bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging, Habitual Exercise, and Dynamic Arterial Compliance
Authors: Tanaka Hirofumi , Dinenno Frank A. , Monahan Kevin D. , Clevenger Christopher M. , DeSouza Christopher A. , Seals Douglas R.
Published: June 2012

Background
—A reduction in compliance of the large-sized cardiothoracic (central) arteries is an independent risk factor for the development of cardiovascular disease with advancing age.

Methods and Results
—We determined the role of habitual exercise on the age-related decrease in central arterial compliance by using both cross-sectional and interventional approaches. First, we studied 151 healthy men aged 18 to 77 years: 54 were sedentary, 45 were recreationally active, and 53 were endurance exercise–trained. Central arterial compliance (simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) was lower (
P
<0.05) in middle-aged and older men than in young men in all 3 groups. There were no significant differences between sedentary and recreationally active men at any age. However, arterial compliance in the endurance-trained middle-aged and older men was 20% to 35% higher than in the 2 less active groups (
P
<0.01). As such, age-related differences in central arterial compliance were smaller in the endurance-trained men than in the sedentary and recreationally active men. Second, we studied 20 middle-aged and older (53±2 years) sedentary healthy men before and after a 3-month aerobic exercise intervention (primarily walking). Regular exercise increased central arterial compliance (
P
<0.01) to levels similar to those of the middle-aged and older endurance-trained men. These effects were independent of changes in body mass, adiposity, arterial blood pressure, or maximal oxygen consumption.

Conclusions
—Regular aerobic-endurance exercise attenuates age-related reductions in central arterial compliance and restores levels in previously sedentary healthy middle-aged and older men. This may be one mechanism by which habitual exercise lowers the risk of cardiovascular disease in this population.
Thyroid Hormone Coordinates Respiratory Control Maturation and Adenine Nucleotide Translocator Expression in Heart In Vivo
Authors: Portman Michael A. , Xiao Yun , Qian Kun , Tucker Russell L. , Parish Steven M. , Ning Xue-Han
Published: June 2012

Background
—The signal transduction mechanism linking mitochondrial ATP synthesis with cytosolic ATP utilization in heart changes during postnatal development in vivo. This maturational process occurs in parallel with accumulation of mitochondrial adenine nucleotide translocator (ANT), which provides a possible site for respiratory control. We postulated that thyroid hormone regulates these maturational processes.

Methods and Results
—We used
31
P MR spectroscopy to determine the relationship between myocardial high-energy phosphates, phosphocreatine, and ADP and oxygen consumption (MV̇
o
2
) during epinephrine stimulation in 32- to 40-day-old lambs thyroidectomized after birth (THY) and age-matched controls. Steady-state protein and mRNA levels for ANT isoforms and β-F
1
-ATPase were assessed from left ventricular tissues by Western and Northern blotting. With greater doses of epinephrine, THY attained lower peak MV̇
o
2
than controls (
P
<0.05). Controls maintained high-energy phosphate levels, unlike THY, which demonstrated significantly decreased phosphocreatine/ATP and increased cytosolic ADP despite lower peak MV̇
o
2
. No significant differences in β-F
1
-ATPase protein or mRNA occurred between groups. However, ANT isoform mRNA levels were 2-fold greater and protein levels 4-fold greater in control hearts.

Conclusions
—These data imply that the maturational shift away from ADP-mediated respiratory control is regulated by thyroid hormone in vivo. Specific thyroid-modulated increases in ANT mRNA and protein imply that this regulation occurs in part at a pretranslational level.
Physical Activity and Mortality in Older Men With Diagnosed Coronary Heart Disease
Authors: Wannamethee S. Goya , Shaper A. Gerald , Walker M.
Published: June 2012

Background
—We have studied the relations between physical activity, types of physical activity, and changes in physical activity and all-cause mortality in men with established coronary heart disease (CHD).

Methods and Results
—In 1992, 12 to 14 years after the initial screening (Q1) of 7735 men 40 to 59 years of age from general practices in 24 British towns, 5934 (91% of available survivors, mean age 63 years) provided further information on physical activity (Q92) and were followed up for 5 years; 963 had a physician’s diagnosis of CHD (myocardial infarction or angina). After exclusions, there were 772 men with established CHD, 131 of whom died of all causes. The lowest risks for all-cause and cardiovascular mortality were seen in light and moderate activity groups (adjusted relative risk compared with inactive/occasionally active: light, 0.42 (0.25, 0.71); moderate, 0.47 (0.24, 0.92); and moderately vigorous/vigorous, 0.63 (0.39, 1.03). Recreational activity of ≥4 hours per weekend, moderate or heavy gardening, and regular walking (>40 min/d) were all associated with a significant reduction in all-cause mortality. Nonsporting activity was more beneficial than sporting activities. Men sedentary at Q1 who began at least light activity by Q92 showed lower mortality rates on follow-up than those who remained sedentary ( relative risk 0.58, 95% CI 0.33 to 1.03;
P
=0.06).

