bluuebunny/crossref_metadata_2025 huggingface dataset:
Origin of Respiratory Sinus Arrhythmia in Conscious Humans
Authors: Piepoli Massimo , Sleight Peter , Leuzzi Stefano , Valle Felice , Spadacini Giammario , Passino Claudio , Johnston Jim , Bernardi Luciano
Published: June 2012

Background
We investigated whether respiratory sinus arrhythmia (RSA) in healthy humans originated from central neuronal oscillations or from peripheral baroreceptors responding to respiratory changes in venous return.

Methods and Results
During subjects’ controlled breathing we used sinusoidal neck suction to influence RSA (spectral analysis of RR interval). In 11 subjects, 20-second apnea greatly reduced RSA, which was restored by neck suction at the frequency of respiration. Counteracting the respiration-induced cycles of carotid blood pressure decreased RSA in 13 subjects (from 2136±682 to 1372±561 ms
2
,
P
<.01). The critical phase of this neck suction was constant for each subject at around the phase shift (with regard to respiration-related fluctuations of blood pressure) best for smoothing respiratory (mechanical) changes in blood pressure. Suction of a nonbaroreceptor area (the thigh) did not affect RSA. In 4 subjects, to separate the effects of peripheral baroreceptor afferents from respiration-entrained central oscillation (15 breaths/min), we cycled the neck suction at 12 cycles/min. Increasing neck suction from −7 to −30 mm Hg increased the ratio of the power of the 12 cycles compared with the 15-cycle RSA oscillation in RR interval spectral analysis from 0.26 to 2.57. A 12-cycle/min suction of an area other than the neck had little effect on the RR interval spectrum.

Conclusions
RSA can be mimicked or reduced by stimulation of arterial baroreceptors with cycles of appropriately phased neck suction at the frequency of respiration. This suggests an important influence of the arterial baroreceptors in the generation of RSA in conscious humans.
Improved Procedural Results of Coronary Angioplasty With Intravascular Ultrasound–Guided Balloon Sizing
Authors: Stone Gregg W. , Hodgson John M. , St Goar Frederick G. , Frey Axel , Mudra Harald , Sheehan Helen , Linnemeier Thomas J.
Published: June 2012

Background
Indiscriminate use of balloons larger than the angiographic reference segment lumen results in high rates of ischemic complications after percutaneous transluminal coronary angioplasty (PTCA). We hypothesized that angiographically unsuspected atheromatous remodeling with vessel expansion (the Glagov phenomenon) at and adjacent to PTCA target lesions would safely accommodate oversized balloons in selected patients undergoing PTCA with intravascular ultrasound (IVUS) guidance.

Methods and Results
After angiographically guided PTCA of 104 lesions in 102 patients, IVUS was performed, and if atheromatous remodeling was present, PTCA was repeated with larger balloons sized halfway between the lumen and external elastic membrane. Plaque occupied a mean of 51±15% of the angiographically “normal” reference segments. Further balloon upsizing by 0.25 to 1.25 mm was therefore performed in 76 lesions (73%), increasing the nominal balloon-to-artery ratio from 1.12±0.15 after standard PTCA to 1.30±0.17 after IVUS-guided PTCA (
P
<.0001). As a result, the angiographic minimal luminal diameter further increased from 1.95±0.49 to 2.21±0.47 mm, the % diameter stenosis fell from 28±15% to 18±14%, and the IVUS lumen area rose from 3.16±1.04 to 4.52±1.14 mm
2
(all
P
<.0001). The incidence of angiographic dissection was not increased after IVUS-guided balloon upsizing (37% versus 40%,
P
=.67), and major complications occurred in only 2 patients (1.9%).

Conclusions
The demonstration by IVUS of atheromatous remodeling permits the safe use of balloons traditionally considered oversized, resulting in significantly improved luminal dimensions without increased rates of dissection or ischemic complications.
Biochemical Evidence for Impaired Nitric Oxide Synthesis in Patients With Peripheral Arterial Occlusive Disease
Authors: Böger Rainer H. , Bode-Böger Stefanie M. , Thiele Wolfgang , Junker Wolfgang , Alexander Klaus , Frölich Jürgen C.
Published: June 2012

Background
We studied urinary nitrate and cGMP excretion rates, indices of systemic NO formation, and plasma concentrations of
l
-arginine and the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) and its inactive stereoisomer, symmetrical dimethylarginine, in 77 patients with peripheral arterial occlusive disease (PAOD) in Fontaine stages IIb through IV and in 47 young and 37 elderly healthy control subjects.

Methods and Results
Urinary nitrate excretion was 182.0±11.4 μmol/mmol creatinine and cGMP excretion was 186.2±13.0 nmol/mmol creatinine in young healthy control subjects. In elderly control subjects, both excretion rates were slightly lower (nitrate, 156.0±7.8 μmol/mmol creatinine; cGMP, 150.0±8.3 nmol/mmol creatinine;
P
=NS). In PAOD patients, there was a significant, progressive reduction of urinary nitrate (IIb, 138.4±11.9; III, 128.6±11.3; and IV, 91.9±8.0 μmol/mmol creatinine;
P
<.05) and cGMP (IIb, 139.9±25.2; III, 115.6±13.1; and IV, 76.9±7.9 nmol/mmol creatinine;
P
<.05) excretion rates related to the Fontaine stage of PAOD. These changes were independent of changes in renal excretory function. Plasma
l
-arginine concentrations were not significantly different between the groups, but ADMA concentrations were elevated in PAOD patients (young control subjects, 1.25±0.11; elderly control subjects, 1.01±0.05 μmol/L; IIb, 2.62±0.24; III, 3.06±0.48; and IV, 3.49±0.26 μmol/L;
P
<.05 for PAOD versus control subjects). There was a significant linear correlation between urinary nitrate and cGMP excretion rates and a significant negative linear correlation between plasma ADMA concentrations and urinary nitrate excretion.

