bluuebunny/crossref_metadata_2025 huggingface dataset:
Index Matching to Improve Optical Coherence Tomography Imaging Through Blood
Authors: Brezinski Mark , Saunders Kathleen , Jesser Christine , Li Xingde , Fujimoto James
Published: June 2012

Background
—Most myocardial infarctions are caused by the rupture of small rather than large plaques in the arteries of the heart that are beyond the detection limit of current technologies.

Methods and Results
—Recently, optical coherence tomography (OCT) has demonstrated considerable potential as a method for high-resolution assessment of vulnerable plaque. However, intravascular OCT imaging is complicated by the need to remove blood from the imaging field because blood results in substantial signal attenuation. This work examines index matching as a method for increasing penetration. Index matching is based on the hypothesis that the predominant source of scattering in blood is the difference in refractive index between the cytoplasm of erythrocytes and serum. By increasing the refractive index of serum to a value near that of the cytoplasm, or index matching, scattering can be substantially reduced. The concept was tested with a system that pumped blood in vitro through transparent tubing. The test compounds, dextran and intravenous contrast agent, both led to significant improvements in penetration (69±12% and 45±4%). No significant effect was seen with the saline control. For dextran, the effect could not be attributed to reductions of red cell number or volume because changes in these parameters were not different from the control. In the case of intravenous contrast, a small but significant relative reduction in red cell volume was seen.

Conclusions
—This study demonstrates the feasibility of index matching for improving OCT imaging through blood. Future studies are required to identify compounds for effective index matching in vivo.
Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic
Authors: Hondeghem L. M. , Carlsson L. , Duker G.
Published: June 2012

Background
—Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class 2I), but paradoxically, it frequently is also proarrhythmic (torsade de pointes).

Methods and Results
—The cardiac electrophysiological effects of 702 chemicals (class 2I or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by >50 ms, with induction of instability, triangulation, and reverse use-dependence (n=59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (n=19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (
P
<0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes).

Conclusions
—Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.
Deficiency of Urokinase-Type Plasminogen Activator–Mediated Plasmin Generation Impairs Vascular Remodeling During Hypoxia-Induced Pulmonary Hypertension in Mice
Authors: Levi Marcel , Moons Lieve , Bouché Ann , Shapiro Steve D. , Collen Desiré , Carmeliet Peter
Published: June 2012

Background
—Chronic hypoxia results in the development of pulmonary hypertension and subsequent right heart failure. A role of the plasminogen system in the pathogenesis of pulmonary hypertension and pulmonary vascular remodeling has been suggested.

Methods and Results
—Mice with targeted deficiency of the gene encoding tissue-type plasminogen activator (t-PA
−/−
), urokinase-type plasminogen activator (u-PA
−/−
), u-PA receptor (u-PAR
−/−
), or plasminogen (plg
−/−
) were subjected to hypoxic conditions. Hypoxia caused a significant 2.5-fold rise in right ventricular pressure in wild-type mice. Deficiency of u-PA or plasminogen prevented this increase in right ventricular pressure, t-PA
−/−
mice showed changes that were fully comparable with wild-type mice, and u-PAR
−/−
mice showed a partial response. Hypoxia induced an increase in smooth muscle cells within pulmonary arterial walls and a vascular rarefaction in the lungs of wild-type but not of u-PA
−/−
or plg
−/−
mice. Elastic lamina fragmentation, observed in hypoxic wild-type but not in u-PA or plasminogen-deficient mice, suggested that proliferation of vascular smooth muscle cells was dependent on u-PA–mediated elastic membrane degradation. Hypoxia-induced right ventricular remodeling in wild-type mice, characterized by cardiomyocyte hypertrophy and increased collagen contents, was not seen in u-PA
−/−
and plg
−/−
mice.

Conclusions
—Loss of the u-PA or plasminogen gene protects against the development of hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. These observations point to an essential role of u-PA–mediated plasmin generation in the adaptive response to chronic hypoxia and the occurrence of hypoxic pulmonary vascular disease.
Cytokines and Cytokine Receptors in Advanced Heart Failure
Authors: Deswal Anita , Petersen Nancy J. , Feldman Arthur M. , Young James B. , White Bill G. , Mann Douglas L.
Published: June 2012

Background
—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure.

Methods and Results
—We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mortality. In men, there was a linear increase in circulating levels of TNF with advancing age. Women ≤50 years of age had relatively low levels of TNF, but TNF levels were disproportionately higher in women >50 years of age. No differences existed in cytokines and/or cytokine receptors in whites versus nonwhites, and circulating levels of cytokines and cytokine receptors were significantly greater in patients with ischemic heart disease.

Conclusions
—Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.
High-Altitude Pulmonary Edema Is Initially Caused by an Increase in Capillary Pressure
Authors: Maggiorini Marco , Mélot Christian , Pierre Sebastien , Pfeiffer Fredi , Greve Ilona , Sartori Claudio , Lepori Mattia , Hauser Markus , Scherrer Urs , Naeije Robert
Published: June 2012

Background
—High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation. It is not known, however, whether the primary event is an increase in pressure or an increase in permeability of the pulmonary capillaries.

