
ACE
gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the
ACE
gene itself influences blood pressure variability in a sex-specific manner.