bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Diagnosis With the Denaturing Gradient Gel Electrophoresis Technique Improves Diagnostic Precision in Familial Hypercholesterolemia
Authors: Nissen Henrik , Hansen Annebirthe Bo , Guldberg Per , Petersen Niels Erik , Larsen Mogens Lytken , Haghfelt Torben , Kristiansen Karsten , Hørder Mogens
Published: June 2012

Background
Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder of lipid metabolism caused by mutations in the LDL receptor gene. FH is characterized clinically by elevated LDL cholesterol level and premature coronary disease. Diagnosing FH on clinical grounds may be difficult, and previous genetic methods are too cumbersome for routine use except in the few populations with FH-founder mutations. A simple mutation screening technique based on denaturing gradient gel electrophoresis (DGGE) has been highly useful in detecting mutations in other genes, and in the present study we evaluated the diagnostic potential of this method for the diagnosis of FH.

Methods and Results
Conditions for screening exon 3 of the LDL receptor gene using the DGGE technique were established and 14 Danish FH families were examined. An index patient from 1 family had an abnormal DGGE pattern; consequently, an examination of exon 3 of the LDL receptor gene in 21 members of this patient’s family was done. The DGGE pattern was seen only in patients with a definite clinical diagnosis of FH. Subsequent sequencing of exon 3 of the LDL receptor gene in these individuals revealed the presence of the French-Canadian type 4 Trp
66
-Gly mutation. However, in 4 of 11 cases in which a definite clinical diagnosis of FH had been made, the inheritance of the French-Canadian type 4 mutation could be rejected on the basis of genetic analysis.

Conclusions
Introduction of a simple genetic analysis based on DGGE may improve the precision of diagnosis in FH families.
Enalapril Treatment Increases Cardiac Performance and Energy Reserve Via the Creatine Kinase Reaction in Myocardium of Syrian Myopathic Hamsters With Advanced Heart Failure
Authors: Nascimben Luigino , Friedrich Jan , Liao Ronglih , Pauletto Paolo , Pessina Achille C. , Ingwall Joanne S.
Published: June 2012

Background
Converting enzyme inhibitor treatment of congestive heart failure slows progression to failure and reduces mortality rate. It is not known whether these benefits are due solely to improved hemodynamics or also to improved myocyte energetics. This study examines the effect of enalapril treatment on both isovolumic contractile performance and its biochemical correlate, flux through the creatine kinase (CK) system, in an animal model of severely failing myocardium.

Methods and Results
Seven-month-old Syrian cardiomyopathic (TO-2 strain) and normal golden Syrian (FIB strain) hamsters were each randomly assigned to one of three groups supplied daily with either no, low (25 mg/kg body wt), or high (100 mg/kg body wt) doses of enalapril for 12 to 14 weeks. At 10 months of age, all substrates and products and flux through the CK reaction were measured in isolated perfused hearts by
31
P magnetization transfer and chemical assay. Compared with normal hamsters, the myopathic hamsters exhibited significantly lower body weights and higher biventricular heart weights, which were partially reversed by drug treatment. The Langendorff-perfused hearts showed decreased isovolumic contractile performance with identical load conditions. This was partially reversed by drug treatment. In the failing hearts, the following substrate and product concentrations and enzyme activities were decreased compared with nonfailing hearts but were unchanged by drug treatment: ATP (−28%), phosphocreatine (−48%), free creatine (−64%), ADP (−51%), and CK (−34%, primarily MM isoenzyme). Flux through the CK reaction for the untreated cardiomyopathic hamster hearts was decreased by 67%, and this decrease was almost completely reversed by enalapril treatment. The increased CK flux is due to an increase in the rate constant for the reaction, since substrate concentrations are unchanged, and is not predicted by the rate equation. In enalapril-treated failing hearts, phosphoryl transfer via the CK reaction increased with contractile performance. This was not observed in the nonfailing hearts, in which energy reserve is adequate to support changes in contractile performance.

Conclusions
Decreased flux through CK reaction leads to decreased capacity for ATP synthesis and may contribute to decreased contractile performance in cardiomyopathic hamster hearts. Enalapril treatment results in increased phosphoryl transfer through the CK reaction in failing myocardium, and this increase is coupled to improved cardiac performance. Decreased CK flux in failing hearts is due to a combination of decreased V
max
and lower guanidino pool; this mechanism fails to explain changes in CK flux in enalapril-treated failing hearts.
Cytomegalovirus Replication Is Not a Cause of Instability in Unstable Angina
Authors: Kol Amir , Sperti Giovanni , Shani Jacob , Schulhoff Nancy , van de Greef Willy , Landini Maria Paola , La Placa Michele , Maseri Attilio , Crea Filippo
Published: June 2012

Background
Unstable angina is most frequently caused by coronary thrombosis, with or without plaque fissure, but the mechanisms underlying these events are still speculative. Since cytomegalovirus (CMV) antigens and DNA encoding CMV major immediate-early (MIE) gene have been detected in atherosclerotic arterial walls, the active replication of CMV may be responsible for plaque instability. Therefore the expression of CMV MIE gene mRNA, an early marker of viral replication, was assessed in coronary atherectomy specimens from patients with stable or unstable angina.