Conclusions
—Light or moderate activity in men with established CHD is associated with a significantly lower risk of all-cause mortality. Regular walking and moderate or heavy gardening were sufficient to achieve this benefit.
Congenital Deficiency of Nitric Oxide Synthase 2 Protects Against Endotoxin-Induced Myocardial Dysfunction in Mice
Authors: Ullrich Roman , Scherrer-Crosbie Marielle , Bloch Kenneth D. , Ichinose Fumito , Nakajima Hiroshi , Picard Michael H. , Zapol Warren M. , Quezado Zenaide M. N.
Published: June 2012

Background
—Sepsis can be complicated by severe myocardial dysfunction and is associated with increased nitric oxide (NO) production by inducible NO synthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocardial dysfunction in vivo, we studied wild-type and NOS2-deficient mice.

Methods and Results
—Serial echocardiographic parameters of myocardial function were measured before and at 4, 7, 16, and 24 hours after an endotoxin challenge. Seven hours after challenge with either endotoxin or saline, systemic and left ventricular pressures were measured, and the first derivative of left ventricular developed pressure (dP/dt), slope of the end-systolic pressure–dimension relationship (Slope
LVESPD
), and time constant of isovolumic relaxation (τ) were calculated. Endotoxin challenge in wild-type mice decreased left ventricular fractional shortening, velocity of circumferential shortening, dP/dt
max
, Slope
LVESPD
, and dP/dt
min
and increased time constant τ. Endotoxin-induced myocardial dysfunction was associated with increased ventricular NOS2 gene expression and cGMP concentrations. Seven hours after endotoxin challenge, NOS2-deficient mice had greater fractional shortening, dP/dt
max
, and Slope
LVESPD
than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt
min
and time constant τ, were preserved in endotoxin-challenged NOS2-deficient mice. After endotoxin challenge in wild-type mice, early (3-hour) inhibition of NOS2 with
l
-
N
6
-(1-iminoethyl)lysine hydrochloride prevented, whereas later (7-hour) inhibition could not reverse, endotoxin-induced myocardial dysfunction.

Conclusions
—These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.
Electrical, Morphological, and Ultrastructural Remodeling and Reverse Remodeling in a Canine Model of Chronic Atrial Fibrillation
Authors: Everett Thomas H. , Li Hui , Mangrum J. Michael , McRury Ian D. , Mitchell Mark A. , Redick Jan A. , Haines David E.
Published: June 2012

Background
—In patients with recurrent persistent atrial fibrillation (AF), vulnerability to AF persists indefinitely despite presumed completion of reverse electrical remodeling within days of return to normal sinus rhythm. Atrial electrical and anatomic remodeling and reverse remodeling were studied in a canine model of chronic AF.

Methods and Results
—Chronic AF was induced in 8 dogs by creating moderate mitral regurgitation and rapidly pacing the right atrium at 640 bpm for >8 weeks. Measurements performed at baseline, after establishment of chronic AF, and then at 4 hours and again at 7 to 14 days after cardioversion to sinus rhythm included atrial effective refractory periods, AF cycle lengths, left atrial dimensions, premature atrial contraction (PAC) frequency, and atrial vulnerability to atrial extrastimuli. After establishing chronic AF, atrial effective refractory period shortening, increases in spontaneous PAC frequency, increases in left atrial size with loss of contractility, and multiple ultrastructural abnormalities were demonstrated. Complete reverse electrical remodeling and decreases in PACs were observed after 7 to 14 days of sinus rhythm, but there was no resolution of anatomic and ultrastructural abnormalities. Occurrence of spontaneous AF paralleled PAC frequency, but vulnerability to AF induction persisted (75% immediately after conversion versus 63% at 4 hours and 50% at 7 to 14 days) despite reverse electrical remodeling.

Conclusions
—After conversion from chronic AF to sinus rhythm in this canine model, electrical remodeling occurs rapidly. However, gross and ultrastructural anatomic changes persist, as does vulnerability to induced AF. Vulnerability to AF initiation 7 to 14 days after cardioversion is more dependent on persisting structural abnormalities than on electrophysiological abnormalities.
Sympathetic Activity and Baroreflex Sensitivity in Young Women Taking Oral Contraceptives
Authors: Minson Christopher T. , Halliwill John R. , Young Tamica M. , Joyner Michael J.
Published: June 2012

Background
—We tested sympathetic and cardiovagal baroreflex sensitivity during the placebo or “low-hormone” phase (LH) and 2 to 3 weeks later during the “high-hormone” phase (HH) of oral contraceptive (OC) use in 9 women.

Methods and Results
—Sympathetic baroreflex sensitivity was assessed by intravenous doses of sodium nitroprusside and phenylephrine and defined as the slope relating muscle sympathetic nerve activity (by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. No difference was observed for resting muscle sympathetic nerve activity or plasma norepinephrine levels. However, sympathetic baroreflex sensitivity was greater and mean arterial pressure was higher during the LH than in the HH phase. Similarly, cardiovagal baroreflex sensitivity was greater in the LH than in the HH phase.