Methods and Results
—We studied pulmonary hemodynamics, including capillary pressure determined by the occlusion method, and capillary permeability evaluated by the pulmonary transvascular escape of
67
Ga-labeled transferrin, in 16 subjects with a previous HAPE and in 14 control subjects, first at low altitude (490 m) and then within the first 48 hours of ascent to a high-altitude laboratory (4559 m). The HAPE-susceptible subjects, compared with the control subjects, had an enhanced pulmonary vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery pressures (37±2 versus 26±1 mm Hg,
P
<0.001) and pulmonary capillary pressures (19±1 versus 13±1 mm Hg,
P
<0.001) at high altitude. Nine of the susceptible subjects developed HAPE. All of them had a pulmonary capillary pressure >19 mm Hg (range 20 to 26 mm Hg), whereas all 7 susceptible subjects without HAPE had a pulmonary capillary pressure <19 mm Hg (range 14 to 18 mm Hg). The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did not differ significantly from the control subjects.

Conclusions
—HAPE is initially caused by an increase in pulmonary capillary pressure.
Bidirectional Glenn Procedure Improves the Mechanical Efficiency of a Total Cavopulmonary Connection in High-Risk Fontan Candidates
Authors: Tanoue Yoshihisa , Sese Akira , Ueno Yasutaka , Joh Kunitaka , Hijii Takayuki
Published: June 2012

Background
—A total cavopulmonary connection (TCPC) is a widely performed surgical procedure for Fontan candidates. High-risk candidates who have undergone the bidirectional Glenn procedure (BDG) before TCPC have shown good results. The exact mechanism of this procedure, however, is still poorly understood. We hypothesized that a volume reduction with BDG improved ventricular contractility, thereby optimizing mechanical efficiency after TCPC.

Methods and Results
—We measured percent normal systemic ventricular end-diastolic volume (%N-EDV), contractility (end-systolic elastance; E
es
), afterload (effective arterial elastance; E
a
), and mechanical efficiency (ventriculoarterial coupling; E
a
/E
es
) on the basis of the cardiac catheterization data before and after TCPC. Eighteen patients who underwent staged TCPC after BDG (staged group) were compared with 29 patients who underwent primary TCPC (primary group). E
es
and E
a
were approximated as follows: E
es
=mean arterial pressure/minimal ventricular volume, and E
a
=maximal ventricular pressure/(maximal ventricular volume−minimal ventricular volume), and E
a
/E
es
was then calculated. The ventricular volume was normalized with the body surface area. A canine experimental model with conductance catheter was used to validate the accuracy of this approximation of E
es
and E
a
. %N-EDV decreased after TCPC in both groups. In the staged group, a smaller ventricular volume resulted in better contractility (E
es
). Although afterload (E
a
) increased in both groups, the increment of E
a
was smaller in the staged group. These changes resulted in an improvement of E
a
/E
es
in the staged group, whereas E
a
/E
es
increased in the primary group.

Conclusions
—The volume reduction of BDG preceding TCPC allows for any afterload mismatch to be corrected, thereby improving ventricular energetics after TCPC.
Effects of In Vivo Nitroglycerin Treatment on Activity and Expression of the Guanylyl Cyclase and cGMP-Dependent Protein Kinase and Their Downstream Target Vasodilator-Stimulated Phosphoprotein in Aorta
Authors: Mülsch Alexander , Oelze Matthias , Klöss Stefan , Mollnau Hanke , Töpfer Andrea , Smolenski Albert , Walter Ulrich , Stasch Johannes-Peter , Warnholtz Ascan , Hink Ulrich , Meinertz Thomas , Münzel Thomas
Published: June 2012

Background
—Chronic in vivo treatment with nitroglycerin (NTG) induces tolerance to nitrates and cross-tolerance to nitrovasodilators and endothelium-derived nitric oxide (NO). We previously identified increased vascular superoxide formation and reduced NO bioavailability as one causal mechanism. It is still controversial whether intracellular downstream signaling to nitrovasodilator-derived NO is affected as well.

Methods and Results
—We therefore studied the effects of 3-day NTG treatment of rats and rabbits on activity and expression of the immediate NO target soluble guanylyl cyclase (sGC) and on the cGMP-activated protein kinase I (cGK-I). Tolerance was induced either by chronic NTG infusion via osmotic minipumps (rats) or by NTG patches (rabbits). Western blot analysis, semiquantitative reverse transcription–polymerase chain reaction, and Northern blot analysis revealed significant and comparable increases in the expression of sGC α
1
and β
1
subunit protein and mRNA. Studies with the oxidative fluorescent dye hydroethidine revealed an increase in superoxide in the endothelium and smooth muscle. Stimulation with NADH increased superoxide signals in both layers. Although cGK-I expression in response to low-dose NTG was not changed, a strong reduction in vasodilator-stimulated phosphoprotein (VASP) serine239 phosphorylation (specific substrate of cGK-I) was observed in tolerant tissue from rats and rabbits. Concomitant in vivo and in vitro treatment with vitamin C improved tolerance, reduced oxidative stress, and improved P-VASP.