Methods and Results
Twenty patients with unstable angina (12 men and 8 women; mean age, 62 years; range, 44 to 89 years) and 20 patients with stable angina (16 men and 4 women; mean age, 62 years; range, 43 to 81 years) who underwent successful directional coronary atherectomy were enrolled in the study. The efficiency of mRNA extraction, transcription, and amplification from each coronary atherectomy specimen was assessed by performance of reverse transcription and thermal cycling amplification of a 548-bp human β-actin cDNA segment. After Southern blotting and hybridization with a specific probe, all specimens but one showed a positive hybridization signal. The negative sample was excluded from the study. Reverse transcription and thermal cycling amplification of a 145-bp CMV cDNA segment of the MIE gene were then carried out. After Southern blotting and hybridization with a specific probe, none of the specimens showed a positive hybridization signal. Plasmid pACYC 184 containing the
Xba
I–inserted MIE gene cDNA was used as a positive control: as few as 10 molecules of the plasmid per reaction were detectable after amplification.

Conclusions
Our results do not support the hypothesis that, in patients with unstable angina, replication of CMV in coronary atherosclerotic plaques is a major cause of plaque instability. These findings suggest that the research for the causes of unstable angina should be directed toward processes other than CMV replication.
Regulation of Potassium Channels by Nonsedating Antihistamines
Authors: Berul Charles I. , Morad Martin
Published: June 2012

Background
Terfenadine and astemizole are widely prescribed nonsedating antihistamines that have been associated with QT-interval prolongation and ventricular arrhythmias. Since potassium channels are intrinsically involved in repolarization, this study was designed to evaluate the effect of the nonsedating antihistamines on potassium channel modulation.

Methods and Results
The whole-cell patch-clamp technique was used to study K
+
currents in enzymatically isolated rat and guinea pig ventricular myocytes. Three distinct K
+
channels were examined: the inward rectifier (I
K1
), the delayed rectifier (I
K
), and the transient outward (I
to
) currents. The dialyzing pipette solution was buffered with EGTA, and ionic channels other than potassium were pharmacologically inhibited or electrically inactivated. Both astemizole and terfenadine suppressed the I
K1
channel by 17% to 50% in a voltage-dependent manner in rat and guinea pig myocytes. I
to
was evaluated in rat ventricular myocytes. Both drugs also inhibited the maintained component of I
to
to a lesser extent, by 23%, in a dose-dependent, reversible manner. I
K
was examined mainly in guinea pig myocytes. Terfenadine but not astemizole slightly inhibited I
K
, by 9%, and only at higher drug concentrations. The medications had dose-dependent inhibitory actions, with specific K
+
channel suppression evident only beginning at concentrations >0.1 μmol/L.

Conclusions
These findings suggest that the mechanism of action of the rare proarrhythmic effects of the nonsedating antihistamines appears to be secondary to potassium channel blockade. A significant voltage-dependent blockade of the I
K1
channel was demonstrated, as well as additional inhibitory effects on I
to
and I
K
channels. These actions lead to delayed repolarization, QT interval prolongation, and enhanced susceptibility to the development of premature ventricular depolarizations. Caution is advised in the prescription of nonsedating antihistamines, particularly in patients at risk of elevated serum levels of the antihistamine or patients with existing repolarization abnormalities.
Radiofrequency Catheter Ablation of the Atria Reduces Inducibility and Duration of Atrial Fibrillation in Dogs
Authors: Elvan Arif , Pride Harald P. , Eble John N. , Zipes Douglas P.
Published: June 2012

Background
The purpose of this study was to prevent induction of sustained atrial fibrillation (AF) by radiofrequency catheter ablation (RFCA) of the atria in an open-chest canine model.

Methods and Results
In dogs randomized to acute studies, RFCA of the atria was performed after reproducible induction of sustained AF (lasting >30 minutes) with burst stimulation or premature atrial pacing and perpetuation by low level cervical vagal stimulation or IV infusion of methacholine. Additionally, in four dogs, the long-term effectiveness of RFCA was assessed 7 to 21 days after ablation. Continuous discrete transmural lesions were produced with radiofrequency energy pulses (20 to 40 W for 60 seconds) delivered to five atrial epicardial sites and endovascularly to the coronary sinus wall. RFCA electrically isolated regions of the atria that became dissociated from the nonisolated parts. Atrial RFCA markedly attenuated vagally induced shortening of effective refractory period (ERP) at both isolated and nonisolated test sites located in the left and right atria (
P
<.001, n=5). RFCA rendered noninducible sustained AF maintained by cervical vagal stimulation. The dose-response curve relating the dose of methacholine required to maintain AF was shifted down and to the right. AF was only inducible with high doses of methacholine. Atrial RFCA reduced the maximal sinus rate and prolonged the corrected sinus-node recovery time (
P
<.001, n=6). However, RFCA did not affect atrial contractile function, AV-nodal ERP, or AV-nodal or His-Purkinje conduction times. In dogs in the chronic group, normal sinus rhythm and normal AV conduction were preserved and AF was only inducible with a high dose of methacholine. No atrial perforations resulted.