Conclusions
—Sympathetic and cardiovagal baroreflex sensitivities change during the 28-day course of OC use. Furthermore, changes in baroreflex sensitivity with OC differ from changes in baroreflex sensitivity during the normal menstrual cycle.
Predictors of Atrial Fibrillation After Conventional and Beating Heart Coronary Surgery
Authors: Ascione Raimondo , Caputo Massimo , Calori Giliola , Lloyd Clinton T. , Underwood Malcom J. , Angelini Gianni D.
Published: June 2012

Background
—Atrial fibrillation (AF) increases the morbidity of CABG. The pathophysiology is uncertain, and its prevention remains suboptimal. This prospective, randomized study was designed to define the role of cardiopulmonary bypass (CPB) and cardioplegic arrest in the pathogenesis of this complication.

Methods and Results
—Two hundred patients were prospectively randomized to (1) on-pump conventional surgery [(100 patients, 79 men, mean age 63 (40 to 77) years)] with normothermic CPB and cardioplegic arrest of the heart or (2) off-pump surgery [(100 patients, 82 men, mean age 63 (38 to 86) years)] on the beating heart. Heart rate and rhythm were continuously monitored with an automated arrhythmia detector during the first 72 hours after surgery. Thereafter, routine clinical observation was performed and continuous monitoring restarted in the case of arrhythmia. The association of perioperative factors with AF was investigated by univariate analysis. Significant variables were then included into a stepwise logistic regression model to ascertain their independent influence on the occurrence of AF. There were no significant baseline differences between groups. Thirty-nine patients in the on-pump group and 8 patients in the off-pump group had postoperative sustained AF (
P
=0.001). Univariate analysis showed that CPB inclusive of cardioplegic arrest, postoperative inotropic support, intubation time, chest infection, and hospital length of stay were predictors of AF (all
P
<0.05). However, stepwise multivariate regression analysis identified CPB inclusive of cardioplegic arrest as the only independent predictor of postoperative AF (OR 7.4; CI 3.4 to 17.9).

Conclusions
—CPB inclusive of cardioplegic arrest is the main independent predictor of postoperative AF in patients undergoing coronary revascularization.
Lipoprotein Lipase Activity Is Associated With Severity of Angina Pectoris
Authors: Kastelein John J. P. , Jukema J. Wouter , Zwinderman Aeilko H. , Clee Suzanne , van Boven Ad J. , Jansen Hans , Rabelink Ton J. , Peters Ron J. G. , Lie Kong I. , Liu George , Bruschke Albert V. G. , Hayden Michael R.
Published: June 2012

Background
—Raised triglyceride-rich lipoproteins significantly increase the risk for cardiovascular disease. Variation in the activity of the enzyme lipoprotein lipase (LPL), which is crucial in the removal of these lipoproteins, may therefore modulate this risk.

Methods and Results
—Postheparin levels of LPL activity and mass were measured in a large cohort of male coronary artery disease patients participating in the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering regression trial. In addition, the relationships between LPL activity and mass and severity of angina pectoris according to the NYHA classification and silent ischemia on 24-hour ambulatory ECG monitoring were assessed. Patients in different LPL activity quartiles and mass had different severities of angina; a total of 47% of patients in the lowest LPL quartile reported class III or IV angina. In contrast, only 29% in the highest activity quartile (
P
=0.002) had severe angina. These parameters were supported by ambulatory ECG results, for which the total ischemic burden in the lowest LPL activity quartile was 36.5±104.1 mm×min compared with 14.8±38.8 mm×min in the highest quartile of LPL activity (
P
=0.001). LPL activity levels were strongly correlated with LPL mass (
r
=0.70,
P
<0.0001). A significant association between the LPL protein mass and NYHA class (
P
=0.012) was also demonstrated.

Conclusions
—We have demonstrated a significant relationship between LPL mass and activity and severity of ischemia as defined by angina class and ambulatory ECG. These results suggest that LPL influences risk for coronary artery disease by both catalytic and noncatalytic mechanisms.
Homozygosity for 807 T Polymorphism in α
2
Subunit of Platelet α
2
β
1
Is Associated With Increased Risk of Cardiovascular Mortality in High-Risk Women
Authors: Roest Mark , Banga Jan Dirk , Grobbee Diederick E. , de Groot Philip G. , Sixma Jan J. , Tempelman Mariëlle J. , van der Schouw Yvonne T.
Published: June 2012

Background
—Platelet adhesion to collagen is the initial step in both hemostasis and thrombosis; this adhesion is mediated by α
2
β
1
on the surface of platelet membranes. An 807 C to T single nucleotide exchange polymorphism close to the gene coding for the α
2
subunit of α
2
β
1
is associated with the density of α
2
β
1
on the platelet membrane.