Conclusions
—We therefore conclude that increased expression of sGC in the setting of tolerance reflects a chronic inhibition rather than an induction of the sGC–cGK-I pathway and may be mediated at least in part by increased vascular superoxide.
Beneficial Effects on Skeletal Muscle of the Angiotensin II Type 1 Receptor Blocker Irbesartan in Experimental Heart Failure
Authors: Dalla Libera Luciano , Ravara Barbara , Angelini Annalisa , Rossini Katia , Sandri Marco , Thiene Gaetano , Battista Ambrosio Giovanni , Vescovo Giorgio
Published: June 2012

Background
—In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-α (TNFα). Angiotensin II receptors are thought to play a role in controlling apoptosis. We tested the hypothesis that angiotensin II receptor blockade could prevent skeletal muscle apoptosis in rats with CHF.

Methods and Results
—CHF was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten additional animals were injected with saline and acted as controls. After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg · kg
–1
· d
–1
irbesartan through osmotic minipumps, and 10 of the 36 rats were treated with 2 mg · kg
–1
· d
–1
nifedipine in drinking water. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspases 3 and 9 were determined, as were plasma levels of TNFα and angiotensin II. Myocyte apoptosis and muscle atrophy were significantly decreased with irbesartan compared with untreated CHF rats. Irbesartan-treated rats had fewer cells labeled positively with terminal deoxynucleotidal transferase–mediated dUTP nick-end labeling and fewer caspases; however, they also had increased Bcl-2 levels and muscle fiber cross-sectional areas. The MHC pattern in irbesartan-treated animals was similar to that in controls. Nifedipine animals behaved like the untreated CHF animals. Angiotensin II was increased 3- to 4-fold in all CHF rats (treated and untreated). TNFα levels were decreased in irbesartan-treated rats but not in nifedipine-treated rats.

Conclusions
—Angiotensin II receptor blockade can protect from the development of apoptosis-dependent atrophy and from changes in MHCs. The reduction of TNFα may play a role in this process.
Controlled Trial of Intravenous Immune Globulin in Recent-Onset Dilated Cardiomyopathy
Authors: McNamara Dennis M. , Holubkov Richard , Starling Randall C. , Dec G. William , Loh Evan , Torre-Amione Guillermo , Gass Alan , Janosko Karen , Tokarczyk Tammy , Kessler Paul , Mann Douglas L. , Feldman Arthur M.
Published: June 2012

Background
—This prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis.

Methods and Results
—Sixty-two patients (37 men, 25 women; mean age ±SD 43.0±12.3 years) with recent onset (≤6 months of symptoms) of dilated cardiomyopathy and LVEF ≤0.40 were randomized to 2 g/kg IVIG or placebo. All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16%. The primary outcome was change in LVEF at 6 and 12 months after randomiz. Overall, LVEF improved from 0.25±0.08 to 0.41±0.17 at 6 months (
P
<0.001) and 0.42±0.14 (
P
<0.001 versus baseline) at 12 months. The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 0.14±0.12, placebo 0.14±0.14; 12 months: IVIG 0.16±0.12, placebo 0.15±0.16). Overall, 31 (56%) of 55 patients at 1 year had an increase in LVEF ≥0.10 from study entry, and 20 (36%) of 56 normalized their ejection fraction (≥0.50). The transplant-free survival rate was 92% at 1 year and 88% at 2 years.

Conclusions
—These results suggest that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF. However, in this overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favorable.
Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure
Authors: Peterson J. Thomas , Hallak Hussein , Johnson Linda , Li Hua , O’Brien Patrick M. , Sliskovic Drago R. , Bocan Thomas M. A. , Coker Mytsi L. , Etoh Takuma , Spinale Francis G.
Published: June 2012

Background
—Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure.

Methods and Results
—LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg · kg
−1
· d
−1
PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116±11 μmol/L) reduced in vitro LV myocardial MMP-2 activity by ≈100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578±477 versus 5983±109 mm Hg/s,
P
≤0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443±12 versus 563±33 mL,
P
≤0.05) and increased further by 13 months (899±64 mL,
P
≤0.05). LV myocardial MMP-2 activity was increased by ≈2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678±28 mL,
P
≤0.05).

Conclusions
—MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.
Fibrin D-Dimer and Coronary Heart Disease
Authors: Danesh John , Whincup Peter , Walker Mary , Lennon Lucy , Thomson Andrew , Appleby Paul , Rumley Ann , Lowe Gordon D.O.
Published: June 2012

Background
—It is unknown whether modest increases of fibrin D-dimer, a circulating marker of fibrin turnover, are relevant to coronary heart disease (CHD) in the general population.