Conclusions
In PAOD patients, there is a progressive reduction in urinary nitrate and cGMP excretion rates, which may be caused in part by accumulation of ADMA, an endogenous inhibitor of NO synthase.
Effects of Cardiac Denervation on Development of Heart Failure and Catecholamine Desensitization
Authors: Sato Naoki , Vatner Stephen F. , Shen You-Tang , Kudej Raymond K. , Ghaleh-Marzban Bijan , Uechi Masami , Asai Kuniya , Mirsky Israel , Patrick Thomas A. , Shannon Richard P. , Vatner Dorothy E.
Published: June 2012

Background
Two signatures of heart failure are activation of the sympathetic nervous system and catecholamine desensitization. However, whether or not the elimination of cardiac nerves affects either the progression of heart failure or catecholamine desensitization is not clear.

Methods and Results
We studied 8 dogs with selective ventricular denervation (VD) (surgical technique) and 10 intact dogs, chronically instrumented for measurement of left ventricular (LV) and arterial pressures, LV dP/dt, LV internal diameter, and wall thickness before and after heart failure was induced by rapid pacing (240 bpm) for 3 to 4 weeks. VD was confirmed by the absence of reflex effects induced by intracardiac veratrine and depletion of tissue norepinephrine and by supersensitive responses to norepinephrine. During the development of heart failure, LV end-systolic and end-diastolic stresses and heart rate increased, while myocardial contractility, as reflected by LV dP/dt and mean velocity of circumferential fiber shortening corrected for heart rate (Vcf
c
), decreased in both intact and VD dogs. However, the increases in LV end-diastolic stress and decreases in LV dP/dt as well as the relationship between LV systolic stress and Vcf
c
in heart failure were less (
P
<.05) in VD dogs. The responses of LV dP/dt and heart rate to both isoproterenol and norepinephrine in intact dogs were reduced in heart failure. The physiological desensitization to the inotropic effects of isoproterenol and norepinephrine was less in dogs with VD (
P
<.05), but chronotropic responses were similar because atrial innervation remained intact. Plasma norepinephrine levels were not different in VD dogs (592±79 pg/mL) compared with intact dogs (576±81 pg/mL) in heart failure.

Conclusions
Dogs with selective VD tolerated the development of heart failure better than intact dogs and demonstrated significantly less catecholamine desensitization. The latter indicates that intact ventricular innervation is required for physiological expression of catecholamine desensitization despite comparable elevation of plasma catecholamines during the development of heart failure.
Pharmacological Modulation of the Human Collateral Vascular Resistance in Acute and Chronic Coronary Occlusion Assessed by Intracoronary Blood Flow Velocity Analysis in an Angioplasty Model
Authors: Piek Jan J. , van Liebergen Rob A. M. , Koch Karel T. , de Winter Rob J. , Peters Ron J. G. , David George K.
Published: June 2012

Background
The pharmacological responsiveness of the coronary collateral circulation in humans has been studied only by indirect means.

Methods and Results
Patients with one-vessel disease and recruitable (n=14) or spontaneously visible (n=24) collateral vessels were studied during coronary angioplasty. Collateral flow in the recipient coronary artery was determined with a 0.014-in Doppler guide wire during balloon coronary occlusion and expressed as the diastolic blood flow velocity integral (dVi). Collateral blood flow velocity, mean aortic pressure (Pao), and coronary wedge pressure (Pw) were used to calculate the collateral vascular resistance index: Rcoll=(Pao−Pw)/dVi (mm Hg/cm) and the peripheral vascular resistance index of the recipient coronary artery: R4=Pw/dVi (mm Hg/cm). Adenosine (12 to 18 μg) and nitroglycerin (0.2 mg) were injected as a bolus in the donor coronary artery during subsequent balloon inflations to assess their effect on these hemodynamic variables. The administration of adenosine or nitroglycerin in patients with recruitable collateral vessels did not induce a change in dVi and Pw/Pao ratio. In patients with spontaneously visible collateral vessels, dVi increased from 8.0±4.5 to 10.8±8.0 cm (
P
=.01) after adenosine and from 7.4±4.5 to 10.3±6.9 cm (
P
=.003) after nitroglycerin. The Pw/Pao ratio remained unchanged after adenosine and nitroglycerin. Rcoll decreased from 10.3±9.5 to 8.6±8.5 mm Hg/cm (
P
=.01) after adenosine and from 11.6±10.4 to 8.3±8.9 mm Hg/cm (
P
<.001) after nitroglycerin. R4 decreased from 7.7±5.5 to 5.9±5.1 mm Hg/cm (
P
<.001) after adenosine and from 8.4±6.6 to 7.1±7.2 mm Hg/cm (
P
=.01) after nitroglycerin.