Methods and Results
—We studied the relation of the α
2
β
1
807 C/T genotype to cardiovascular mortality in a prospective cohort study of 12 239 women who were invited for the breast cancer screening program of Utrecht, the Netherlands. The initial age was between 52 and 67 years. Women were followed on vital status between 1976 and 1995 (168 513 women-years). Data were analyzed by using a nested case-control design. The α
2
β
1
807 C/T genotype was not associated with cardiovascular mortality in the total population: the rate ratio for cardiovascular mortality in 807 TT homozygotes compared with 807 CC wild types was 1.2 (95% CI 0.8 to 1.7). However, the α
2
β
1
807 T polymorphism was associated with an increased risk of cardiovascular mortality in women who smoked or in women who had indications of compromised endothelium, such as diabetes and microalbuminuria. In those who were exposed to ≥2 of these factors, the risk ratio (95% CI) between α
2
β
1
807 TT homozygotes and 807 CC wild types was 14.1 (5.0 to 39.9).

Conclusions
—α
2
β
1
807 TT homozygosity, coding for increased α
2
β
1
density on the platelet membrane, is associated with an increased risk of cardiovascular mortality in those women with indications of compromised endothelium.
Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue
Authors: Qu Zhilin , Garfinkel Alan , Chen Peng-Sheng , Weiss James N.
Published: June 2012

Background
—T-wave alternans, which is associated with the genesis of cardiac fibrillation, has recently been related to discordant action potential duration (APD) alternans. However, the cellular electrophysiological mechanisms responsible for discordant alternans are poorly understood.

Methods and Results
—We simulated a 2D sheet of cardiac tissue using phase 1 of the Luo-Rudy cardiac action potential model. A steep (slope >1) APD restitution curve promoted concordant APD alternans and T-wave alternans without QRS alternans. When pacing was from a single site, discordant APD alternans occurred only when the pacing rate was fast enough to engage conduction velocity (CV) restitution, producing both QRS and T-wave alternans. Tissue heterogeneity was not required for this effect. Discordant alternans markedly increases dispersion of refractoriness and increases the ability of a premature stimulus to cause localized wavebreak and induce reentry. In the absence of steep APD restitution and of CV restitution, sustained discordant alternans did not occur, but reentry could be induced if there was marked electrophysiological heterogeneity. Both discordant APD alternans and preexisting APD heterogeneity facilitate reentry by causing the waveback to propagate slowly.

Conclusion
—Discordant alternans arises dynamically from APD and CV restitution properties and markedly increases dispersion of refractoriness. Preexisting and dynamically induced (via restitution) dispersion of refractoriness independently increase vulnerability to reentrant arrhythmias. Reduction of dynamically induced dispersion by appropriate alteration of electrical restitution has promise as an antiarrhythmic strategy.
Electrical Remodeling of the Atria Associated With Paroxysmal and Chronic Atrial Flutter
Authors: Sparks Paul B. , Jayaprakash Shenthar , Vohra Jitendra K. , Kalman Jonathan M.
Published: June 2012

Background
—Atrial electrical remodeling may be important for the initiation and perpetuation of atrial arrhythmias. Whether paroxysmal atrial flutter (AFL) and chronic AFL cause electrical remodeling of the atria has not been conclusively determined.

Methods and Results
—Before radiofrequency ablation of paroxysmal AFL, 15 patients in sinus rhythm were evaluated under autonomic blockade. Lateral right atrial (LRA) effective refractory periods (ERPs) at 600 and 450 ms were measured before and at 1-minute intervals for 10 minutes after spontaneous or pace termination of a 5- to 10-minute period of induced AFL. In 10 patients with chronic AFL, LRA, septal, and coronary sinus (CS) ERPs and corrected sinus node recovery times (cSNRTs) at 600 and 450 ms were measured under autonomic blockade 15 minutes, 30 minutes, and 3 weeks after termination of chronic AFL by ablation. In the paroxysmal AFL group, LRA ERPs decreased by 18% at 600 ms and 12% at 450 ms (
P
<0.01) after induced AFL and recovered to baseline over ≈5 minutes. Atrial fibrillation developed during AFL in 3 patients and during ERP testing in 3 patients when refractoriness was at its nadir. In the chronic AFL group, LRA, septal, and CS ERPs at 3 weeks were significantly greater than at 15 and 30 minutes after termination of chronic AFL at both cycle lengths (
P
<0.01). Three weeks after ablation, cSNRT decreased 35% at 600 ms (
P
<0.05) and decreased 44% at 450 ms (
P
<0.05). Both ERPs and cSNRTs measured 15 and 30 minutes after ablation of chronic AFL were not significantly different.

Conclusions
—Both paroxysmal AFL and chronic AFL cause reversible electrical remodeling of the atria but demonstrate different time courses of recovery.
Peroxisome Proliferator-Activated Receptor γ Activators Downregulate Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells
Authors: Takeda Kotaro , Ichiki Toshihiro , Tokunou Tomotake , Funakoshi Yuko , Iino Naoko , Hirano Katsuya , Kanaide Hideo , Takeshita Akira
Published: June 2012

Background
—Peroxisome proliferator-activated receptor γ (PPARγ) activators, such as troglitazone (Tro), not only improve insulin resistance but also suppress the neointimal formation after balloon injury. However, the precise mechanisms have not been determined. Angiotensin II (Ang II) plays crucial roles in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after angioplasty. We examined the effect of PPARγ activators on the expression of Ang II type 1 receptor (AT
1
-R) in cultured vascular smooth muscle cells (VSMCs).