Methods and Results
—We measured serum concentrations of D-dimer antigen in the stored baseline blood samples of 630 CHD cases and 1269 controls “nested” in a prospective cohort of 5661 men who were monitored for 16 years, and we conducted a meta-analysis of previous relevant studies to place our findings in context. In a comparison of men in the top third compared with those in the bottom third of baseline fibrin D-dimer values (tertile cutoffs, >94 versus <49 ng/mL), the odds ratio for CHD was 1.67 (95% CI, 1.31 to 2.13;
P
<0.0001) after adjustments for age and town. The odds ratio increased slightly after further adjustment for smoking, other classic risk factors, and indicators of socioeconomic status (1.79; 95% CI, 1.36 to 2.36). Strong correlations were observed of fibrin D-dimer values with circulating concentrations of C-reactive protein and serum amyloid A protein but not with smoking, blood lipids, blood pressure, and other risk factors.

Conclusion
—Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.
Paradoxically Enhanced Endothelin-B Receptor–Mediated Vasoconstriction in Conscious Old Monkeys
Authors: Asai Kuniya , Kudej Raymond K. , Takagi Gen , Kudej Amelia B. , Natividad Filipinas , Shen You-Tang , Vatner Dorothy E. , Vatner Stephen F.
Published: June 2012

Background
—We investigated the effects of aging on the responses to endothelin (ET) in conscious old (19.8±0.6 years) and young adult (6.8±0.3 years) monkeys and compared these results with those of other vasoconstrictors, eg, phenylephrine (PE) and angiotensin II (Ang II).

Methods and Results
—The monkeys (
Macaca fascicularis
) were chronically instrumented. Baseline total peripheral resistance (TPR) was not different between the 2 groups. As expected, TPR rose less (
P
<0.05) with PE (5 μg/kg) in old monkeys (34±3%) than in young monkeys (57±6%); TPR also rose less with Ang II. Surprisingly, TPR rose more (
P
<0.05) with endothelin-1 (ET-1, 25 ng · kg
−1
· min
−1
) in old monkeys (36±6%) than in young monkeys (10±2%). An ET
B
receptor agonist, sarafotoxin (S6c, 30 ng · kg
−1
· min
−1
) was administered in the presence of an ET
A
receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more (
P
<0.05) in old monkeys (59±10%) than in young monkeys (31±4%). In the presence of nitric oxide synthase (NOS) inhibition with
N
W
-nitro-
l
-arginine methyl ester (60 mg/kg), vasoconstriction induced by S6c no longer differed with age, because it was enhanced in young monkeys (
P
<0.05) (68±9% versus 31±4%) but not in old monkeys (58±6% versus 59±10%). Thus, after NOS inhibition, vasoconstrictor responses to ET were no longer enhanced in old monkeys.

Conclusions
—Peripheral vasoconstriction (PE and Ang II) is reduced in old monkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was actually enhanced in old monkeys, which appears to be a result of impaired endothelium-dependent vasodilation, which with ET-1 should involve the ET
B
receptor.
Oxidative Stress and Lipid Retention in Vascular Grafts
Authors: Shi Yi , Patel Sachin , Davenpeck Kelly L. , Niculescu Rodica , Rodriguez Evelio , Magno Michael G. , Ormont Michael L. , Mannion John D. , Zalewski Andrew
Published: June 2012

Background
—Because saphenous vein grafts (SVGs) exhibit greater cellular heterogeneity and worse clinical outcomes than arterial grafts (AGs), we examined oxidative stress and lipid retention in different vascular conduits.

Methods and Results
—In a porcine model of graft interposition into carotid artery, superoxide anion (·O
2
−
) was measured at 2 weeks after surgery. SVGs demonstrated increased ·O
2
−
production compared with AGs (SOD-inhibitable nitro blue tetrazolium reduction,
P
<0.01). The NAD(P)H oxidase inhibitor diphenyleneiodonium (
P
<0.01) abolished SVG-derived ·O
2
−
, whereas the inhibitors of other pro-oxidant enzymes were ineffective. The change in oxidative stress was also reflected by lower activity of the endogenous antioxidant superoxide dismutase in SVGs than in AGs (
P
<0.001). SVG remodeling was associated with increased synthesis of sulfated glycosaminoglycans and augmented expression of a core protein, versican. These changes were accompanied by SVGs retaining significantly more
125
I-labeled LDL than AGs ex vivo (
P
<0.001). In hyperlipemic animals, lipid accumulation and oxidized epitopes were preferentially noted in the intima of SVGs at 1 month after surgery.

Conclusions
—This study demonstrated significant differences in the biology of SVGs and AGs. SVGs exhibited higher oxidative stress, LDL accumulation, and the presence of oxidized epitopes. These findings suggest that proatherogenic changes in SVGs may commence early after surgical revascularization.
Mutations in the Cardiac Ryanodine Receptor Gene (
hRyR2
) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Priori Silvia G. , Napolitano Carlo , Tiso Natascia , Memmi Mirella , Vignati Gabriele , Bloise Raffaella , Sorrentino Vincenzo , Danieli Gian Antonio
Published: June 2012

Background
—Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene (
hRyR2
) a likely candidate for this genetically transmitted arrhythmic disorder.

Methods and Results
—Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction–amplified exons of the
hRyR2
gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband.