Conclusions
Coronary collateral blood flow can be increased with adenosine and nitroglycerin in patients with one-vessel disease and spontaneously visible collateral vessels, which is in contrast to patients with recruitable collateral vessels. This effect is the result of a reduction in the collateral vascular resistance and peripheral vascular resistance of the recipient coronary artery.
End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality. The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators
Authors: Migrino RQ , Young JB , Ellis SG , White HD , Lundergan CF , Miller DP , Granger CB , Ross AM , Califf RM , Topol EJ
Published: June 2012

BACKGROUND: Left ventricular remodeling is an important sequela of myocardial infarction (MI). Although remodeling occurs soon after MI, the effect of early left ventricular dilatation on outcome is not established and may be useful for early risk stratification. We assessed whether end-systolic volume index (ESVI) at 90 to 180 minutes into thrombolytic therapy for MI is associated with adverse outcomes. METHODS AND RESULTS: In the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I study, 41021 patients with evolving MI received one of four thrombolytic regimens. At 90 or 180 minutes into reperfusion therapy, 1300 patients underwent left ventriculography. ESVI was measured and correlated with adverse outcomes: 30-day and 1-year mortality and in-hospital congestive heart failure, shock, and reinfarction. Clinical variables were also tested in a stepwise logistic regression analysis to determine predictors of left ventricular dilatation. ESVI was directly related to all adverse outcomes with univariate analysis. ESVI of > or = 40 mL/m2 was independently associated with mortality (adjusted odds ratio [95% confidence interval]: 30-day, 3.4 [2.0 to 5.9]; 1-year, 4:1 [2.6 to 6.2], both P < .001). Male sex, prior angina or MI, weight of < 70 kg, heart rate of > or = 80 bpm, systolic blood pressure of < 110 mm.Hg, and anterior infarction were independent predictors of an ESVI of > or = 40 mL/m2. CONCLUSIONS: Left ventricular ESVI early into reperfusion therapy for MI strongly predicts adverse outcomes, including early and late mortality. The study establishes the role of very early left ventricular dilatation on outcome in MI and may be useful in identifying high-risk patients who might benefit from aggressive treatment, including the early use of ACE inhibitors.
Long-term Sequential Changes in Exercise Capacity and Chronotropic Responsiveness After Cardiac Transplantation
Authors: Givertz Michael M. , Hartley L. Howard , Colucci Wilson S.
Published: June 2012

Background
Peak exercise capacity improves early after orthotopic cardiac transplantation. However, the physiological response to exercise remains abnormal, with a reduced rate of heart rate (HR) rise and reductions in peak exercise HR and the increment in HR from rest to peak exercise. This chronotropic incompetence is due in large part to cardiac denervation. If reinnervation occurs after transplantation, it might result in an improvement in both chronotropic responsiveness and maximal exercise capacity. We therefore hypothesized that the chronotropic response to exercise and maximal exercise capacity would improve with time after transplantation.

Methods and Results
Peak symptom-limited cardiopulmonary exercise tests performed in 57 clinically stable cardiac transplant recipients (mean age, 45±2 years) serially for up to 5 years after transplantation and in 33 control subjects without heart disease were analyzed retrospectively. Pretransplantation exercise tests were also performed in 41 patients an average of 4.7±0.6 months before transplantation. At 1 year after transplantation, peak oxygen consumption was 16.6±0.9 mL·kg
−1
·min
−1
, reflecting a 43% increase versus pretransplantation. Nevertheless, compared with control subjects, maximal exercise capacity and the HR response to exercise were subnormal in transplant recipients. There were no further increases in peak exercise capacity, peak exercise HR, or the peak increment in HR with exercise up to 5 years after transplantation.

Conclusions
One year after cardiac transplantation, peak exercise capacity and chronotropic responsiveness are subnormal. There is no further improvement in peak exercise capacity or chronotropic responsiveness as late as 5 years after transplantation. These data indicate that with regard to chronotropic responsiveness, functionally significant cardiac reinnervation does not occur between the first and fifth years after transplantation.
A Population-Based Method for the Estimation of Defibrillation Energy Requirements in Humans
Authors: Newman David , Barr Aiala , Greene Mary , Martin David , Ham Miney , Thorne Sally , Dorian Paul
Published: June 2012

Background
A weighted logistic regression analysis was developed to allow pooling of patient data for the study of the stability of defibrillation energy requirements with a new nonthoracotomy lead defibrillation system.

Methods and Results
One hundred twenty patients were prospectively studied with a single-model nonthoracotomy implantable cardioverter defibrillator (ICD) system at the time of implant and at 3 months. The pooled data of all shocks delivered to all patients were fitted to a logistic function to construct a defibrillation voltage/energy dose-response relationship. The crude logit curve was weighted in quartiles according to the average shock energy delivered per patient. Shocks at implant (n=802; 6.6±2.5 shocks/patient) and follow-up (n=292; 2.4±1.2 shocks/patient) were analyzed. The modeled voltage/energy required for 50% successful defibrillation (95% CI) in the pooled data was 367 V (273, 461) and 9.8 J (6.7, 12.9) at implant and 338 V (264, 412) and 10.5 J (8, 13.0) at follow-up. The conventional measure of lowest successful voltage/energy (95% CI) was 430 V (411, 449) and 12.1 J (11, 13.2) at implant and 415 V (391, 439) and 11.3 J (10, 12.6) at follow-up. There were no statistically significant differences between implant and follow-up energy requirements with either method.