Methods and Results
—AT
1
-R mRNA and AT
1
-R protein levels were determined by Northern blot analysis and radioligand binding assay, respectively. Natural PPARγ ligand 15-deoxy-Δ
12,14
-prostaglandin J
2
, as well as Tro, reduced the AT
1
-R mRNA expression and the AT
1
-R protein level. The PPARγ activators also reduced the calcium response of VSMCs to Ang II. PPARγ activators suppressed the AT
1
-R promoter activity measured by luciferase assay but did not affect the AT
1
-R mRNA stability, suggesting that the suppression occurs at the transcriptional level.

Conclusions
—PPARγ activators reduced the AT
1
-R expression and calcium response to Ang II in VSMCs. Downregulation of AT
1
-R may contribute to the inhibition of neointimal formation by PPARγ activators.
Acute Endothelin-A Receptor Antagonism Prevents Normal Reduction of Myocardial Ischemia on Repeated Balloon Inflations During Angioplasty
Authors: Kyriakides Zenon S. , Kremastinos Dimitrios Th. , Kolettis Theofilos M. , Tasouli Androniki , Antoniadis Aias , Webb David J.
Published: June 2012

Background
—Myocardial ischemia and reperfusion are associated with increased production of endothelin (ET)-1.

Methods and Results
—We examined the effects of BQ-123, a selective ET
A
receptor antagonist, in 80 patients. All patients were randomly allocated to an intracoronary infusion of saline or BQ-123 (6 μmol/L over 20 minutes). The reference group consisted of 20 patients undergoing coronary angiography. BQ-123 produced a 10% (
P
<0.005) increase in distal coronary artery diameter. The main study group consisted of 30 patients undergoing coronary angioplasty. All patients underwent a minimum of 3 balloon inflations (BIs). Surface and intracoronary electrocardiographic ST-segment shift as well as pain score were recorded at the end of each BI. BQ-123 or saline was given by intracoronary infusion between the second and the third BI in random allocation. In the saline group, intracoronary ST-elevation decreased from 1.26±0.55 mV during the first BI to 0.77±0.56 mV during the third BI (
P
<0.05) and the surface ST elevation decreased from 0.20±0.15 to 0.10±0.07 mV (
P
<0.05). In the BQ-123 group, the respective values were 1.22±0.48 mV and 1.13±0.62 mV (intracoronary) and 0.17±0.18 and 0.17±0.21 mV (surface) (both
P
=NS). The decrease in pain score was significantly higher in the saline group (
F
=5.97,
P
=0.004). In 30 patients (collateral circulation group), the angioplasty protocol was repeated with the use of a pressure guide wire. BQ-123 produced a significant (
F
=3.30,
P
=0.04) decrease in coronary wedge pressure.

Conclusions
—Acute ET
A
receptor antagonism prevents the normal reduction of myocardial ischemia on repeated BIs during angioplasty. This may be explained by a “steal” effect through coronary collaterals.
Homozygous Mutation in Cardiac Troponin T
Authors: Ho Carolyn Y. , Lever Harry M. , DeSanctis Roman , Farver Carol F. , Seidman J. G. , Seidman Christine E.
Published: June 2012

Background
—Mutations in the gene that encode cardiac troponin T (cTnT) account for ≈15% of cases of familial hypertrophic cardiomyopathy (HCM). These mutations are associated with a particularly severe form of HCM characterized by a high incidence of sudden death and a poor overall prognosis, despite subclinical or mild left ventricular hypertrophy.

Methods and Results
—We evaluated a family with HCM and multiple occurrences of sudden death in children. DNA samples were isolated from peripheral blood or paraffin-embedded tissue, and all protein-encoding exons of the cTnT gene were sequenced. A mutation was identified in exon 11 and is predicted to substitute a phenylalanine-for-serine mutation at residue 179 (Ser
179
Phe) in cTnT. Both parents and 3 of 4 surviving and clinically unaffected children were heterozygous for this mutation; another clinically unaffected child did not carry the mutation. Genetic analysis of DNA from a child who died suddenly at age 17 years demonstrated he was homozygous for this mutation. A review of his echocardiogram revealed profound left and right ventricular hypertrophy.