Conclusions
—We demonstrated that, in agreement with our hypothesis,
hRyR2
is a gene responsible for catecholaminergic polymorphic ventricular tachycardia.
Mechanical Circulatory Support for Advanced Heart Failure
Authors: Deng Mario C. , Loebe Matthias , El-Banayosy Aly , Gronda Edoardo , Jansen Piet G. M. , Vigano Mario , Wieselthaler Georg M. , Reichart Bruno , Vitali Ettore , Pavie Alain , Mesana Thierry , Loisance Daniel Y. , Wheeldon Dereck R. , Portner Peer M.
Published: June 2012

Background
—Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival.

Methods and Results
—Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LVAS implantation: respiratory failure associated with septicemia (odds ratio 11.2), right heart failure (odds ratio 3.2), age >65 years (odds ratio 3.01), acute postcardiotomy (odds ratio 1.8), and acute infarction (odds ratio 1.7). For patients without any of these factors, the 1-year survival after LVAS implantation including the posttransplantation period was 60%; for the combined group with at least 1 risk factor, it was 24%.

Conclusions
—Careful selection, specifically implantation before patients become moribund, and improvement of management may result in improved outcomes of LVAS treatment for advanced heart failure.
Overnight Shift From Obstructive to Central Apneas in Patients With Heart Failure
Authors: Tkacova Ruzena , Niroumand Mitra , Lorenzi-Filho Geraldo , Bradley T. Douglas
Published: June 2012

Background
—Obstructive (OSA) and central sleep apnea (CSA) can coexist in patients with congestive heart failure (CHF). However, the reason why OSA events occur at one time and CSA events at another has not been determined. We hypothesized that a change in P
co
2
would be associated with an alteration in apnea type: a decrease in P
co
2
should lead to CSA.

Methods and Results
—To test this hypothesis, we evaluated minute ventilation (V
I
), transcutaneous P
co
2
(Ptc
co
2
), circulation time, and periodic breathing cycle length during overnight polysomnography in 12 patients with CHF and coexisting OSA and CSA. V
I
was significantly greater (mean±SEM, 9.4±1.3 versus 8.0±0.9 L/min;
P
<0.05) and Ptc
co
2
was lower (39.4±1.0 versus 41.9±1.1 mm Hg,
P
<0.01) during episodes of CSA than of OSA. These changes were associated with significant lengthening of circulation time (23.6±3.7 versus 21.1±3.6 seconds,
P
<0.01) and periodic breathing cycle length (53.7±3.5 versus 49.6±2.9 seconds,
P
<0.01). In addition, the proportion of obstructive events decreased (from 68.5±11.4% to 22.5±7.2%,
P
<0.001) and of CSA events increased (from 31.5±11.4% to 77.5±7.2%,
P
<0.001) from the first to the last quarter of the night in association with a significant decrease in Ptc
co
2
(from 42.6±0.9 to 40.8±0.9 mm Hg,
P
<0.01).

Conclusions
—In patients with CHF, the shift from OSA to CSA is associated with a reduction in P
co
2
. This appears to be related to an overnight deterioration in cardiac function as suggested by the concurrent lengthening of circulation time. Therefore, in CHF patients, alterations in cardiac function may influence apnea type.
Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder
Authors: Vaughan Carl J. , Casey Mairead , He Jie , Veugelers Mark , Henderson Kiersten , Guo Dongchuan , Campagna Robert , Roman Mary J. , Milewicz Dianna M. , Devereux Richard B. , Basson Craig T.
Published: June 2012

Background
—Aortic aneurysms cause significant mortality, and >20% relate to hereditary disorders. Familial aortic aneurysm (FAA) has been described in such conditions as the Marfan and Ehlers-Danlos type IV syndromes, due to defects in the
fibrillin-1
and
type III procollagen
genes, respectively. Other gene defects that cause isolated aneurysms, however, have not thus far been described.

Methods and Results
—We studied 3 families affected by FAA. No family met the diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocardiography defined involvement of both the thoracic and abdominal aorta. In family ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including
fibrillin-1
,
fibrillin-2
, and
type III procollagen
, and chromosome 3p24.2-p25. Genome-wide linkage analysis identified a 2.3-cM FAA locus (
FAA1
) on chromosome 11q23.3-q24 with a maximum multipoint logarithm of the odds score of 4.4. In family ANB, FAA was linked to
fibrillin-1
. In family ANF, however, FAA was not linked to any locus previously associated with aneurysm formation, including
fibrillin-1
and
FAA1
.

Conclusions
—FAA disease is genetically heterogeneous. We have identified a novel FAA locus at chromosome 11q23.3-q24, a critical step toward elucidating 1 gene defect responsible for aortic dilatation. Future characterization of the
FAA1
gene will enhance our ability to achieve presymptomatic diagnosis of aortic aneurysms and will define molecular mechanisms to target therapeutics.
Noninvasive Quantification of Left-to-Right Shunt in Pediatric Patients
Authors: Beerbaum Philipp , Körperich Hermann , Barth Peter , Esdorn Hermann , Gieseke Jürgen , Meyer Hans
Published: June 2012

Background
—Blood flow can be quantified noninvasively by phase-contrast cine MRI (PC-MRI) in adults. Little is known about the feasibility of the method in children with congenital heart disease.