Conclusions
RFCA in open-chest dogs produces partial vagal denervation and reduces the inducibility of AF.
Regional Left Ventricular Systolic Function in Relation to the Cavity Geometry in Patients With Chronic Right Ventricular Pressure Overload
Authors: Dong Sheng-Jing , Crawley Adrian P. , MacGregor John H. , Petrank Yael Fisher , Bergman Dale W. , Belenkie Israel , Smith Eldon R. , Tyberg John V. , Beyar Rafael
Published: June 2012

Background
Distortion of the left ventricular (LV) cavity in patients with right ventricular pressure overload (RVPO) is well known. However, no direct measurements of regional myocardial function in terms of myocardial shortening and wall thickening are available; therefore, exactly how RVPO disturbs LV regional performance remains unclear. By using three-dimensional (3D) tagged magnetic resonance imaging, we were able to measure regional systolic function directly. Our objective was to study the relation between the distortion of the LV circular shape and regional LV function.

Methods and Results
In nine patients with RVPO and six healthy volunteers, four parallel short-axis images (with 12 radial tags) and two mutually orthogonal long-axis images (with four parallel tags) were generated, and endocardial and epicardial borders were manually traced. By integration of the short- and long-axis images, 3D reconstruction of the LV tracking points from end diastole to end systole was obtained. Data from the midventricular two short-axis image slices were analyzed. These were then divided into anterior, lateral, posterior, and septal regions. Circumferential and longitudinal shortening were then calculated from the endocardial and epicardial tag intersection points. Wall thickness and thickening were calculated by the 3D volume-element approach. An eccentricity index (EI), the ratio of septum-to-free-wall to anteroposterior diameters, was used to describe the shape of the LV cavity. The regional curvature was also measured. The RVPO group was characterized by flattening of the septum and LV lateral wall, decreased EI reflecting the distorted LV shape, altered distribution of endocardial circumferential shortening, and preserved ejection fraction. Changes in EI closely correlated with the septal curvature. The EI was smaller at end systole, reflecting further shape distortion relative to end diastole. Reduced myocardial performance, as measured by wall thickening and circumferential and longitudinal shortening fractions, was observed for the septum. A reduction in endocardial circumferential shortening of the septal and lateral walls was directly related to the end-systolic EI. In addition, whereas for healthy subjects a linear relation between area ejection fraction and endocardial circumferential shortening was observed, in RVPO patients a curvilinear (quadratic) relation was observed.

Conclusions
In patients with RVPO, compared with healthy subjects, the septal function was reduced, as evidenced by reduced thickening and shortening fractions. The distortion in LV cavity at end systole due to the flattening of the septum contributes to preserved systolic ventricular function and nonuniform distribution in endocardial circumferential shortening.
Effect of Subendocardial Resection on Sinus Rhythm Endocardial Electrogram Abnormalities
Authors: Miller John M. , Tyson George S. , Hargrove W. Clark , Vassallo Joseph A. , Rosenthal Mark E. , Josephson Mark E.
Published: June 2012

Background
Patients with sustained ventricular tachycardia after acute myocardial infarction frequently have characteristic abnormalities of left ventricular endocardial electrical activity, including fractionated (prolonged, multicomponent, low-amplitude), split (having discrete widely separated deflections), and late (extending after the end of the QRS complex) electrograms. The exact cause and source of these electrograms are not clear.

Methods and Results
In this study, endocardial electrograms from 18 patients were recorded with a 20-electrode array from the same area immediately before and immediately after resection of subendocardial tissue at the time of surgery for ventricular tachycardia. Electrograms could be compared before and after resection from 298 of 360 (83%) of the electrodes. Before resection, split electrograms were present in 130 (44%) and late components in 81 (27%) of the recordings. Recordings made after resection showed fewer abnormalities, including complete absence of split electrograms as well as all previously recorded late components (
P
<.02). Mean electrogram amplitude increased from 0.5±0.8 to 1.0±1.6 mV (
P
<.0001) because of removal of the attenuating effect of endocardial scar; mean duration decreased from 112±38 to 65±27 ms (
P
<.0001) mainly because of loss of late and split components. Overall electrogram contour was very similar aside from these changes.

Conclusions
These data show that (1) some of the signal recorded on the endocardial surface is derived from deeper tissue layers and (2) split and late electrogram components appear to be generated by cells in the superficial endocardial layers, since they are eradicated by removal of this tissue. These findings correspond well with previous histological studies of resection specimens that show bundles of surviving muscle cells separated by layers of dense scar that act as an insulator.
Steroid Elution Improves the Stimulation Threshold in an Active-Fixation Atrial Permanent Pacing Lead
Authors: Crossley George H. , Brinker Jeffrey A. , Reynolds Dwight , Spencer William , Johnson W. Ben , Hurd Howard , Tonder Lisa , Zmijewski Matt
Published: June 2012

Background
Prior work suggests that the addition of a steroid-eluting reservoir to a passive-fixation permanent pacemaker lead improves the stimulation threshold; however, no large randomized study has addressed this issue. Over the last several years, there has been an increase in enthusiasm for the use of active-fixation permanent pacemaker leads for various reasons in spite of the generally accepted notion that active-fixation leads have higher stimulation thresholds.

Methods and Results
This multicenter, randomized, controlled study examined the difference in performance between a standard active-fixation atrial lead (Medtronic model 4058) and a steroid-eluting lead (Medtronic model 4068). Stimulation thresholds were obtained in a four-point strength-duration fashion. Evaluations of sensing and impedance were performed as well. These evaluations were performed at implantation, at weeks 1 through 4, and at weeks 6, 12, 24, and 52. Stimulation thresholds were significantly better in the steroid lead than in the nonsteroid lead at each measurement point from 1 week to 12 months. The mean 1.6-V stimulation threshold at 12 months was 0.19±0.2 ms in the steroid lead and 0.41±0.30 ms in the control lead. No acute peaking was observed with the steroid lead, whereas significant peaking was observed with the control lead. There was no difference in long-term sensing or impedance.

Conclusions
Inclusion of a steroid-eluting reservoir in an active-fixation permanent pacing lead improved stimulation thresholds in both the subacute and chronic periods and therefore should extend pulse-generator longevity.
Regional Differences in Transient Outward Current Density and Inhomogeneities of Repolarization in Rabbit Right Atrium
Authors: Yamashita Takeshi , Nakajima Toshiaki , Hazama Hisanori , Hamada Eiji , Murakawa Yuji , Sawada Kouhei , Omata Masao
Published: June 2012

Background
Recent experimental and clinical studies on atrial flutter have demonstrated that the crista terminalis (CT) plays an important role in the genesis of atrial reentry. To elucidate the underlying mechanism of its role, we characterized the electrophysiological repolarization properties of CT cells by comparing them with those of the pectinate muscles (PM).

Methods and Results
After action potential properties of both regions were compared by conventional microelectrode technique in multicellular atrial tissues, the whole-cell clamp experiments were applied in atrial cells isolated from both regions. Action potential duration (APD) was more prolonged in CT than in PM in multicellular preparations (APD
90
77±5 ms versus 52±8 ms at 1 Hz,
P
<.01), though the other properties did not differ significantly. Similarly, in isolated atrial cells, APD was more prolonged in CT cells than in PM cells (APD
90
63±7 ms versus 41±6 ms at 0.1 Hz,
P
<.01). Isolated single cells were larger in CT than in PM. The whole-cell clamp recordings showed no definite distinctions in the density of the voltage-dependent L-type Ca
2+
current and the inwardly rectifying K
+
current between these cells but revealed a significant reduction of the density of the 4-aminopyridine–sensitive transient outward current (I
to
) in CT cells compared with that in PM cells (6.3±0.7 pA/pF versus 10.3±0.8 pA/pF at +20 mV,
P
<.05). However, no differences in the kinetics or the voltage dependence of I
to
were observed between the cells. The time course of recovery from inactivation of I
to
was also similar in both types of cells.

Conclusions
These results suggest that the preferential reduction in the density of I
to
in the CT cells could contribute to prolong their APD, which may be related to the genesis of atrial reentry.
Effect of Thromboxane A
2
Blockade on Clinical Outcome and Restenosis After Successful Coronary Angioplasty
Authors: Savage Michael P. , Goldberg Sheldon , Bove Alfred A. , Deutsch Ezra , Vetrovec George , Macdonald Robert G. , Bass Theodore , Margolis James R. , Whitworth Hall B. , Taussig Andrew , Hirshfeld John W. , Cowley Michael , Hill James A. , Marks Ronald G. , Fischman David L. , Handberg Eileen , Herrmann Howard , Pepine Carl J.
Published: June 2012

Background
Antithromboxane therapy with aspirin reduces acute procedural complications of coronary angioplasty (PTCA) but has not been shown to prevent restenosis. The effect of chronic aspirin therapy on long-term clinical events after PTCA is unknown, and the utility of more specific antithromboxane agents is uncertain. The goal of this study was to assess the effects of aspirin (a nonselective inhibitor of thromboxane A
2
synthesis) and sulotroban (a selective blocker of the thromboxane A
2
receptor) on late clinical events and restenosis after PTCA.

Methods and Results
Patients (n=752) were randomly assigned to aspirin (325 mg daily), sulotroban (800 mg QID), or placebo, started within 6 hours before PTCA and continued for 6 months. The primary outcome was clinical failure at 6 months after successful PTCA, defined as (1) death, (2) myocardial infarction, or (3) restenosis associated with recurrent angina or need for repeat revascularization. Neither active treatment differed significantly from placebo in the rate of angiographic restenosis: 39% (73 of 188) in the aspirin-assigned group, 53% (100 of 189) in the sulotroban group, and 43% (85 of 196) in the placebo group. In contrast, aspirin therapy significantly improved clinical outcome in comparison to placebo (
P
=.046) and sulotroban (
P
=.006). Clinical failure occurred in 30% (49 of 162) of the aspirin group, 44% (73 of 166) of the sulotroban group, and 41% (71 of 175) of the placebo group. Myocardial infarction was significantly reduced by antithromboxane therapy: 1.2% in the aspirin group, 1.8% in the sulotroban group, and 5.7% in the placebo group (
P
=.030).

Conclusions
Thromboxane A
2
blockade protects against late ischemic events after angioplasty even though angiographic restenosis is not significantly reduced. While both aspirin and sulotroban prevent the occurrence of myocardial infarction, overall clinical outcome appears superior for aspirin compared with sulotroban. Therefore, aspirin should be continued for at least 6 months after coronary angioplasty.
Effect of Lean Body Mass, Fat Mass, Blood Pressure, and Sexual Maturation on Left Ventricular Mass in Children and Adolescents
Authors: Daniels Stephen R. , Kimball Thomas R. , Morrison John A. , Khoury Philip , Witt Sandra , Meyer Richard A.
Published: June 2012

Background
Left ventricular hypertrophy has been established as an independent risk factor for the development of cardiovascular morbidity and mortality. It is clear that left ventricular mass increases during childhood and adolescence with body growth. The extent to which other factors, such as obesity, stage of sexual maturation, and level of blood pressure, determine left ventricular mass has been controversial.

Methods and Results
The study was a cross-sectional evaluation of the relationship of left ventricular mass determined by echocardiography with lean body mass and fat mass determined by dual-energy x-ray absorptiometry, which is the most valid and reliable method for determination of body composition in children and adolescents. The relationship of left ventricular mass with the stage of sexual maturation and with systolic and diastolic blood pressure was also evaluated. Two hundred one subjects (105 boys, 96 girls; 103 white and 98 black) 6 to 17 years old were studied. Age (
r
=.72), height (
r
=.81), weight (
r
=.84), body surface area (
r
=.87), sexual maturation (
r
=.75), lean body mass (
r
=.86), fat mass (
r
=.54), systolic BP (
r
=.58), and diastolic BP (
r
=.48) were all univariate correlates of left ventricular mass. In a multiple regression analysis, only lean body mass, fat mass, and systolic blood pressure were statistically significant independent correlates of left ventricular mass. Lean body mass alone explained 75% of the variance of left ventricular mass, whereas fat mass and systolic blood pressure explained only 1.5% and 0.5% of the variance, respectively. Lean body mass was the strongest determinant of left ventricular mass in all four race-sex groups.

Conclusions
This study provides an opportunity to separate the effects on left ventricular mass of lean body mass resulting from linear growth from those of fat mass resulting from obesity. Lean body mass, fat mass, and systolic blood pressure all have a statistically significant independent association with left ventricular mass, suggesting that all three play an important biological role in determining left ventricular mass. However, fat mass and systolic blood pressure have only a small impact on left ventricular mass. This indicates that fat mass and blood pressure would be expected to be of only minor clinical importance in determining left ventricular mass in normal children and adolescents.
Quantitative Relation Between Myocardial Viability and Improvement in Heart Failure Symptoms After Revascularization in Patients With Ischemic Cardiomyopathy
Authors: Di Carli Marcelo F. , Asgarzadie Farbod , Schelbert Heinrich R. , Brunken Richard C. , Laks Hillel , Phelps Michael E. , Maddahi Jamshid
Published: June 2012

Background
Studies of patients with coronary artery disease and left ventricular dysfunction have shown that preoperative quantification of myocardial viability may be clinically useful to identify those patients who will benefit most from revascularization both functionally and prognostically. However, the relation between preoperative extent of viability and change in heart failure symptoms has not been documented carefully. We assessed the relation between the magnitude of improvement in heart failure symptoms after coronary artery bypass surgery (CABG) and the extent of myocardial viability as assessed by use of quantitative analysis of preoperative positron emission tomography (PET) images.

Methods and Results
We studied 36 patients with ischemic cardiomyopathy (mean left ventricular ejection fraction, 28±6%) undergoing CABG. Preoperative extent and severity of perfusion abnormalities and myocardial viability (flow-metabolism mismatch) were assessed by use of quantitative analysis of PET images with
13
N ammonia and fluorine-18-deoxyglucose. Each patient’s functional status was determined before and after CABG by use of a Specific Activity Scale. Mean perfusion defect size and severity were 63±13% and 33±12%, respectively. Total extent of a PET mismatch correlated linearly and significantly with percent improvement in functional status after CABG (
r
=.87,
P
<.0001). A blood flow–metabolism mismatch ≥18% was associated with a sensitivity of 76% and a specificity of 78% for predicting a change in functional status after revascularization. Patients with large mismatches (≥18%) achieved a significantly higher functional status compared with those with minimal or no PET mismatch (<5%) (5.7±0.8 versus 4.9±0.7 metabolic equivalents,
P
=.009). This resulted in an improvement of 107% in patients with large mismatches compared with only 34% in patients with minimal or no PET mismatch.

Conclusions
In patients with ischemic cardiomyopathy, the magnitude of improvement in heart failure symptoms after CABG is related to the preoperative extent and magnitude of myocardial viability as assessed by use of PET imaging. Patients with large perfusion-metabolism mismatches exhibit the greatest clinical benefit after CABG.
31
P Nuclear Magnetic Resonance Spectroscopic Imaging of Regions of Remodeled Myocardium in the Infarcted Rat Heart
Authors: Friedrich Jan , Apstein Carl S. , Ingwall Joanne S.
Published: June 2012

Background
The clinical course of a patient with a myocardial infarction (MI) depends largely on the ability of the noninfarcted region to remodel and compensate for the loss of the infarcted region. Previous studies have shown that the remaining viable myocardium remodels morphologically, functionally, and biochemically. The purpose of this study was to define the regional distribution of the biochemical remodeling that occurs after MI in rat hearts by use of a technique that could be applied noninvasively to human subjects.

Methods and Results
Infarcts of the left ventricular apex and anterolateral wall were induced by occluding a coronary artery. Eight to 10 weeks after infarction, one-dimensional chemical shift imaging (CSI) was used to obtain
31
P nuclear magnetic resonance (NMR) spectra of eight 2.5-mm-thick cross-sectional slices along the long axis (from base to apex) of isolated buffer-perfused rat hearts. Regional ATP and phosphocreatine (PCr) contents were compared in remodeled versus normal (sham) myocardium. Spin-echo
1
H MR images identified the mass of each slice, allowing calculations of metabolite amount per unit myocardium in each slice.
1
H MR images identify the hypertrophy of remodeled myocardium but do not discriminate between scar and viable tissue. In contrast,
31
P CSI does distinguish viable tissue. Compared with shams, there was less
31
P signal in the slices distal to the occlusion containing mainly scar tissue and increased signal intensity in slices proximal to the occlusion because of myocyte hypertrophy. The ATP signal intensity changed in direct proportion to the viable tissue mass in the slice, suggesting that the amount of ATP per unit mass in viable remodeled myocardium is the same as that of the shams. In contrast, the amount of PCr per unit mass in remodeled myocardium decreased. This decrease is uniform across the slices, correlates with infarct size, and parallels a similar decrease in tissue creatine content.

Conclusions
31
P CSI of post-MI hearts shows that (1) PCr decreases uniformly (ie, independent of the distance from the scar) in the noninfarcted remodeled myocardium, and its amount inversely correlates with infarct size; and (2) the ATP signal provides a profile of viable myocardium and is a biochemical marker of morphological remodeling and hypertrophy that has occurred in noninfarcted regions. Thus,
31
P CSI provides both a marker that tissue injury has occurred (decreased PCr) and a marker of the extent of remodeling in response to injury (ATP distribution) in a single set of noninvasive measurements.
Relation Between Diastolic Perfusion Time and Coronary Artery Stenosis During Stress-Induced Myocardial Ischemia
Authors: Ferro Giuseppe , Duilio Carlo , Spinelli Letizia , Liucci Giovanni Antonio , Mazza Felice , Indolfi Ciro
Published: June 2012

Background
Experimental studies have demonstrated that during stress-induced myocardial ischemia, coronary obstruction and diastolic perfusion time are factors that limit subendocardial perfusion and correlate to degree of myocardial dysfunction. The relation between these two factors has not yet been investigated in humans. The aim of the present study was to assess the relation between diastolic perfusion time and degree of coronary stenosis during different types of stress tests.

Methods and Results
Nine patients with isolated and proximal stenosis of the left anterior descending coronary artery were selected. Patients underwent three different randomized stress tests (upright, supine bicycle stress test, and transesophageal atrial pacing). Diastolic perfusion time, heart rate (RR interval), and systolic and diastolic pressures were measured during the test and at the ischemic threshold (0.1-mV ST-segment depression). Angiographic measurements of coronary stenosis were evaluated by quantitative coronary angiography. At the ischemic threshold, significant differences among tests were found in heart rate (
P
<.05), systolic pressure (
P
<.001), and diastolic pressure (
P
<.05). In each stress test, diastolic perfusion time at the ischemic threshold was closely correlated with minimal stenosis diameter (
r
=.97;
P
<.001) and percent diameter stenosis (
r
=.92;
P
<.001) with no difference among the tests. In contrast, heart rate, rate-pressure product, and time to ischemic threshold were not significantly correlated with percent diameter stenosis and minimal stenosis diameter. No significant correlation was observed at the ischemic threshold between diastolic perfusion time and corresponding values of heart rate, despite the close correlation at rest (
r
=.95;
P
<.001).

Conclusions
Despite differences in associated hemodynamic responses to various stress tests, a close relation exists between stenosis severity and diastolic perfusion time at the onset of stress-induced myocardial ischemia. Therefore, diastolic perfusion time at the ischemic threshold may be an indirect estimate of the hemodynamic significance of coronary stenosis.
Relationship of the Third Heart Sound to Transmitral Flow Velocity Deceleration
Authors: Manson Abigail L. , Nudelman Scott P. , Hagley Michael T. , Hall Andrew F. , Kovács Sándor J.
Published: June 2012

Background
The third heart sound (S
3
) occurs shortly after the early (E-wave) peak of the transmitral diastolic Doppler velocity profile (DVP). It is thought to be due to cardiohemic vibrations powered by rapid deceleration of transmitral blood flow. Although the presence, timing, and clinical correlates of the S
3
have been extensively characterized, derivation and validation of a causal, mathematical relation between transmitral flow velocity and the S
3
are lacking.

Methods and Results
To characterize the kinematics and physiological mechanisms of S
3
production, we modeled the cardiohemic system as a forced, damped, nonlinear harmonic oscillator. The forcing term used a closed-form mathematical expression for the deceleration portion of the DVP. We tested the hypothesis that our model’s predictions for amplitude, timing, and frequency of S
3
accurately predict the transthoracic phonocardiogram, using the simultaneously recorded transmitral Doppler E wave as input, in three subject groups: those with audible pathological S
3
, those with audible physiological S
3
, and those with inaudible S
3
.

Conclusions
We found excellent agreement between model prediction and the observed data for all three subject groups. We conclude that, in the presence of a normal mitral valve, the kinematics of filling requires that all hearts have oscillations of the cardiohemic system during E-wave deceleration. However, the oscillations may not have high enough amplitude or frequency to be heard as an S
3
unless there is sufficiently rapid fluid deceleration (of the Doppler E-wave contour) with sufficient cardiohemic coupling.
The Risk of Atrial Fibrillation Following Radiofrequency Catheter Ablation of Atrial Flutter
Authors: Philippon François , Plumb Vance J. , Epstein Andrew E. , Kay G. Neal
Published: June 2012

Background
Although radiofrequency catheter ablation of atrial flutter is associated with a high rate of initial success, several clinical issues regarding this therapy remain to be defined. For example, the risks of recurrent atrial flutter and of developing atrial fibrillation after flutter ablation are unknown. In addition, it is not known whether elimination of atrial flutter will modify the natural history of atrial fibrillation in patients who experience both of these arrhythmias. The purpose of the present study was to determine the actuarial freedom from recurrent or new atrial arrhythmias in patients with atrial flutter undergoing catheter ablation.

Methods and Results
The study population consisted of 59 consecutive patients (mean age, 61.9±12.6 years) with typical atrial flutter who underwent catheter ablation of the reentrant circuit. Catheter ablation was not advised for patients in whom paroxysmal atrial fibrillation had been a major clinical problem. The inducibility of atrial fibrillation and atrial flutter was assessed after successful atrial flutter ablation with programmed atrial stimulation and rapid atrial pacing to a cycle length of 180 ms or 2:1 atrial capture. Atrial flutter was successfully ablated and rendered noninducible in 53 of 59 patients (90%). Over a mean follow-up period of 13.2±6.6 months, atrial flutter recurred in 5 patients (9.4%). Atrial fibrillation occurred in 14 of 53 patients after successful ablation (26.4%). Four clinical variables were associated by univariate analysis with the late occurrence of atrial fibrillation: (1) the presence of structural heart disease, (2) a history of atrial fibrillation before ablation of atrial flutter, (3) inducible sustained atrial fibrillation after ablation, and (4) a greater number of failed antiarrhythmic drugs. By multivariate analysis, only the persistent inducibility of sustained atrial fibrillation predicted the later development of atrial fibrillation.

Conclusions
Although atrial flutter ablation is highly effective and associated with a low risk of recurrent atrial flutter, atrial fibrillation continues to be a long-term risk for individuals undergoing this procedure. The risk of later atrial fibrillation is especially high for patients in whom sustained atrial fibrillation remains inducible after ablation of atrial flutter.
Longitudinal Gradients for Endothelium-Dependent and -Independent Vascular Responses in the Coronary Microcirculation
Authors: Kuo Lih , Davis Michael J. , Chilian William M.
Published: June 2012

Background
Coronary microvessels (<300 μm in diameter) have been demonstrated to be important in the regulation of local resistance and flow. Recent studies also suggest that these microvessels are more responsive to physiological and pharmacological stimuli than conduit vessels. However, little is known regarding the relative sensitivity of different microvascular segments in response to flow (shear stress) and agonists. The goal of this study was to test the hypothesis that a longitudinal gradient for shear stress– and agonist-induced dilation exists in the coronary microcirculation.

Methods and Results
Experiments were performed in four different sizes of porcine subepicardial coronary arterial microvessels: small arterioles (40±1-μm ID with resting tone); intermediate arterioles (60±1 μm); large arterioles (106±4 μm); and small arteries (179±9 μm). Vessels were isolated and cannulated to allow luminal pressure and flow to be independently controlled. All vessels developed active tone (to ≈65% to 75% of maximum diameter) at their control luminal pressures and showed graded dilations to stepwise increases in shear stress (0 to 10 dynes/cm
2
). For arterioles, the magnitude of the dilations increased as vessel size increased. The highest shear stress produced 21±3%, 32±2%, and 52±5% increases in diameter in small, intermediate, and large arterioles, respectively. Small arteries dilated only 22±6%. The endothelium-dependent vasodilator substance P (SP) produced dose-dependent dilation of all vessels with a threshold at 10
−16
mol/L. Arterioles were maximally dilated at 10
−9
mol/L SP. However, this dose produced only 80% dilation in small arteries. The ED
50
for SP was shifted to the right by two orders of magnitude in small arteries compared with the arterioles. Adenosine preferentially dilated small arterioles, and the dose-response curves shifted to the right for larger vessels. The thresholds for adenosine-induced dilation were 10
−12
, 10
−11
, and 10
−9
mol/L for small, intermediate, and large arterioles, respectively. The endothelium-independent vasodilator nitroprusside produced identical dose-dependent dilations in all vessel segments.

Conclusions
The results indicate that the pig coronary circulation exhibits a heterogeneity in physiological and pharmacological responses along the microvascular network. Small arterioles are more sensitive to adenosine, but large arterioles are more responsive to shear-stress stimulation. We speculate that site-specific preferential responses may play a crucial role in coordinating overall vascular function in the coronary microvascular network.
Effects of Aortic Constriction During Experimental Acute Right Ventricular Pressure Loading
Authors: Belenkie Israel , Horne S. Gabrielle , Dani Rosa , Smith Eldon R. , Tyberg John V.
Published: June 2012

Background
Acute right ventricular (RV) hypertension may result in hemodynamic collapse. The associated reduction in left ventricular (LV) end-diastolic volume is thought to result from reduced RV output (secondary to RV ischemia) and adverse direct ventricular interaction. Aortic constriction improves cardiac function in these circumstances; this has been attributed to a reversal of the RV ischemia caused by an increased coronary perfusion pressure. We hypothesized that altered ventricular interaction, potentially via altered septal mechanics, may also contribute to the beneficial effects of aortic constriction.

Methods and Results
We instrumented nine dogs with ultrasonic dimension crystals to measure RV segment length, septum–to–RV free wall and septum–to–LV free wall diameters, and LV anteroposterior diameter. Catheter-tipped manometers were used to measure LV and RV pressures. Pericardial pressure was measured with flat, liquid-containing balloon transducers. Inflatable cuff constrictors were placed on the pulmonary artery (PA) and aorta, and a flow probe was placed on the PA. The right coronary artery (RCA) was perfused independently by a roller pump calibrated for flow. During moderate PA constriction, while RCA pressure was maintained at control level, RCA flow did not change significantly (15.8±6.2 to 16.9±11.5 mL/min) and was similar during severe PA constriction (18.6±9.8 mL/min). During severe PA constriction, RV stroke volume decreased from a control value of 10.3±4.9 to 2.3±1.4 mL/beat (
P
<.05). When aortic constriction was added while RCA pressure was maintained at control level, there was an increase in RV stroke volume to 4.5±2.0 mL/beat (
P
<.05) with no associated change in RCA flow (17.8±9.5 mL/min). However, pressure-dimension loops clearly demonstrated changes in diastolic and systolic ventricular interaction; with aortic constriction, there was a large increase in the transseptal pressure gradient associated with a rightward septal shift. During either isolated severe PA constriction or simultaneous severe PA and aortic constriction, RCA flow was increased until RCA pressure was approximately equal to that in the aorta. This produced an increase in RCA flow of 50% (
P
<.05); however, this increase in coronary flow was ineffective in improving any measure of RV function.

Conclusions
In this model of acute RV hypertension, aortic constriction improves cardiac function, at least in part, by altering ventricular interaction independent of changes in RCA flow. Changes in RCA flow do not appear to have a significant impact on cardiac function in this model in which coronary artery pressure was maintained at normal or increased levels.
Blood Pressure Measurement in Childhood Epidemiological Studies
Authors: Gillman Matthew W. , Cook Nancy R.
Published: June 2012

Background
Accurate measurement of blood pressure in childhood epidemiological studies requires standardized conditions, valid instruments, and multiple measurements.

Methods and Results
We used published literature and our own data to make recommendations on the reduction of biases caused by various technical factors, to discuss the advantages and disadvantages of selected measurement devices, and to evaluate the optimal number of visits and measurements per visit for accurate estimation of a child’s blood pressure level. The conditions under which blood pressure is measured should be standardized. This includes training and certification to minimize observer biases; equipment factors such as use of an appropriate cuff bladder size, subject factors such as minimizing activities before and during the reading, environmental factors such as accounting for the time of day and ambient temperature, and technique factors such as recording both the fourth and fifth Korotkoff sounds. The choice of instrument for measuring blood pressure depends on the goals of the study and the resources available to the investigators.

Conclusions
Although relatively economical and easy to use, the standard mercury sphygmomanometer is subject to the bias resulting from knowledge of earlier readings. The random-zero sphygmomanometer overcomes this bias, but it is more expensive and difficult to use and may underestimate blood pressure levels. In contrast to auscultatory devices, automated oscillometric devices are not subject to observer biases. They are gaining wider use and may be especially appropriate for younger children. However, they are expensive, and each model requires validation before use in epidemiological studies. Ambulatory blood pressure monitoring represents a potentially useful technique for future epidemiological studies. Multiple measurements are vital in estimating a child’s blood pressure, and the number of visits, days or weeks apart, is at least as important as the number of measurements per visit.
Osteopontin Expression Is Increased in the Heritable Cardiomyopathy of Syrian Hamsters
Authors: Williams Errol B. , Halpert Igor , Wickline Samuel , Davison Glenn , Parks William C. , Rottman Jeffrey N.
Published: June 2012

Background
Osteopontin, a noncollagenous matrix protein, is transiently expressed in the heart after experimental cardiac injury, but its expression in states of continuing cardiac remodeling is unknown. We evaluated osteopontin expression in the heritable cardiomyopathy of the Syrian hamster.

Methods and Results
Hamster hearts were obtained for RNA isolation and analysis and in situ hybridization from two groups: normal control animals (n=4) and untreated cardiomyopathic hamsters (n=5). Osteopontin mRNA was 12-fold greater in cardiomyopathic hearts compared with normal controls (1.76±0.31 versus 0.14±0.04 arbitrary units normalized to GAPDH, mean±SEM,
P
<.05). In situ hybridization was used to define the origin of osteopontin in the heart. Osteopontin mRNA above background levels was not detected in sections from noncardiomyopathic hamster hearts but was readily detected in sections from cardiomyopathic hamsters, in which it originated in cells morphologically consistent with tissue macrophages.

Conclusions
In the hamster, osteopontin is expressed in heritably cardiomyopathic hearts under conditions of chronic injury and repair, and the source of osteopontin message appears to be tissue macrophage-like cells in foci of inflammation. This model could be used to evaluate the biological role of osteopontin in myocardial inflammation and remodeling.