Conclusions
—An homozygous Ser
179
Phe mutation in cTnT causes a severe form of HCM characterized by striking morphological abnormalities and juvenile lethality. In contrast, the natural history of the heterozygous mutation is benign. These studies emphasize the relevance of genetic diagnosis in hypertrophic cardiomyopathy and provide a new perspective on the clinical consequences of troponin T mutations.
Na
+
/H
+
Exchange Inhibitor Cariporide Attenuates Cell Injury Predominantly During Ischemia and Not at Onset of Reperfusion in Porcine Hearts With Low Residual Blood Flow
Authors: Klein Hermann H. , Pich Sibylle , Bohle Rainer M. , Lindert-Heimberg Stephanie , Nebendahl Klaus
Published: June 2012

Background
—This study investigated whether myocardial protection by inhibition of Na
+
/H
+
exchange (NHE) occurs during ischemia and/or during reperfusion.

Methods and Results
—The left anterior descending coronary artery was occluded in 32 pigs for 60 minutes and then reperfused for 24 hours. Infarct sizes (nitroblue tetrazolium [NBT] stain, histology) were determined at the end of the experiments. An extracorporeal bypass was used to achieve a constant residual blood flow of 3 mL/min in the myocardium at risk during ischemia. The NHE-1 inhibitor cariporide or distilled water was infused into the extracorporeal bypass system. In group 1, active treatment was administered from the onset of ischemia until 10 minutes of reperfusion (n=8). In group 2, active treatment was infused during the first 30 minutes of ischemia only (n=8). The group 3 animals (n=8) received intracoronary cariporide after 45 minutes of ischemia until 10 minutes of reperfusion. The control animals (group 4, n=7) were treated similarly to group 1 animals, with the cariporide solution being replaced by distilled water. Infarct sizes of group 1 (NBT stain, 41.5±20%; histology, 44.6±12%) and group 2 (NBT stain, 33.5±14%; histology 34.9±15%) differed significantly (at least
P
=0.012) from infarct sizes of group 3 (NBT stain, 71.6±15%; histology, 69.2±12%) and the control group (NBT stain, 76±9%; histology 72.4±12%). Cariporide treatment in group 1 and group 2 significantly improved functional recovery after 24 hours of reperfusion.

Conclusions
—Myocardial protection by cariporide is predominantly achieved by NHE inhibition during ischemia and not during early reperfusion.
Effects of Dopamine β-Hydroxylase Inhibition With Nepicastat on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure
Authors: Sabbah Hani N. , Stanley William C. , Sharov Victor G. , Mishima Takayuki , Tanimura Mitsuhiro , Benedict Claude R. , Hegde Sharath , Goldstein Sidney
Published: June 2012

Background
—Inhibition of dopamine β-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF).

Methods and Results
—Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus–arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86±20 versus 13±14 pg/mL,
P
<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28±4 and 39±17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3±10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not

Conclusions
—In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.
Quantitative General Theory for Periodic Breathing in Chronic Heart Failure and its Clinical Implications
Authors: Francis Darrel P. , Willson Keith , Davies L. Ceri , Coats Andrew J.S. , Piepoli Massimo
Published: June 2012

Background
—In patients with chronic heart failure (CHF), periodic breathing (PB) predicts poor prognosis. Clinical studies have identified numerous risk factors for PB (which also includes Cheyne-Stokes respiration). Computer simulations have shown that oscillations can arise from delayed negative feedback. However, no simple general theory quantitatively explains PB and its mechanisms of treatment using widely-understood clinical concepts. Therefore, we introduce a new approach to the quantitative analysis of the dynamic physiology governing cardiorespiratory stability in CHF.

Methods and Results
—An algebraic formula was derived (presented as a simple 2D plot), enabling prediction from easily acquired clinical data to determine whether respiration will be unstable. Clinical validation was performed in 20 patients with CHF (10 with PB and 10 without) and 10 healthy normal subjects. Measurements, including chemoreflex sensitivity (S) and delay (δ), alveolar volume (V
L
), and end-tidal CO
2
fraction (C̄), were applied to the stability formula. The breathing pattern was correctly predicted in 28 of the 30 subjects. The principal combined parameter (C̄S)×(δ/V
L
) was higher in patients with PB (14.2±3.0) than in those without PB (3.1±0.5;
P
=0.0005) or in normal controls (2.4±0.5;
P
=0.0003). This was because of differences in both chemoreflex sensitivity (1749±235 versus 620±103 and 526±104 L/min per atm CO
2
;
P
=0.0001 and
P
<0.0001, respectively) and chemoreflex delay (0.53±0.06 vs 0.40±0.06 and 0.30±0.04 min;
P
=NS and
P
=0.02).

Conclusion
—This analytical approach identifies the physiological abnormalities that are important in the genesis of PB and explicitly defines the region of predicted instability. The clinical data identify chemoreflex gain and delay time (rather than hyperventilation or hypocapnia) as causes of PB.
Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats
Authors: Sakata Yasushi , Masuyama Tohru , Yamamoto Kazuhiro , Nishikawa Nagahiro , Yamamoto Hideyuki , Kondo Hiroya , Ono Keiko , Otsu Kinya , Kuzuya Tsunehiko , Miwa Takeshi , Takeda Hiroshi , Miyamoto Eishichi , Hori Masatsugu
Published: June 2012

Background
—There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.