Methods and Results
—In 50 children (mean age 6.2 years, range 1.1 to 17.7 years) with an atrial- or ventricular-level shunt, blood flow rate in the great vessels was determined by PC-MRI, and the ratio of pulmonary to aortic flow (Q̇p/Q̇s) was compared with Q̇p/Q̇s by oximetry. We found a difference of 2% and a range of −20% to +26% (limits of agreement, mean±2 SD). In another 7 children with congenital heart disease but no cardiac shunting (mean age 7.9 years, range 1.3 to 13.5 years), Q̇p/Q̇s by PC-MRI was 1.02 (SD ±0.06). No difference between systemic venous and aortic flow volumes was found (range −17% to +20%, n=37). Blood flow through a secundum atrial septal defect as assessed by PC-MRI (n=24) overestimated the shunt compared with the difference between pulmonary and aortic flows. The mean difference between 3 repeated PC-MRI measurements in each location was 5.3% (SD ±4.0%, n=522), demonstrating good precision. The interobserver variability was low. The accuracy of PC-MRI was confirmed by in vitro experiments.

Conclusions
—Determination of Q̇p/Q̇s by PC-MRI in children is quick, safe, and reliable compared with oximetry. Systemic venous flow can be quantified by PC-MRI, whereas through-plane shunt measurement within an atrial septal defect is inaccurate.
Impact of Pulmonary Valve Replacement on Arrhythmia Propensity Late After Repair of Tetralogy of Fallot
Authors: Therrien J. , Siu S. C. , Harris L. , Dore A. , Niwa K. , Janousek J. , Williams W. G. , Webb G. , Gatzoulis M. A.
Published: June 2012

Background
—Chronic pulmonary regurgitation after repair of tetralogy of Fallot (TOF) may lead to right ventricular dilatation, which may be accompanied by ventricular tachycardia and sudden death. We aimed to examine the effects of pulmonary valve replacement (PVR) on (1) certain electrocardiographic markers predictive of monomorphic ventricular arrhythmia and sudden death and (2) sustained atrial flutter/fibrillation and monomorphic ventricular tachycardia.

Methods and Results
—We studied 70 patients who underwent PVR for pulmonary regurgitation and/or right ventricular outflow tract obstruction late after repair of TOF. Maximum QRS duration and QT dispersion were measured from standard ECGs before PVR and at the latest follow-up. Arrhythmia was defined as sustained atrial flutter/fibrillation or sustained monomorphic ventricular tachycardia. Concomitant intraoperative electrophysiological mapping and/or cryoablation were performed in 9 patients (60%) with preexisting ventricular tachycardia and 6 patients (50%) with preexisting atrial flutter. QRS duration remained unchanged in the study group (
P
=0.46), but it was significantly prolonged (
P
<0.001) in a comparable group of patients with repaired TOF who did not undergo PVR. At a mean follow-up of 4.7 years, the incidence of ventricular tachycardia diminished from 22% to 9% (
P
<0.001), and atrial flutter/fibrillation decreased from 17% to 12% (
P
=0.32). Intraoperative ablation prevented recurrence of preexisting tachyarrhythmia (0 of 15 patients).

Conclusions
—PVR in patients with previous TOF repair and chronic pulmonary regurgitation leads to stabilization of QRS duration and, in conjunction with intraoperative cryoablation, to a decrease in the incidence of preexisting atrial and ventricular tachyarrhythmia. When applicable, this combined approach should be used in patients late after repair of TOF.
Intercaval Block in Normal Canine Hearts
Authors: Becker Ruediger , Bauer Alexander , Metz Stephan , Kinscherf Ralf , Senges Julia C. , Schreiner Kirsten D. , Voss Frederik , Kuebler Wolfgang , Schoels Wolfgang
Published: June 2012

Background
—The intriguing monotony in the occurrence of intercaval conduction block during typical atrial flutter suggests an anatomic or electrophysiological predisposition for conduction abnormalities.

Methods and Results
—To determine the location of and potential electrophysiological basis for conduction block in the terminal crest region, a high-density patch electrode (10×10 bipoles) was placed on the terminal crest and on the adjacent pectinate muscle region in 10 healthy foxhounds. With a multiplexer mapping system, local activation patterns were reconstructed during constant pacing (S
1
S
1
=200 ms) and introduction of up to 2 extrastimuli (S
2
, S
3
). Furthermore, effective refractory periods were determined across the patch. If evident through online analysis, the epicardial location of conduction block was marked for postmortem verification of its endocardial projection. Marked directional differences in activation were found in the terminal crest region, with fast conduction parallel to and slow conduction perpendicular to the intercaval axis (1.1±0.4 versus 0.5±0.2 m/s,
P
<0.01). In the pectinate muscle region, however, conduction velocities were similar in both directions (0.5±0.3 versus 0.6±0.2 m/s,
P
=NS). Refractory patterns were relatively homogeneous in both regions, with local refractory gradients not >30 ms. During S
3
stimulation, conduction block parallel to the terminal crest was inducible in 40% of the dogs compared with 0% in the pectinate muscle region.