Conclusions
The nonthoracotomy lead system used in this study demonstrated stability of defibrillation energy requirements at implant and 3-month follow-up. A new technique for the estimation of the defibrillation energy dose-response relationship was derived by using a weighted logistic regression analysis.
Late Surgical Fenestration for Complications After the Fontan Operation
Authors: Rychik Jack , Rome Jonathan J. , Jacobs Marshall L.
Published: June 2012

Background
Significant morbidity after Fontan operation results in either takedown, heart transplantation, or death. Initial creation of a fenestration results in less morbidity and mortality; however, the role of late creation of a fenestration in aiding patients manifesting morbidity after an initial nonfenestrated Fontan operation is unclear.

Methods and Results
We reviewed our experience with late creation of a surgical fenestration in 9 patients (5.2±3.1 years old) exhibiting chronic effusions (n=4) or protein-losing enteropathy (PLE) (n=5) after lateral tunnel-type Fontan operation. Patients with effusions had creation via coronary punch of two or three 3-mm defects; patients with PLE had creation of a large, 5-mm defect. One child with effusions and multisystem organ failure before fenestration died 7 weeks after surgery secondary to low cardiac output; the other 3 had resolution of effusions within 4 to 6 weeks. Of the 5 with PLE, 3 had normalization of serum proteins and resolution of symptoms at 2 to 6 weeks. The 2 failures had arterial saturations >89% after surgery. Follow-up was from 25 to 30 months. Spontaneous closure of defects occurred in all 3 with effusions. No return of symptoms was noted in 2; however, the third reaccumulated effusions and has undergone refenestration with a large defect. All 3 patients with PLE have remained asymptomatic with patency of the fenestration (4 to 5 mm on echocardiography) and arterial saturation ≤85% for >2 years.

Conclusions
Late surgical creation of fenestration results in resolution of morbidity after Fontan operation. Improvement is related to the degree of right-to-left shunt created.
D
Allele of the Angiotensin I–Converting Enzyme Is a Major Risk Factor for Restenosis After Coronary Stenting
Authors: Amant Carole , Bauters Christophe , Bodart Jean-Christophe , Lablanche Jean-Marc , Grollier Gilles , Danchin Nicolas , Hamon Martial , Richard Florence , Helbecque Nicole , McFadden Eugène P. , Amouyel Philippe , Bertrand Michel E.
Published: June 2012

Background
Although intracoronary stent implantation significantly reduces restenosis compared with balloon angioplasty, a minority of patients still develop restenosis predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an
I/D
genetic polymorphism in the
ACE
gene,
DD
patients having higher levels.

Methods and Results
We investigated a possible relation between the
ACE I/D
polymorphism and restenosis in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (
DD
,
ID
, and
II
). At follow-up, MLD had a significant inverse relationship to the number of
D
alleles present (
DD
, 1.65±0.71 mm;
ID
, 1.84±0.60 mm;
II
, 2.05±0.61 mm;
P
<.007). Late luminal loss during the follow-up period was significantly related to the number of
D
alleles (
DD
, 0.89±0.61 mm;
ID
, 0.60±0.52 mm;
II
, 0.40±0.53 mm;
P
<.0001). The relative risk of restenosis (defined as a >50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of
D
alleles (95% confidence interval, 1.03 to 3.88,
P
<.04).

Conclusions
The
ACE I/D
polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting.
Diabetes Mellitus, Hypercholesterolemia, and Hypertension but Not Vascular Disease Per Se Are Associated With Persistent Platelet Activation In Vivo
Authors: Davı̀ Giovanni , Gresele Paolo , Violi Francesco , Basili Stefania , Catalano Mariella , Giammarresi Carlo , Volpato Raul , Nenci Giuseppe G. , Ciabattoni Giovanni , Patrono Carlo
Published: June 2012

Background
Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function.

Methods and Results
We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA
2
biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB
2
, by radioimmunoassay. Urinary 11-dehydro-TXB
2
was significantly (
P
=.0001) higher in patients with peripheral arterial disease (57±26 ng/h) than in control subjects (26±7 ng/h). Seventy percent of patients had metabolite excretion >2 SD above the normal mean. However, 11-dehydro-TXB
2
excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB
2
excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (
P
=.001) higher 11-dehydro-TXB
2
excretion at baseline than patients who remained event free.

Conclusions
The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA
2
biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA
2
biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.
Determination of Human Coronary Artery Composition by Raman Spectroscopy
Authors: Brennan James F. , Römer Tjeerd J. , Lees Robert S. , Tercyak Anna M. , Kramer John R. , Feld Michael S.
Published: June 2012

Background
We present a method for in situ chemical analysis of human coronary artery using near-infrared Raman spectroscopy. It is rapid and accurate and does not require tissue removal; small volumes, ≈1 mm
3
, can be sampled. This methodology is likely to be useful as a tool for intravascular diagnosis of artery disease.

Methods and Results
Human coronary artery segments were obtained from nine explanted recipient hearts within 1 hour of heart transplantation. Minces from one or more segments were obtained through grinding in a mortar and pestle containing liquid nitrogen. Artery segments and minces were excited with 830 nm near-infrared light, and Raman spectra were collected with a specially designed spectrometer. A model was developed to analyze the spectra and quantify the amounts of cholesterol, cholesterol esters, triglycerides and phospholipids, and calcium salts present. The model provided excellent fits to spectra from the artery segments, indicating its applicability to intact tissue. In addition, the minces were assayed chemically for lipid and calcium salt content, and the results were compared. The relative weights obtained using the Raman technique agreed with those of the standard assays within a few percentage points.

Conclusions
The chemical composition of coronary artery can be quantified accurately with Raman spectroscopy. This opens the possibility of using histochemical analysis to predict acute events such as plaque rupture, to follow the progression of disease, and to select appropriate therapeutic interventions.
Changing Features of Anginal Pain After PTCA Suggest a Stenosis on a Different Artery Rather Than Restenosis
Authors: Pasceri Vincenzo , Patti Giuseppe , Maseri Attilio
Published: June 2012

Background
We recently found that patients who had had two myocardial infarctions in different myocardial regions frequently reported different locations of infarct pain, whereas patients who had had two infarcts at the same site had a similar distribution of pain. The aim of this study was to assess whether a different location of anginal pain may help identify patients with a new stenosis on an artery perfusing another myocardial region as opposed to those with restenosis after coronary angioplasty (PTCA).

Methods and Results
We studied 38 patients (59±11 years old) who underwent PTCA for single-vessel disease, with recurrence of symptoms requiring repeat coronary angiography during a 3-year follow-up. According to our inclusion criteria, angiography showed either a significant restenosis of the dilated lesion, with no evidence of lesions in the other vessels (n=26), or a new stenosis in either of the other coronary arteries, with no restenosis in the dilated vessel (n=12). Before each procedure, patients reported the location and radiation of anginal pain. There was no relation between location of pain and site of the coronary stenosis. However, none of the patients with restenosis reported a different location of pain after angioplasty, compared with 5 patients with new stenosis (0% versus 42%,
P
=.002). Radiation of pain involved different areas of the body in 1 patient with restenosis and in 6 with new stenosis (4% versus 50%,
P
=.002). Overall, location or radiation of pain in a different body area had a specificity of 96% and a sensitivity of 58% in detecting a stenosis on a new artery.

Conclusions
A different location of anginal pain may distinguish patients with a new coronary stenosis from those with restenosis after PTCA for single-vessel disease. These findings suggest that in individual patients, differences in the location of cardiac pain may be indicative of the occurrence of ischemia in different myocardial regions.
Analysis of the Degree of QRS Fusion Necessary for Its Visual Detection
Authors: Ormaetxe José M. , Almendral Jesús , Martínez-Alday Jesús D. , Villacastín Julián P. , Arenal Angel , Pastor Agustín , Echeverría Tomás , Delcán Juan L.
Published: June 2012

Background
Fixed fusion is the hallmark for the demonstration of transient entrainment. However, the degree of accuracy of its recognition on the surface ECG is unknown. The purpose of the present study was to evaluate the ability to detect fusion in the QRS complex.

Methods and Results
While pacing the ventricles at a fixed rate, a model of ventricular fusion was created by introducing late extrastimuli at a second site. In this model, the presence and degree of fusion are known. Pacing sites were the RV apex, outflow tract, and left ventricle in various configurations. We analyzed 433 QRS complexes with different degrees of fusion (or no fusion) in 21 patients. Each QRS was “read” by three investigators blinded to intracardiac recordings but having a reference QRS with no fusion. There was a statistically significant correlation between the degree of fusion and its recognition. Fusion was detected with a sensitivity of 75% and a specificity of 87%. Fusion was accurately detected in all configurations only when >22% of the QRS was fused. In patients with organic left ventricular disease, fusion was better recognized when the driving pacing site was the left ventricle than when it was a right ventricular site. The interobserver agreement was moderate between two pairs of observers and only fair between the remaining pair.

Conclusions
Our results suggest that an accurate detection of ventricular fusion can only be accomplished when fusion occurs during a significant proportion of the QRS duration. The potential lack of recognition of minor degrees of fusion may produce underdetection of transient entrainment.
Strength-Duration Relationship for Human Transvenous Defibrillation
Authors: Gold Michael R. , Shorofsky Stephen R.
Published: June 2012

Background
One of the basic characteristics of electrical defibrillation is the strength-duration relationship, or the effect of pulse width on defibrillation efficacy. This relationship is important for understanding the mechanism of defibrillation and for the design of optimal waveforms. However, a detailed evaluation of the strength-duration relationship for human transvenous defibrillation has not been performed previously.

Methods and Results
This was a prospective study of 29 patients undergoing initial defibrillator implantation with a uniform dual coil, transvenous lead. In each patient defibrillation thresholds were measured for either short (2, 3, 4, 6 ms) or long (6, 12, 18 ms) pulse durations, with the order of testing randomized. The shock waveform was a truncated monophasic pulse from a capacitor of 150 μF. The leading edge voltage at defibrillation threshold was 566±100 V for 2-ms pulses. Voltages declined exponentially with increasing pulse width reaching an asymptote by 6 ms (451±68 V,
P
<.05). Defibrillation threshold voltage was insensitive to longer pulse widths. Stored energy at defibrillation threshold showed a similar relationship with pulse width. In contrast, mean current decreased monotonically over the full range of pulse durations evaluated, and there was no evidence of a rheobase.

Conclusions
The shape of the strength-duration curve and the lack of rheobase current indicate a fundamental difference between cardiac stimulation and defibrillation. The relationship between pulse duration and defibrillation threshold voltage or stored energy is well modeled by a parallel capacitor resistor circuit with a time constant of 5.3 ms.
Cardiovascular Phenotype of a Mouse Strain With Disruption of Bradykinin B
2
-Receptor Gene
Authors: Madeddu Paolo , Varoni Maria Vittoria , Palomba Domenico , Emanueli Costanza , Demontis Maria Piera , Glorioso Nicola , Dessı̀-Fulgheri Paolo , Sarzani Riccardo , Anania Vittorio
Published: June 2012

Background
To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B
2
-receptor gene (Bk 2r
−/−
).

Methods and Results
Under basal conditions, tail-cuff blood pressure was higher in Bk2r
−/−
than in wild-type Bk2r
+/+
and heterozygous Bk2r
+/−
mice (124±1 versus 109±1 and 111±2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice. Heart weight was greater in Bk2r
−/−
than in Bk2r
+/+
and Bk2r
+/−
mice (505±10 versus 449±12 and 477±10 mg/100 g body wt, P<.05). Chronic blockade of B
2
-receptors by Icatibant (50 nmol/100 g body wt twice a day SC) or inhibition of nitric oxide synthase by nitro-
l
-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r
+/+
to the levels of Bk2r
−/−
mice. Compared with the wild-type strain, both Bk2r
−/−
and Bk2r
+/−
mice showed exaggerated vasopressor responses to angiotensin II. In addition, chronic administration of an angiotensin AT
1
-receptor antagonist reduced the basal blood pressure of Bk2r
−/−
by 21±3 mm Hg (P<.05) to the levels of Bk2r
+/+
. No difference was detected between strains as far as plasma renin activity and the expression of renin and AT
1
-receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15 days) increased the blood pressure of Bk2r
−/−
and Bk2r
+/−
by 34±3 and 14±6 mm Hg, respectively, whereas it was ineffective in Bk2r
+/+
.

Conclusions
Our results suggest that a normally functioning B
2
-receptor is essential for the maintenance of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system could contribute to increase blood pressure levels by leaving the activity of vasoconstrictor agents unbalanced.
Vitamins C and E Inhibit O
2
−
Production in the Pig Coronary Artery
Authors: Nunes Gilberto L. , Robinson Keith , Kalynych Anna , King Spencer B. , Sgoutas Demetrios S. , Berk Bradford C.
Published: June 2012

Background
We previously found in a pig coronary balloon injury model that vitamins C and E as well as probucol had beneficial effects on the vessel response to injury measured by morphometry
.
These effects correlated with an inhibition in the ability to oxidize LDLs ex vivo, suggesting that the morphological response was due to the antioxidant effect of the treatments.

Methods and Results
In the present study, the production of O
2
−
by vessels 14 days after balloon injury was determined and correlated with circulating and tissue levels of vitamins C and E. Twenty-five domestic pigs were divided into four groups: control (n=7), vitamin C (500 mg/d, group C, n=6), vitamin E (1000 IU/d, group E, n=6), and vitamins C and E (500 mg/d and 1000 IU/d, group C+E, n=6). Vitamins were administered 7 days before oversized balloon injury of the left anterior descending coronary artery (LAD) and continued for 14 days after injury. Vitamin C and E concentrations were determined in plasma and lymphocytes as an index for tissue levels. Vessels were harvested after animals were killed, and O
2
−
production was measured by lucigenin chemiluminescence. O
2
−
production by the injured LAD was 2.5-fold greater than O
2
−
production by the uninjured LAD or right coronary artery (RCA). The increase in O
2
−
was caused primarily by cells present in the media and neointima. All vitamin-treated groups showed significantly decreased O
2
−
production in both the RCA and LAD (≈45% inhibition) relative to vessels in the control, untreated group. There was a significant correlation between LAD O
2
−
production and lymphocyte vitamin E levels.

Conclusions
The present study is the first to show increased O
2
−
production in injured vessels and to demonstrate that antioxidant vitamins reduce O
2
−
production. These results suggest that beneficial effects of antioxidant vitamins in coronary artery disease are related, in part, to alterations in vessel redox state.
Differential Effects of Endothelin Receptor Activation on Cyclic Flow Variations in Rat Mesenteric Arteries
Authors: Fujise Kenichi , Stacy Lowell , Beck Pamela , Yeh Edward T.H. , Chuang Alice , Brock Tommy A. , Willerson James T.
Published: June 2012

Background
Cyclic flow variations (CFVs) represent repetitive cycles of platelet adherence–aggregation and vasoconstriction, followed by dislodgment of platelet thrombi and restoration of blood flow at the site of vascular injury. Although activation of endothelin A (ETA) and endothelin B (ETB) receptors leads to vasoconstriction and nitric oxide release, respectively, the roles of endogenous endothelin-1 (ET-1) and its receptors in CFVs are unknown.

Methods and Results
A side branch of a mesenteric artery of male Wistar rats was cannulated and a short segment of the artery was mechanically injured to induce CFVs. After 20 minutes of saline infusion, either saline (negative control), BQ-123 (ETA receptor antagonist, 10 μg/min), BQ-788 (ETB receptor antagonist, 10 μg/min), or sarafotoxin S6c (ETB receptor agonist, 10 ng/min) was infused for 20 minutes from the side branch into the injured arterial segment. Percent (%) luminal stenosis as well as proximal and distal vessel diameters were observed and quantitatively measured every minute using intravital video microscopy and a micrometer-calibrated video screen. Both BQ-123 and sarafotoxin S6c significantly reduced CFVs represented by the mean luminal stenosis (BQ-123=29±13% and sarafotoxin S6c=27±11% reduction, respectively;
P
<.05 for both, compared with saline). In contrast, BQ-788 significantly increased CFVs (33±6% increase,
P
<.05 compared with saline). Moreover, the inhibitory effect of sarafotoxin S6c on CFVs was completely abolished in the presence of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) (a nitric oxide synthase inhibitor, 10
−5
mol/L) in superfusate over the arteries (16.1±5% increase,
P
=NS compared with saline in the presence of L-NAME). In addition, BQ-123 caused a significant increase in the diameter of the vessel distal to the injured segment (12±4% increase,
P
<.05 compared with saline).

Conclusions
Endogenous ET-1 release from sites of vascular injury contributes to CFVs and vasomotor tone in the rat mesenteric artery CFV model. ETA and ETB receptors have differential roles in CFVs: ETA receptor antagonism and ETB receptor stimulation reduce CFVs, the latter at least partially through increased nitric oxide formation.
Stabilization of Chronic Remodeling by Asynchronous Cardiomyoplasty in Dilated Cardiomyopathy
Authors: Patel Himanshu J. , Polidori David J. , Pilla James J. , Plappert Theodore , Kass David , Sutton Martin St John , Lankford Edward B. , Acker Michael A.
Published: June 2012

Background
Dynamic cardiomyoplasty is a promising new therapy for dilated cardiomyopathy. The girdling effects of a conditioned muscle wrap alone have recently been postulated to partly explain its mechanism. We investigated this effect in a canine model of chronic dilated cardiomyopathy.

Methods and Results
Twenty dogs underwent rapid ventricular pacing (RVP) for 4 weeks to create a model of dilated cardiomyopathy. Seven dogs were then randomly selected to undergo subsequent cardiomyoplasty, and all dogs had 6 weeks of additional RVP. The cardiomyoplasty group also received 6 weeks of concurrent skeletal muscle stimulation consisting of single twitches delivered asynchronously at 2 Hz to transform the wrap without active assistance. All dogs were studied by pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of pacing. Systolic indices, including ejection fraction (EF), end-systolic elastance (Ees), and preload-recruitable stroke work (PRSW) were all increased at 10 weeks in the wrap versus controls (EF, 34.0 versus 27.1,
P
=.008; Ees, 1.65 versus 1.26,
P
=.09; PRSW, 35.9 versus 25.5,
P
=.001). Ventricular volumes, diastolic relaxation, and left ventricular end-diastolic pressures stabilized in the cardiomyoplasty group but continued to deteriorate in controls. Both the end-systolic and end-diastolic pressure-volume relationships shifted farther rightward in controls but remained stable in the cardiomyoplasty group.

Conclusions
In addition to potential benefits from active systolic assistance, benefits from dynamic cardiomyoplasty appear to be partially accounted for by the presence of a conditioned muscle wrap alone. This conditioned wrap stabilizes the remodeling process of heart failure, arresting progressive deterioration of systolic and diastolic function.
Vesnarinone Prolongs Action Potential Duration Without Reverse Frequency Dependence in Rabbit Ventricular Muscle by Blocking the Delayed Rectifier K
+
Current
Authors: Toyama Junji , Kamiya Kaichiro , Cheng Jianhua , Lee Jong-Kook , Suzuki Ryoko , Kodama Itsuo
Published: June 2012

Background
Methanesulfonanilide derivatives, selective inhibitors of the rapidly activating component (
I
Kr
) of the delayed rectifier potassium current (
I
K
), prolong action potential duration (APD) of cardiac muscles with reverse frequency dependence, which limits their clinical use because of proarrhythmia. Vesnarinone, a quinolinone derivative developed as a cardiotonic agent, has complex pharmacological properties, but its clinical efficacy is explained in part by
I
K
reduction. Therefore, we investigated the mode of
I
K
block by vesnarinone.

Methods and Results
I
K
of the rabbit ventricular myocyte was activated by voltage-clamp steps applied from a holding potential to various depolarizing levels. The development of
I
K
block at depolarization (+10 mV) and its recovery process at hyperpolarization (−75 mV) were compared between vesnarinone and E-4031. The
I
K
block by vesnarinone (3 μmol/L) developed and recovered monoexponentially, with time constants of 361 ms (n=5) and 1.87 seconds (n=4), respectively.
I
K
block by E-4031 (0.3 μmol/L) developed instantaneously, with no recovery from the block at hyperpolarization. The
I
K
block by vesnarinone, estimated by
I
K
tail after a train of depolarizing pulses (for 30 seconds at 0.2 to 2 Hz), was increased with increasing frequency (twofold at 2 from 0.2 Hz), but that by E-4031 was unchanged. In rabbit papillary muscles, vesnarinone (10 μmol/L) prolonged APD at stimulation frequencies >0.2 Hz, whereas E-4031 (0.3 μmol/L) prolonged that in a reverse frequency-dependent manner.

Conclusions
Vesnarinone may prolong the repolarization of human cardiac muscle without reverse frequency dependence, because
I
Kr
is expressed in humans as well as in the rabbit. Thus, this drug may be a model for an ideal class III drug without the risk of proarrhythmia.
Electrical Remodeling due to Atrial Fibrillation in Chronically Instrumented Conscious Goats
Authors: Wijffels Maurits C. E. F. , Kirchhof Charles J. H. J. , Dorland Rick , Power John , Allessie Maurits A.
Published: June 2012

Background
Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling.

Methods and Results
Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6) or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K
+
ATP
channels by glibenclamide (10 μmol/kg; n=6) slightly increased the AFI from 95±4 to 101±5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69±14 versus 75±15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 μg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP from 134±10 to 105±6 ms and inversed its physiological rate adaptation.

Conclusions
Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.
Exaggerated Blood Pressure Responses During Mental Stress Are Associated With Enhanced Carotid Atherosclerosis in Middle-Aged Finnish Men
Authors: Kamarck Thomas W. , Everson Susan A. , Kaplan George A. , Manuck Stephen B. , Jennings J. Richard , Salonen Riitta , Salonen Jukka T.
Published: June 2012

Background
Exaggerated cardiovascular reactivity to mental stress is hypothesized to increase atherosclerotic risk. We examined this hypothesis using cross-sectional data from the Kuopio Ischemic Heart Disease study, a population-based epidemiological sample.

Methods and Results
901 Eastern Finnish men from four age cohorts (age, 42 to 60 years) were administered a standardized testing battery to assess cardiovascular reactivity to mental stress. Ultrasound measures of intima-medial thickness (IMT) and plaque height from the common carotid arteries were used as noninvasive markers of atherosclerosis. Diastolic blood pressure (DBP) responses to mental stress were significantly associated with mean IMT (
b
=.021,
P
=.006), maximum IMT (
b
=.026,
P
=.013), and mean plaque height (
b
=.017,
P
=.041). Significant associations were also shown between stress-related systolic blood pressure (SBP) reactivity and mean IMT (
b
=.0151,
P
=.042). When examined separately by age, associations with IMT were significant only in the youngest half of the sample (age, 46 and 52 years, n=433; for mean IMT, DBP
b
=.033,
P
=.0002, SBP
b
=.0266,
P
=.003; for maximum IMT, DBP
b
=.039,
P
=.002, SBP
b
=.032,
P
=.011). Results remained significant in the younger subjects after adjustment for smoking, lipid profiles, fasting glucose, and resting blood pressure (
b
=.024,
P
=.011); results also remained significant in a subgroup of unmedicated younger subjects without symptomatic cardiovascular disease (n=135; for SBP reactivity,
b
=.031,
P
=.036; for DBP,
b
=.037,
P
=.007).

Conclusions
The tendency to show exaggerated pressor responses to mental stress is a significant independent correlate of atherosclerosis in this population sample of Finnish men. The effect does not appear to be accounted for by the confounding influence of other risk factors or preexisting clinical disease.
Three-dimensional Mapping of the Common Atrial Flutter Circuit in the Right Atrium
Authors: Shah Dipen C. , Jaïs Pierre , Haïssaguerre Michel , Chouairi Salah , Takahashi Atsusi , Hocini Mélèze , Garrigue Stéphane , Clémenty Jacques
Published: June 2012

Background
The full circuit of common atrial flutter using conventional methods of sequential or multielectrode activation mapping is not completely understood.

Methods and Results
We performed three-dimensional right atrial endocardial activation mapping during common counterclockwise atrial flutter in 17 patients (16 men, 1 woman; mean age, 53±11 years) by using the Cordis-Biosense EP Navigation system and assessed the distribution of estimated conduction velocities and double and fractionated potentials. ECG flutter wave morphologies were compared with activation patterns. Points (91±29) were sequentially acquired covering 88±11% of the flutter cycle length of 239±22 ms. A wide and variable posterior zone of double and fractionated potentials coincided with blocking and colliding wave fronts and formed the posterior limit of the circuit. A progressively widening septal (sep) wave front ascending from just beyond the coronary sinus ostium, passed cranially as a broad front anterior to the superior vena cava (SVC) in 14 patients, whereas fusion around the SVC formed the superior (sup) limb of the circuit in 3. Bounded anteriorly by the tricuspid valve, the wave front descended down the lateral (lat) aspect of the right atrium before completing the circuit in all cases through the inferior vena cava–tricuspid annulus isthmus. The estimated conduction velocity in the medial isthmus (0.6±0.3 m/s) was lower than in the other limbs of the circuit (sup=1±0.5 m/s, lat=1±0.5 m/s, sep=0.9±0.4 m/s,
P
=.05). Double and fractionated potentials were constant and more prevalent in the posterior right atrium. ECG flutter wave morphology did not correlate with three-dimensional activation maps.

Conclusions
Interindividual variations occur in the right atrial circuit of common atrial flutter, with constant activation through the cavotricuspid isthmus. A variable zone of block forms the posterior limit. Fusion around the SVC can occur, and ascending medial septal activation does not follow a consistent pattern.