Methods and Results
—Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg · kg
−
1
· d
−
1
) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.

Conclusions
—Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.
Striking Increase of Natriuresis by Low-Dose Spironolactone in Congestive Heart Failure Only in Combination With ACE Inhibition
Authors: Bauersachs J. , Fraccarollo D. , Ertl G. , Gretz N. , Wehling M. , Christ M.
Published: June 2012

Background
—A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the mineralocorticoid receptor antagonist spironolactone to ACE inhibition. The aim of the present study was to examine a hypothesized interaction of spironolactone and ACE inhibitors in renal electrolyte and volume regulation.

Methods and Results
—Wistar rats with extensive myocardial infarction or sham operation were treated with either placebo, the ACE inhibitor trandolapril, low-dose spironolactone, or a combination of the 2. Twelve weeks after infarction, rats were housed in metabolic cages. Urinary volume and sodium excretion were significantly increased in CHF rats on a combined treatment with spironolactone and trandolapril (21.2±2.6 mL/d, 2489±320 mmol/d, mean±SD;
P
<0.05 versus other experimental groups) versus placebo-treated rats (16.7±5.6 mL/d, 1431±458 mmol/d),whereas these parameters were not affected in rats on either spironolactone (16.1±6.6 mL/d, 1153±273 mmol/d) or trandolapril alone (15.9±4.2 mL/d, 1392±294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone (10.8±8.2 mm Hg;
P
<0.05 versus CHF placebo: 23.3±7.2 mm Hg; sham-operated rats: 5.1±0.9 mm Hg), whereas LVEDP remained elevated in rats treated with either compound alone.

Conclusions
—In the present study, we found an unexpected interaction of low-dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may explain the beneficial effects of spironolactone in CHF patients.
Oral Magnesium Therapy Improves Endothelial Function in Patients With Coronary Artery Disease
Authors: Shechter Michael , Sharir Michael , Labrador Maura J. Paul , Forrester James , Silver Burton , Bairey Merz C. Noel
Published: June 2012

Background
—Magnesium blocks many of the physiological actions of calcium. Nevertheless, the impact of magnesium supplementation on endothelial function and exercise tolerance in stable coronary artery disease (CAD) patients has not been assessed.

Methods and Results
—In a randomized, double-blind, placebo-controlled trial, 50 stable CAD patients (41 men and 9 women, mean±SD age 67±11 years, age range 42 to 82 years) were randomized to receive either magnesium (n=25) (30 mmol/d Magnosolv-Granulat; Asta Medica Company, Inc) or placebo (n=25) for 6 months. Before and after 6 months, endothelium-dependent brachial artery flow-mediated vasodilation (FMD) and endothelium-independent NTG-mediated vasodilation were assessed with high-resolution (10-MHz) ultrasound. Exercise stress testing was performed with use of the Bruce protocol. Intracellular magnesium concentrations ([Mg
2+
]
i
) were assessed from sublingual cells through x-ray dispersion (EXA) (normal mean±SD values 37.9±4.0 mEq/L). The magnesium therapy significantly increased postintervention ([Mg
2+
]
i
versus placebo (36.2±5.0 versus 32.7±2.7 mEq/L,
P
<0.02). There was a significant correlation in the total population between baseline [Mg
2+
]
i
and baseline FMD (
r
=0.48,
P
<0.01). The magnesium intervention resulted in a significant improvement in postintervention FMD (15.5±12.0%,
P
=0.02 compared with baseline), which was not evident with placebo (4.4±2.5%,
P
=0.78 compared with baseline). There was better exercise tolerance (9.3±2.0 versus 7.3±3.1 minutes,
P
=0.05) and less ischemic ST-segment changes (4 versus 10 patients,
P
=0.05) in the magnesium versus placebo groups, respectively.

Conclusions
—Oral magnesium therapy in CAD patients is associated with significant improvement in brachial artery endothelial function and exercise tolerance, suggesting a potential mechanism by which magnesium could beneficially alter outcomes in CAD patients.
Endothelial Activation in Patients With Cardiac Syndrome X
Authors: Desideri Giovambattista , Gaspardone Achille , Gentile Marco , Santucci Anna , Gioffrè Pier Agostino , Ferri Claudio
Published: June 2012

Background
—The presence of endothelial dysfunction with increased endothelin-1 plasma concentrations in patients with cardiac syndrome X is still under debate. The aim of the present study was to evaluate the presence of endothelial dysfunction in patients with cardiac syndrome X.