Conclusions
—Even in normal hearts, inducible intercaval block is a relatively common finding. Anisotropic conduction properties would not explain conduction block parallel to the intercaval axis in the terminal crest region, and obviously, refractory gradients do not seem to play a role either. Thus, the change in fiber direction associated with the terminal crest/pectinate muscle junction might form the anatomic/electrophysiological basis for intercaval conduction block.
Plasma Total Cysteine as a Risk Factor for Vascular Disease
Authors: El-Khairy Lina , Ueland Per M. , Refsum Helga , Graham Ian M. , Vollset Stein E.
Published: June 2012

Background
—Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. Although cysteine is structurally similar and metabolically linked to tHcy, its relation to the risk of cardiovascular disease has received little attention. We studied the relation between plasma total cysteine (tCys) levels and the risk of vascular disease in the coronary, cerebral, and peripheral vessels.

Methods and Results
—This case-control study included 750 patients with vascular disease and 800 age- and sex-matched control subjects recruited from 19 centers in 9 European countries. Conventional risk factors for cardiovascular disease were recorded. In addition, plasma levels of tCys, tHcy, folate, B
6
, B
12
, and creatinine were measured. Overall, a U-shaped relationship was observed between tCys and risk of vascular disease. With the middle range of 250 to 275 μmol/L tCys used as the reference category, the adjusted risk of vascular disease at low (≤225 μmol/L) tCys levels was 2.1 (95% CI 1.2 to 3.6), and the risk at high (>300 μmol/L) tCys levels was 1.6 (95% CI 1.1 to 2.3). Different shapes of the dose-response relationship were seen for the 3 vascular disease categories. The relation with peripheral vascular and cerebrovascular disease was U-shaped, whereas a weak positive relation was observed with coronary heart disease.

Conclusions
—Our data show a significant U-shaped relationship between tCys and cardiovascular disease after adjustment for tHcy, creatinine, and other cardiovascular disease risk factors.
Different Prognostic Impact of 24-Hour Mean Blood Pressure and Pulse Pressure on Stroke and Coronary Artery Disease in Essential Hypertension
Authors: Verdecchia Paolo , Schillaci Giuseppe , Reboldi Gianpaolo , Franklin Stanley S. , Porcellati Carlo
Published: June 2012

Background
—We tested the hypothesis that the steady and pulsatile components of blood pressure (BP) exert a different influence on coronary artery disease and stroke in subjects with hypertension.

Methods and Results
—We analyzed data on 2311 subjects with essential hypertension. All subjects (mean age 51 years, 47% women) underwent off-therapy 24-hour ambulatory BP monitoring. Over a follow-up period of up to 14 years (mean 4.7 years), there were 132 major cardiac events (1.20 per 100 person-years) and 105 cerebrovascular events (0.90 per 100 person-years). After adjustment for age, sex, diabetes, serum cholesterol, and cigarette smoking (all
P
<0.01), for each 10 mm Hg increase in 24-hour pulse pressure (PP), there was an independent 35% increase in the risk of cardiac events (95% CI 17% to 55%). Twenty-four–hour mean BP was not a significant predictor of cardiac events after controlling for PP. After adjustment for age, sex, and diabetes (all
P
<0.05), for every 10 mm Hg increase in 24-hour mean BP, the risk of cerebrovascular events increased by 42% (95% CI 19% to 69%), and 24-hour PP did not yield significance after controlling for 24-hour mean BP. Twenty-four–hour PP was also an independent predictor of fatal cardiac events, and 24-hour mean BP was an independent predictor of fatal cerebrovascular events.

Conclusions
—In subjects with predominantly systolic and diastolic hypertension, ambulatory mean BP and PP exert a different predictive effect on the cardiac and cerebrovascular complications. Although PP is the dominant predictor of cardiac events, mean BP is the major independent predictor of cerebrovascular events.
Permanent Epicardial Pacing in Pediatric Patients
Authors: Cohen Mitchell I. , Bush David M. , Vetter Victoria L. , Tanel Ronn E. , Wieand Tammy S. , Gaynor J. William , Rhodes Larry A.
Published: June 2012

Background
—The purpose of this study was to evaluate the long-term outcome of all pediatric epicardial pacing leads.

Methods and Results
—All epicardial leads and 1239 outpatient visits between January 1, 1983, and June 30, 2000, were retrospectively reviewed. Pacing and sensing thresholds were reviewed at implant, at 1 month, and at subsequent 6-month intervals. Lead failure was defined as the need for replacement or abandonment due to pacing or sensing problems, lead fracture, or phrenic/muscle stimulation. A total of 123 patients underwent 207 epicardial lead (60 atrial/147 ventricular, 40% steroid) implantations (median age at implant was 4.1 years [range 1 day to 21 years]). Congenital heart disease was present in 103 (84%) of the patients. Epicardial leads were followed for 29 months (range 1 to 207 months). The 1-, 2-, and 5-year lead survival was 96%, 90%, and 74%, respectively. Compared with conventional epicardial leads, both atrial and ventricular steroid leads had better stimulation thresholds 1 month after implantation; however, only ventricular steroid leads had improved chronic pacing thresholds (at 2 years: for steroid leads, 1.9 μJ [from 0.26 to 16 μJ]; for nonsteroid leads, 4.7 μJ [from 0.6 to 25 μJ];
P
<0.01). Ventricular sensing was significantly better in steroid leads 1 month after lead implantation (at 2 years: for steroid leads, 8 mV [from 4 to 31 mV]; for nonsteroid leads, 4 mV [from 0.7 to 10 mV];
P
<0.01). Neither congenital heart disease, lead implantation with a concomitant cardiac operation, age or weight at implantation, nor the chamber paced was predictive of lead failure.

Conclusions
—Steroid epicardial leads demonstrated relatively stable acute and chronic pacing and sensing thresholds. In this evaluation of >200 epicardial leads, lead survival was good, with steroid-eluting leads demonstrating results similar to those found with historical conventional endocardial leads.
Astroglial Protein S-100 Is an Early and Sensitive Marker of Hypoxic Brain Damage and Outcome After Cardiac Arrest in Humans
Authors: Böttiger Bernd W. , Möbes Stefan , Glätzer Rolf , Bauer Harald , Gries André , Bärtsch Peter , Motsch Johann , Martin Eike
Published: June 2012

Background
—The results of early conventional tests do not correlate with cerebral outcome after cardiac arrest. We investigated the serum levels of astroglial protein S-100 as an early marker of brain damage and outcome after cardiac arrest.

Methods and Results
—In 66 patients undergoing cardiopulmonary resuscitation after nontraumatic cardiac arrest, blood samples for the evaluation of S-100 were drawn immediately after and 15, 30, 45, and 60 minutes; 2, 8, 24, 48, and 72 hours; and 7 days after initiation of cardiopulmonary resuscitation. Moreover, the serum levels of neuron-specific enolase were determined between 2 hours and 7 days. If patients survived for >48 hours, brain damage was assessed by a combination of neurological, cranial CT, and electrophysiological examinations. Overall, 343 blood samples were taken for the determination of S-100. Maximum S-100 levels within 2 hours after cardiac arrest were significantly higher in patients with documented brain damage (survivors and nonsurvivors, 3.70±0.77 μg/L) than in patients without brain damage (0.90±0.29 μg/L). Significant differences between these 2 groups were observed from 30 minutes until 7 days after cardiac arrest. In addition, the positive predictive value of the S-100 test at 24 hours for fatal outcome within 14 days was 87%, and the negative predictive value was 100% (
P
<0.001). With regard to neuron-specific enolase, significant differences between patients with documented brain damage and those with no brain damage were found at 24, 48, and 72 hours and 7 days.

Conclusions
—Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and short-term outcome after cardiac arrest in humans.
Double-Outlet Right Ventricle and Overriding Tricuspid Valve Reflect Disturbances of Looping, Myocardialization, Endocardial Cushion Differentiation, and Apoptosis in TGF-β
2
–Knockout Mice
Authors: Bartram Ulrike , Molin Daniël G. M. , Wisse Lambertus J. , Mohamad Azhar , Sanford L. Philip , Doetschman Thomas , Speer Christian P. , Poelmann Robert E. , Gittenberger-de Groot Adriana C.
Published: June 2012

Background
—Transforming growth factor-β
2
(TGF-β
2
) is a member of a family of growth factors with the potential to modify multiple processes. Mice deficient in the TGF-β
2
gene die around birth and show a variety of defects of different organs, including the heart.

Methods and Results
—We studied the hearts of TGF-β
2
–null mouse embryos from 11.5 to 18.5 days of gestation to analyze the types of defects and determine which processes of cardiac morphogenesis are affected by the absence of TGF-β
2
. Analysis of serial sections revealed malformations of the outflow tract (typically a double-outlet right ventricle) in 87.5%. There was 1 case of common arterial trunk. Abnormal thickening of the semilunar valves was seen in 4.2%. Associated malformations of the atrioventricular (AV) canal were found in 62.5% and were composed of perimembranous inlet ventricular septal defects (37.5%), AV valve thickening (33.3%), overriding tricuspid valve (25.0%), and complete AV septal defects (4.2%). Anomalies of the aorta and its branches were seen in 33.3%. Immunohistochemical staining showed failure of myocardialization of the mesenchyme of the atrial septum and the ventricular outflow tract as well as deficient valve differentiation. Morphometry documented this to be associated with absence of the normal decrease of total endocardial cushion volume in the older stages. Apoptosis in TGF-β
2
–knockout mice was increased, although regional distribution was normal.

Conclusions
—TGF-β
2
–knockout mice exhibited characteristic cardiovascular anomalies comparable to malformations seen in the human population.