Methods and Results
—Endothelin-1 levels were evaluated with a sensitive radioimmunoassay with previous purification through reverse phase HPLC in 24 patients (3 men and 21 women, mean age 54±7 years) with typical angina, instrumental evidence of ischemia, and normal coronary angiograms both under baseline conditions and after oral glucose load (75 g
d
-glucose). We also measured plasma nitrite-plus-nitrate levels, a sharp index of endothelial nitric oxide production, and circulating concentrations of the soluble fraction of the endothelial adhesion molecule vascular cell adhesion molecule-1, a well-recognized marker of early endothelial dysfunction. Fourteen healthy subjects (1 man and 13 women, mean age 47±15 years) served as controls. There were no significant differences in baseline plasma endothelin-1 concentrations between patients and control subjects (0.55±0.34 versus 0.48±0.22 pg/mL,
P
=0.503). Plasma nitrite-plus-nitrate and soluble vascular cell adhesion molecule-1 concentrations were also similar between the 2 groups. After glucose ingestion, circulating endothelin-1 concentrations were significantly higher in patients with cardiac syndrome X than in control subjects (
P
<0.03 at 60, 90, and 120 minutes).

Conclusions
—Our findings show that no basal endothelial damage is present in patients with cardiac syndrome X. Nevertheless, increased responsiveness of endothelin-1 to glucose loading suggests that patients with cardiac syndrome X present an increased susceptibility to releasing endothelin-1 under stressful circumstances.
Long-Term Effects on Clinical Outcomes of Aggressive Lowering of Low-Density Lipoprotein Cholesterol Levels and Low-Dose Anticoagulation in the Post Coronary Artery Bypass Graft Trial
Authors: Knatterud Genell L. , Rosenberg Yves , Campeau Lucien , Geller Nancy L. , Hunninghake Donald B. , Forman Sandra A. , Forrester James S. , Gobel Fredarick L. , Herd J. Alan , Hickey Ann , Hoogwerf Byron J. , Terrin Michael L. , White Carl
Published: June 2012

Background
—The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression.

Methods and Results
—Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up,
P
=0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed,
P
=0.008 and 0.003, respectively.

Conclusions
—The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.
Insertion/Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene Is Not Associated With Restenosis After Coronary Stent Placement
Authors: Koch Werner , Kastrati Adnan , Mehilli Julinda , Böttiger Corinna , von Beckerath Nicolas , Schömig Albert
Published: June 2012

Background
—The renin-angiotensin system is thought to play a role in coronary thrombosis and restenosis. Plasma angiotensin I-converting enzyme (ACE) activity is associated with an insertion/deletion polymorphism in the gene coding for ACE. The objective of this study was to test the hypothesis that the D allele of the ACE gene is associated with a higher risk for restenosis after coronary stent placement.

Methods and Results
—This prospective study included 1850 consecutive patients with coronary artery disease who underwent intracoronary stent implantation. The adverse clinical events recorded were death, myocardial infarction, and target vessel revascularization. The primary end point of the study was restenosis (≥50% diameter stenosis at follow-up angiography performed in 84% of the patients). The secondary end point was clinical outcome 1 year after the procedure. The restenosis rate at the 6-month angiographic follow-up was 32.8% in patients with the II genotype, 34.0% for patients with the ID genotype, and 31.2% for patients with the DD genotype (
P
=0.62). One-year event-free survival was 77.7% in patients with genotype II, 75.2% in patients with genotype ID, and 75.5% in patients with genotype DD (
P
=0.54). The lack of association was also present in the subgroup of patients with a low risk for restenosis: the restenosis rate was 21.7% in II carriers, 23.4% in ID carriers, and 19.7% in DD carriers (
P
=0.83).

Conclusions
—The ACE DD genotype or D allele does not influence the 1-year clinical and angiographic outcome of patients undergoing coronary stent placement. These data suggest that routine determination of the ACE genotype may not help identify patients who are at a higher risk of thrombotic and restenotic events after coronary stent placement.
Glycoprotein IIb/IIIa Receptor Blockade Improves Outcomes in Diabetic Patients Presenting With Unstable Angina/Non–ST-Elevation Myocardial Infarction
Authors: Théroux Pierre , Alexander Joe , Pharand Chantal , Barr Eliav , Snapinn Steven , Ghannam Asma F. , Sax Frederic L.
Published: June 2012

Background
—Diabetic patients who present with unstable angina or non–ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor–mediated inhibition of platelet aggregation by tirofiban.

Methods and Results
—Of the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), ≈23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14.8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%,
P
=0.03; 1.2% versus 9.3%,
P
=0.005; 4.7% versus 15.5%,
P
=0.002; and 11.2% versus 19.2%,
P
=0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant.

Conclusions
—The addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non–ST-elevation MI.
Effects of Sildenafil Citrate (Viagra) Combined With Nitrate on the Heart
Authors: Ishikura Fuminobu , Beppu Shintaro , Hamada Toshiaki , Khandheria Bijoy K. , Seward James B. , Nehra Ajay
Published: June 2012

Background
—Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking sildenafil citrate combined with nitroglycerin. We studied the effect of sildenafil citrate on the relationship between changes in systemic blood pressure and coronary blood flow.

Methods and Results
—Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg sildenafil citrate was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with sildenafil citrate was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after sildenafil citrate. Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0±5.8 to 24.6±8.7 mL/min 1 hour after administration of sildenafil citrate. The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after sildenafil citrate were significantly larger and longer than those before sildenafil citrate.

Conclusions
—Sildenafil citrate had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis.