bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade.
Authors: London G M , Pannier B , Guerin A P , Marchais S J , Safar M E , Cuche J L
Published: June 2012

BACKGROUND

We wished to assess the respective roles of the antihypertensive and blood pressure (BP)-independent effects of antihypertensive drugs on arterial hemodynamics and left ventricular hypertrophy (LVH) in end-stage renal disease (ESRD) patients.

METHODS AND RESULTS

In a double-blind study, 24 ESRD patients with LVH were randomized to 12 months' administration of either the angiotensin-converting enzyme (ACE) inhibitor perindopril (n = 14) or the calcium channel blocker nitrendipine (n = 10). Repeated measurements of the following parameters were performed: BP (mercury sphygmomanometry), left ventricular mass (LVM, echocardiography), cardiac output (aortic cross-section and velocity integral), total peripheral resistance (cardiac output and mean BP), aortic and large-artery compliance (pulse wave velocity, Doppler flowmeter), and arterial wave reflections (augmentation index, applanation tonometry). Radioimmunoassay was used to determine plasma renin activity, aldosterone, and plasma catecholamine levels. Two-way (time-treatment) ANOVA for repeated measures was used for statistical analysis. Perindopril and nitrendipine induced significant and similar decreases in BP, total peripheral resistance (P < .001), aortic and arterial pulse wave velocities (P < .001), and arterial wave reflections (P < .01). At baseline, the two groups had LVH mostly due to increased LV end-diastolic diameter (LVEDD) (perindopril, 54.3 +/- 1.4 and nitrendipine, 54.3 +/ 2.4 mm) with near-normal mean LV wall thickness (perindopril, 11.4 +/- 0.3 and nitrendipine, 11.2 +/- 0.4 mm). A decrease in LVM was observed only in patients receiving perindopril (from 317 +/- 18 to 247 +/- 21 g) (time-treatment interaction, P = .036). Nitrendipine had no significant effect on LVM (314 +/- 29 versus 286 +/- 32 g). The decrease in LVM observed with perindopril was associated with a reduction in LVEDD (49.9 +/- 1.6 versus 54.3 +/- 1.4 mm after 12 months) (time-treatment interaction, P = .04), while the mean LV wall thickness was unchanged (11.4 +/- 0.3 versus 10.5 +/- 0.5 mm). Cardiac alterations were not correlated with changes in BP or with alterations in plasma renin activity or aldosterone or catecholamine levels.

CONCLUSIONS

In ESRD patients with LVH, ACE inhibition decreases LVM independently of its antihypertensive effect and of associated alterations in arterial hemodynamics. The decrease in LVM was due primarily to a decrease in LV volume, which may have resulted in these patients from chronic volume overload.
Relation of smoking with carotid artery wall thickness and stenosis in older adults. The Cardiovascular Health Study. The Cardiovascular Health Study (CHS) Collaborative Research Group.
Authors: Tell G S , Polak J F , Ward B J , Kittner S J , Savage P J , Robbins J
Published: June 2012

BACKGROUND

Cigarette smoking has been associated with increased risk of atherosclerotic diseases in hospital-based studies and in studies of middle-aged populations but not in population-based studies of older adults with and without clinical cardiovascular disease.

METHODS AND RESULTS

We investigated the relation of smoking to carotid artery atherosclerotic disease, expressed as intimal-medial wall thickness and arterial lumen narrowing (stenosis) measured by ultrasound. Subjects were 5116 older adults participating in the baseline examination of the Cardiovascular Health Study, a community-based study of cardiovascular diseases in older age. With increased smoking there was significantly greater internal and common carotid wall thickening and internal carotid stenosis: current smokers > former smokers > never-smokers; for instance, the unadjusted percent stenosis was 24%, 20%, and 16%, respectively (P < .0001). A significant dose-response relation was seen with pack-years of smoking. These findings persisted after adjusting for other cardiovascular risk factors and were also confirmed when analyses were restricted to those without prevalent cardiovascular disease. The difference in internal carotid wall thickness between current smokers and nonsmokers was greater than the difference associated with 10 years of age among never-smoking participants (0.39 mm versus 0.31 mm). Among all participants, the prevalence of clinically significant (> or = 50%) internal carotid stenosis increased from 4.4% in never-smokers to 7.3% in former smokers to 9.5% in current smokers (P < .0001).

CONCLUSIONS

These findings extend previous reports of a positive relation between smoking and carotid artery disease to a population-based sample of older adults using several different indicators of atherosclerotic disease.
Role of arterial chemoreceptors in mediating the effects of endogenous adenosine on sympathetic nerve activity.
Authors: Engelstein E D , Lerman B B , Somers V K , Rea R F
Published: June 2012

BACKGROUND

Exogenous adenosine has been shown to increase muscle sympathetic nerve activity (MSNA), blood pressure, heart rate, and ventilation in conscious humans, effects attributed to peripheral chemoreceptor activation.

METHODS AND RESULTS

To determine whether endogenous adenosine has similar effects and whether they are mediated through chemoreceptor activation, we examined the effects of dipyridamole, an inhibitor of adenosine reuptake, on sympathetic nerve activity and ventilation. Twenty studies were conducted on separate days in 15 healthy volunteers. We examined responses to dipyridamole 0.56 mg/kg during room air breathing (n = 7), during hyperoxia (100% O2, n = 6), and during room air breathing after pretreatment with aminophylline (n = 7). During room air breathing, dipyridamole increased MSNA from 231 +/- 42 to 504 +/- 136 U/min, heart rate from 65 +/- 3.8 to 96 +/- 4.7 beats per minute, and systolic blood pressure from 129 +/- 3.5 to 140 +/- 4.8 mm Hg; central venous pressure decreased from 5.5 +/- 0.4 to 4.5 +/- 0.3 mm Hg (P < .01), and minute ventilation increased from 7.8 +/- 0.6 to 9.1 +/- 0.5 L/min (P < .01). During peripheral chemoreceptor suppression (with hyperoxia), there was a dissociation of the effects of dipyridamole on ventilation and sympathoexcitation. Effects on ventilation were attenuated, but sympathoexcitatory effects were not. Pretreatment with aminophylline, an adenosine receptor antagonist, either abolished (blood pressure, minute ventilation, and end-tidal CO2) or markedly attenuated (MSNA and heart rate) the effects of dipyridamole during room air breathing.

CONCLUSIONS

Augmentation of endogenous adenosine with dipyridamole increases sympathetic nerve activity and ventilation in conscious humans. The ventilatory effects of endogenous adenosine are mediated predominantly by chemoreceptor activation, but the sympathetic and hemodynamic responses to endogenous adenosine are probably mediated by an additional afferent mechanism that is independent of peripheral chemoreceptor activation.
Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation.
Authors: Fischell T A , Kharma B K , Fischell D R , Loges P G , Coffey C W , Duggan D M , Naftilan A J
Published: June 2012

BACKGROUND

Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium "stent" wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition.

METHODS AND RESULTS

A series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm).

CONCLUSIONS

We conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.
Geometric remodeling is not the principal pathogenetic process in restenosis after balloon angioplasty. Evidence from correlative angiographic-histomorphometric studies of atherosclerotic arteries in rabbits.
Authors: Gertz S D , Gimple L W , Banai S , Ragosta M , Powers E R , Roberts W C , Perez L S , Sarembock I J
Published: June 2012

BACKGROUND

Restenosis after balloon angioplasty of coronary arteries is thought to be a proliferative response of the arterial wall to injury. Recently, it has been suggested that geometric remodeling of the arterial wall, rather than intimal fibromuscular hyperplasia, may be the major pathophysiological mechanism underlying restenosis. In this study, we evaluated the relative contribution of a geometric decrease in arterial size versus neointimal growth to luminal narrowing associated with restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.

METHODS AND RESULTS

Focal femoral atherosclerosis was induced by endothelial desiccation injury followed by a 2% cholesterol diet. After 1 month on the high cholesterol diet, the animals were subjected to one of four strategies: (1) balloon angioplasty, (2) balloon angioplasty followed by treatment with the factor Xa inhibitor antistasin, (3) combined laser and balloon angioplasty, or (4) no angioplasty. Animals were killed 2 hours or 28 days after angioplasty, and excised femoral artery segments were prepared for histomorphometric analysis. Angiography was performed serially before and immediately after angioplasty and before the animals were killed. An initial postprocedural gain in luminal diameter at sites of angioplasty was followed by a significant reduction in diameter by angiography and a significant increase in luminal cross-sectional area narrowing by plaque by histomorphometry 28 days after angioplasty compared to adjacent nonangioplastied segments of the same arteries, to nonangioplastied control arteries, or to angioplastied segments of animals treated with the factor Xa inhibitor antistasin. By contrast, the overall arterial size (cross-sectional area bounded by the external elastic lamina) at sites of restenosis was not significantly different from adjacent nonangioplastied segments in the majority of arteries excised at 28 days, and the mean overall arterial size at sites of restenosis was not significantly different from corresponding segments of nonangioplastied control arteries or from angioplastied segments of animals treated with antistasin. In the minority of angioplastied arteries in which the arterial size did change, most got larger.

CONCLUSIONS

Geometric remodeling resulting in a decrease in overall cross-sectional arterial size does not appear to be the principal pathogenetic mechanism for restenosis after balloon angioplasty with or without laser in this experimental model.
Effect of myocardial fiber direction on epicardial potentials.
Authors: Taccardi B , Macchi E , Lux R L , Ershler P R , Spaggiari S , Baruffi S , Vyhmeister Y
Published: June 2012

BACKGROUND

Understanding the relations between the architecture of myocardial fibers, the spread of excitation, and the associated ECG signals is necessary for addressing the forward problem of electrocardiography, that is, predicting intracardiac and extracardiac ECGs from known intracardiac activity. So far, these relations have been studied experimentally only in small myocardial areas. In this study, we tested the hypothesis that potential distributions measured over extensive epicardial regions during paced beats reflect the direction of superficial and intramural fibers through which excitation is spreading in both the initial and later stages of ventricular excitation. We also tried to establish whether the features of the epicardial potential distribution that correlate with fiber direction vary as a function of pacing site, intramural pacing depth, and time elapsed after the stimulus. An additional purpose was to compare measured epicardial potentials with recently published numerical simulations depicting the three-dimensional spread of excitation in the heart muscle and the associated potential fields.

METHODS AND RESULTS

The hearts of 18 mongrel dogs were exposed and 182 to 744 unipolar electrograms were recorded from epicardial electrode arrays (2.3 x 3.0 to 6.5 x 6.5 cm). Hearts were paced at various intramural depths through an intramural needle. The overall number of pacing sites in 18 dogs was 241. Epicardial potential distributions, electrographic waveforms, and excitation time maps were displayed, and fiber directions in the ventricular wall underlying the electrodes were determined histologically. During the early stages of ventricular excitation, the position of the epicardial maxima and minima revealed the orientation of myocardial fibers near the pacing site in all cases of epicardial and intramural pacing and in 60% of cases of endocardial or subendocardial pacing. During later stages of propagation, the rotation and expansion of the positive areas correlated with the helical spread of excitation through intramurally rotating fibers. Marked asymmetry of potential patterns probably reflected epicardial-endocardial obliqueness of intramural fibers. Multiple maxima appeared in the expanding positive areas.

CONCLUSIONS

For 93% of pacing sites, results verified our hypothesis that epicardial potential patterns elicited by ventricular pacing reflect the direction of fibers through which excitation is spreading during both the initial and later stages of propagation. Epicardial potential distributions provided information on the site of origin and subsequent helical spread of excitation in an epicardial-endocardial, endocardial-epicardial, or double direction. Results were in agreement with previously published numerical simulations except for the asymmetry and fragmentation of the positive areas.
Probucol Protects Against Adriamycin Cardiomyopathy Without Interfering With Its Antitumor Effect
Authors: Siveski-Iliskovic N. , Hill M. , Chow D.A. , Singal P.K.
Published: June 2012

Background
The usefulness of adriamycin (ADR), a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy and congestive heart failure. Subcellular changes leading to heart failure are suggested to be mediated by a drug-induced increase in free radicals and lipid peroxidation. In an earlier study, concurrent treatment with probucol (PROB), a lipid-lowering drug with strong antioxidant properties, was shown to offer only partial protection against ADR cardiomyopathy. The present study had two aims: to determine whether this protective effect can be improved further by extended treatment with PROB, and to determine whether PROB affects the antitumor properties of ADR.

Methods and Results
ADR (cumulative dose, 15 mg/kg body wt) was administered in rats in six equal injections (IP) over a period of 2 weeks. Three weeks after the end of treatment, cardiomyopathy and congestive heart failure were characterized by ascites, congested liver, depressed cardiac function, elevated left ventricular end-diastolic pressure, and myocardial cell damage. Myocardial glutathione peroxidase (GSHPx) activity was decreased and lipid peroxidation was increased. Administration of PROB (cumulative dose, 120 mg/kg body wt) in 12 equal injections (IP), before and concurrent with ADR, completely prevented these cardiomyopathic changes, normalized left ventricular function, lowered mortality, and eliminated ascites. Treatment with PROB was also accompanied by an increase in myocardial GSHPx and superoxide dismutase activities with a concomitant decrease in lipid peroxidation. Tumor regression in syngeneic DBA/2 mice inoculated with L5178Y-F9 lymphoma cells in the ADR+PROB group was significant and comparable to the ADR group.

Conclusions
These data show for the first time that PROB can provide complete protection against ADR cardiomyopathy without interfering with antitumor properties of the drug. This protective effect of PROB may be related to the maintenance of the antioxidant status of the heart.
Acoustic Propagation Properties of Normal, Stunned, and Infarcted Myocardium
Authors: O’Brien William D. , Sagar Kiran B. , Warltier David C. , Rhyne Theodore L.
Published: June 2012

Background
Identification of viable but stunned myocardium remains a major problem. Since stunned myocardium results in impairment of myocardial function without any structural damage and infarcted myocardium causes major structural disruption, we postulated that acoustic properties could distinguish between the two insults.

Methods and Results
Anesthetized open-chest dogs underwent a total occlusion of the left anterior descending coronary artery for 15 minutes (stunned, n=7) and 90 minutes (infarcted, n=8), followed by reperfusion for 3 hours. Circumflex coronary artery perfusion territory (n=15) served as normal control tissue. Regions of myocardium were quantitatively evaluated with a scanning laser acoustic microscope operating at 100 MHz and a research ultrasound system operating at 4 to 7 MHz. Four ultrasonic parameters were determined: attenuation coefficient (an index of loss per unit distance), speed of propagation, a spatial variation of propagation speed called the heterogeneity index (HI), and ultrasonic backscatter at 5 MHz (IBR5). Myocardial water, lipid, and protein contents of normal, stunned, and infarcted myocardium were also determined. The attenuation coefficient of normal myocardium (179±20 dB/cm) was significantly greater than that of stunned (136±7 dB/cm,
P
<.001) and infarcted (130±8 dB/cm,
P
<.001) myocardium. The propagation speed of normal myocardium (1597±6 m/s) was similar to that of stunned (1600±6 m/s) and significantly higher than that of infarcted (1575±7 m/s,
P
<.001) myocardium. The HI for specimen thicknesses of 75 to 100 μm showed an increase of 33% between normal (5.0±0.8 m/s) and stunned (7.5±2.3 m/s,
P
<.05) myocardium. However, for the infarcted myocardium (5.8±2.0 m/s), the HI was essentially the same as that of the normal myocardium (5.0±0.8 m/s). The IBR5 of normal (−47.1±1.0 dB) was not significantly different from that of stunned myocardium (−46.8±0.9 dB). The IBR5 of infarcted myocardium (−42.4±1.0 dB) was significantly greater than that of normal myocardium. Myocardial water and protein contents were similar in the normal and stunned myocardium. Water content in the infarcted myocardium (80.8±2%) was significantly greater (
P
<.05) than in the normal (72.7±1.3%), and protein content of 18.5±0.7% was significantly lower (
P
<.05) than the normal (21.4±0.8%). Lipid content was increased in the stunned (8.5±0.5%) and virtually absent in the infarcted myocardium (0.8±0.3%) compared with normal (5.5±0.6%).

Conclusions
We conclude that acoustic propagation properties can identify stunned and infarcted myocardium and may be related to biochemical/morphological differences.
Comparison of Cost-Effectiveness and Utility of Exercise ECG, Single Photon Emission Computed Tomography, Positron Emission Tomography, and Coronary Angiography for Diagnosis of Coronary Artery Disease
Authors: Patterson Randolph E. , Eisner Robert L. , Horowitz Steven F.
Published: June 2012

Background
To compare cost-effectiveness and utility of four clinical algorithms to diagnose obstructive coronary atherosclerotic heart disease (CAD), we compared exercise ECG (ExECG), stress single photon emission computed tomography (SPECT), positron emission tomography (PET), and coronary angiography.

Methods and Results
Published data and a straightforward mathematical model based on Bayes’ theorem were used to compare strategies. Effectiveness was defined as the number of patients with diagnosed CAD, and utility was defined as the clinical outcome, ie, the number of quality-adjusted life years (QALY) extended by therapy after the diagnosis of CAD. Our model used published values for costs, accuracy, and complication rates of tests. Analysis of the model indicates the following results. (1) The direct cost (fee) for each test differs considerably from total cost per ΔQALY. (2) As pretest likelihood of CAD (pCAD) in the population increases, there is a linear increase in cost per patient tested but a hyperbolic decrease in cost per effect and cost per utility unit, ie, increased cost-effectiveness and decreased cost per utility unit. (3) At pCAD<0.70, analysis of the model indicates that stress PET is the most cost-effective test, with the lowest cost per utility, followed by SPECT, ExECG, and angiography, in that order. (4) Above a threshold value of pCAD of 0.70 (for example, middle-aged men with typical angina), proceeding directly to angiography as the first test showed the lowest cost per effect or utility. This quantitative model has the advantage of estimating a threshold value of pCAD (0.70) at which the rank order of cost-effectiveness and cost per utility unit change. The model also allows substitution of different values for any variable as a way to account for the uncertainties of clinical data, ie, changing costs, test accuracy and risk, etc. This procedure, called sensitivity analysis, showed that the rank order of cost-effectiveness did not change despite changes in several variables.

Conclusions
(1) Estimation of total costs of diagnostic tests for CAD requires consideration not only of the direct cost of the test per se (eg, test fees) but also of the indirect and induced costs of management algorithms based on the test (eg, cost/ΔQALY). (2) It is essential to consider the clinical history (pCAD) when selecting the clinical algorithm to make a diagnosis with the lowest cost per effect or cost per utility unit. (3) Stress PET shows the lowest cost per effect or cost per utility unit in patients with pCAD<0.70. (4) Angiography shows the lowest cost per effect or cost per utility unit in patients with pCAD>0.70.
Do Increases in Markers of Vagal Activity Imply Protection From Sudden Death?
Authors: Hull Stephen S. , Vanoli Emilio , Adamson Philip B. , De Ferrari Gaetano M. , Foreman Robert D. , Schwartz Peter J.
Published: June 2012

Background
Low-dose scopolamine increases heart rate variability (HRV) in patients with a prior myocardial infarction (MI). This observation, combined with the evidence that elevated cardiac vagal activity during acute myocardial ischemia is antifibrillatory, has generated the hypothesis that scopolamine might be protective after MI. We tested low-dose scopolamine in a clinically relevant experimental preparation for sudden death in which other vagomimetic interventions are effective.

Methods and Results
Nineteen mongrel dogs that survived an anterior MI were used in the study. Occurrence or lack of ventricular fibrillation (VF) due to acute myocardial ischemia during submaximal exercise identified dogs at high and low risk for sudden death. Dose-response curves performed in 12 dogs at high (n=6) and low (n=6) risk showed that scopolamine at 3 μg/kg exerts the greatest effect on HRV. A second group of 7 high-risk dogs were exposed to an exercise-and-ischemia test after treatment with scopolamine (3 μg/kg IV). Scopolamine increased the standard deviation of RR intervals by 41%, increased the high-frequency band of spectral analysis by 48%, and decreased resting heart rate by 14%. Despite the increase in markers of vagal activity, VF recurred during the exercise-and-ischemia test in 6 dogs (86%).

Conclusions
The significant increase in HRV induced by acute scopolamine did not result in a decreased risk for VF due to acute myocardial ischemia in association with sympathetic activation. Caution must be applied when extrapolating the potential antifibrillatory activity of an intervention from its influence on autonomic markers.
Alterations of Coagulation and Fibrinolytic and Kallikrein-Kinin Systems in the Acute and Postacute Phases in Patients With Unstable Angina Pectoris
Authors: Hoffmeister Hans Martin , Jur Michael , Wendel Hans Peter , Heller Wolfgang , Seipel Ludger
Published: June 2012

Background
Unstable angina pectoris is frequently associated with intracoronary thrombus formation. In a prospective study, we investigated in 35 patients with unstable angina pectoris markers of coagulation and the kallikrein-kinin and fibrinolytic systems in the acute and postacute phases.

Methods and Results
We determined serially in the patients up to 10 days after admission factor XII and the β–factor XIIa inhibition, kallikrein-like activity, prekallikrein, C
1
-esterase inhibitor, kallikrein inhibition, high molecular weight kininogen as indicators of the contact phase and bradykinin generation, thrombin–antithrombin III (TAT) complex as marker of the activated coagulation cascade, fibrinogen, plasminogen, plasminogen activator inhibitor–1 (PAI-1), tissue-type plasminogen activator (TPA), and D-dimers as indicators of the fibrinolytic system. Data were compared with those from control subjects (n=25) and from patients with stable angina pectoris (n=25). In patients with unstable angina pectoris, initially the contact phase and the kallikrein-kinin system were markedly elevated (factor XII, 96±5% versus 117±5%; kallikrein-like activity, 35.7±2.9 versus 27.4±1.3 U/L; high molecular weight kininogen, 52.7±5.2% versus 87.7±3.9%;
P
<.01 versus control subjects). Contact-phase activation persisted for the following 10 days, whereas the initially enhanced bradykinin generation normalized after 2 days. Furthermore, we had evidence of a hypercoagulative state (TAT, 10.9±3.1 versus 4.5±0.7 μg/L,
P
<.05; D-dimer, 474±81 versus 272±71 ng/mL) persisting longer than the clinically symptomatic period in association with disturbed fibrinolysis (TPA, 15.9±1.9 versus 5.1±0.4 ng/mL;
P
<.01; PAI-1, 9.9±2.6 versus 4.6±1.6 AU/mL;
P
=NS) in the presence of elevated fibrinogen levels.

Conclusions
Our data indicate that in patients with unstable angina pectoris, intracoronary thrombus formation is associated with a hypercoagulative state, including activation of the contact phase and of the kallikrein system and increased bradykinin generation. The persistence of this hypercoagulative state, together with a disturbed fibrinolysis, might indicate an increased risk for further coronary events.
Reduced Alveolar–Capillary Membrane Diffusing Capacity in Chronic Heart Failure
Authors: Puri Sundeep , Baker B. Leigh , Dutka David P. , Oakley Celia M. , Hughes J. Michael B. , Cleland John G. F.
Published: June 2012

Background
The pulmonary diffusing capacity for carbon monoxide (
dlco
) is reduced in chronic heart failure (CHF) and is an independent predictor of peak exercise oxygen uptake. The pathophysiological basis for this remains unknown. The aim of this study was to partition
DLco
into its membrane conductance (D
M
) and capillary blood volume components (Vc) and to assess if alveolar–capillary membrane function correlated with functional status, exercise capacity, and pulmonary vascular resistance.

Methods and Results
The classic Roughton and Forster method of measuring single-breath
DLco
at varying alveolar oxygen concentrations was used to determine D
M
and Vc in 15 normal subjects and 50 patients with CHF. All performed symptom-limited maximal bicycle exercise tests with respiratory gas analysis; 15 CHF patients underwent right heart catheterization.
DLco
was significantly reduced in CHF patients compared with normal subjects, predominantly because of a reduction in D
M
(7.0±2.6 versus 12.9±3.8 versus 20.0±6.1 mmol · min
−1
· kPa
−1
in New York Heart Association class III, class II, and normal subjects, respectively,
P
<.0001), even when the reduction in lung volumes was accounted for by the division of D
M
by the effective alveolar volume. The Vc component of
DLco
was not impaired. D
M
significantly correlated with maximal exercise oxygen uptake (
r
=.72,
P
<.0001) and inversely correlated with pulmonary vascular resistance (
r
=.65,
P
<.01) in CHF.

Conclusions
Reduced alveolar–capillary membrane diffusing capacity is the major component of impaired pulmonary gas transfer in CHF, correlating with maximal exercise capacity and functional status. D
M
may be a useful marker for the alveolar–capillary barrier damage induced by raised pulmonary capillary pressure.
Reduced Epicardial Coronary Vasodilator Capacity in Patients With Left Ventricular Hypertrophy
Authors: Vassalli Giuseppe , Kaufmann Philipp , Villari Bruno , Jakob Markus , Boj Hildegard , Kiowski Wolfgang , Hess Otto M.
Published: June 2012

Background
Enlargement of the epicardial coronary arteries occurs in left ventricular (LV) hypertrophy as an adaptation to the increased coronary blood flow.

Methods and Results
Vasodilator capacity of the epicardial coronary arteries was determined in 44 patients. The dose-response relation of intracoronary nitroglycerin was assessed in 14 patients (7 control subjects and 7 patients with aortic stenosis [study A]) using quantitative coronary angiography. In a second study (B), vasodilator capacity of the epicardial coronary arteries was determined in 15 control subjects and 15 patients with valvular heart disease. In study A, a curvilinear dose-response relation with maximal vasodilation after 90 μg intracoronary nitroglycerin was found in both control subjects and patients with aortic stenosis. Vasodilator capacity was reduced in those with aortic stenosis, although sensitivity to nitroglycerin was similar in both groups. In study B, coronary circumferential length at baseline was larger in those with LV hypertrophy (12.2±2.2 mm) than in control subjects (8.6±1.5 mm;
P
<.001); after 100 μg intracoronary nitroglycerin, it increased to 12.9±2.2 mm (6±5%) in those with LV hypertrophy and to 10.3±1.5 mm (21±8%;
P
<.001) in control subjects. An inverse relation between baseline circumferential length and its percent increase after nitroglycerin was found (
r
=−.71,
P
<.001).

Conclusions
Vasodilator capacity of the epicardial coronary arteries is reduced in patients with LV hypertrophy, although sensitivity to nitroglycerin is normal. This may be due to a flow-mediated decrease in coronary vasomotor tone and/or the occurrence of vascular remodeling with an enlargement of the coronary arteries.
Apolipoprotein E Polymorphism Predicts Death From Coronary Heart Disease in a Longitudinal Study of Elderly Finnish Men
Authors: Stengård Jari H. , Zerba Kim E. , Pekkanen Juha , Ehnholm Christian , Nissinen Aulikki , Sing Charles F.
Published: June 2012

Background
There is ample evidence from cross-sectional studies of an association between allelic variation of the gene coding for apolipoprotein E (apoE) and interindividual variation in plasma lipids, and the presence of coronary heart disease (CHD). There have been no prospective studies, however, to evaluate the usefulness of allelic variation of the apoE gene for predicting CHD.

Methods and Results
Two samples of elderly Finnish men were followed for 5 years, one in the east (n=297) and the other in the southwest of Finland (n=369). At baseline, when the apoE genotypes were assessed, the men were 65 to 84 years old. At the end of the follow-up, the vital status of each man was determined, and cause of death was coded. At baseline, relative frequencies of the three alleles–ε2, ε3, and ε4–were 0.037, 0.827, and 0.136 in the eastern and 0.062, 0.763, and 0.175 in the southwestern samples, respectively (χ
2
=8.89,
df
=2,
P
<.012 for difference between the samples). During the 5-year follow-up, a total of 28 deaths from CHD were recorded in the eastern and 42 in the southwestern sample. Relative CHD mortality was not heterogeneous between the samples. Among those who died from CHD, there was a doubling of the relative ε4 allele frequency in both samples (χ
2
=4.70,
df
=1,
P
<.03 for the eastern sample; χ
2
=7.11,
df
=1,
P
<.01 for the southwestern sample).

Conclusions
Allelic variation in the apoE gene is a statistically significant predictor of CHD death in these samples of elderly Finnish men.
Benefit of Selective Respiratory Muscle Training on Exercise Capacity in Patients With Chronic Congestive Heart Failure
Authors: Mancini Donna M. , Henson David , Manca John La , Donchez Lisa , Levine Sanford
Published: June 2012

Background
Diminished respiratory muscle strength and endurance have been demonstrated in patients with heart failure. This may contribute to exertional dyspnea and reduced exercise capacity in these patients. The purpose of this study was to investigate whether selective respiratory muscle training could alleviate dyspnea and improve exercise performance in patients with chronic congestive heart failure.

Methods and Results
Fourteen patients with chronic heart failure (left ventricular ejection fraction, 22±9%) were enrolled in a supervised respiratory muscle training program. This consisted of three weekly sessions of isocapnic hyperpnea at maximal sustainable ventilatory capacity, resistive breathing, and strength training. Maximum sustainable ventilatory capacity, maximum voluntary ventilation, maximal inspiratory and expiratory pressures, peak V̇
o
2
, and the 6-minute walk test were measured before (pre) and after (post) 3 months of training. Eight patients completed the training program. Respiratory muscle endurance was improved with training, as evidenced by increases in maximal sustainable ventilatory capacity (pre, 48.6±10.7 versus post, 76.9±14.5 L/min;
P
<.05) and in maximal voluntary ventilation (pre, 100±36 versus post, 115±39 L/min;
P
<.05). Respiratory muscle strength was also increased with training as maximal inspiratory (pre, 64±31 versus post, 78±33 cm H
2
O;
P
<.01) and expiratory (pre, 94±30 versus post, 133±53 cm H
2
O;
P
<.001) pressures rose. Submaximal and maximal exercise capacity were significantly improved with selective respiratory muscle training as the 6-minute walk (pre, 1101±351 versus post, 1421±328 ft;
P
<.001) and peak exercise V̇
o
2
(pre, 11.4±3.3 versus post, 13.3±2.7 mL · kg
−1
· min
−1
;
P
<.05) both significantly increased. Dyspnea during activities of daily living was subjectively improved in the majority of trained patients. Dyspnea quantified by the Borg scale was significantly reduced during progressive isocapnic hyperpnea but not during bicycle exercise. No statistically significant improvement in maximal sustainable ventilatory capacity, maximum voluntary ventilation, maximal inspiratory or expiratory mouth pressures, 6-minute walk, or peak V̇
o
2
was observed in the 6 patients who did not complete the training program.

Conclusions
Selective respiratory muscle training improves respiratory muscle endurance and strength, with an enhancement of submaximal and maximal exercise capacity in patients with heart failure. Dyspnea during activities of daily living was subjectively improved in the majority of trained patients.
Effects of Aging on the Responsiveness of the Human Cardiac Sympathetic Nerves to Stressors
Authors: Esler Murray D. , Thompson Jane M. , Kaye David M. , Turner Andrea G. , Jennings Garry L. , Cox Helen S. , Lambert Gavin W. , Seals Douglas R.
Published: June 2012

Background
Aging increases human sympathetic nervous activity at rest. Because of the probable importance of neural stress responses in the heart as triggers for clinical end points of coronary artery disease, it is pertinent to investigate whether sympathetic nervous responses to stresses are increased by aging.

Methods and Results
We applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20 to 30 years) and older (aged 60 to 75 years) healthy men during mental stress (difficult mental arithmetic), isometric exercise (sustained handgrip), and dynamic exercise (supine cycling). The increase in total norepinephrine spillover to plasma with mental stress was unaffected by age. In contrast, the increase in cardiac norepinephrine spillover was two to three times higher in the older subjects (
P
<.05). The probable mechanism of this higher cardiac norepinephrine spillover was reduced neuronal reuptake of the transmitter, because age had no influence on the overflow of the norepinephrine precursor, dihydroxyphenylalanine, or intraneuronal metabolite, dihydroxyphenylglycol (levels of these two substances reflect rates of cardiac norepinephrine synthesis and intraneuronal metabolism), and the transcardiac extraction of plasma radiolabeled norepinephrine was lower in the older subjects (
P
<.05). An almost identical pattern of neurochemical response was seen with isometric exercise. During cycling, total norepinephrine spillover was 16% lower in the older men, but cardiac norepinephrine spillover was 53% higher.

Conclusions
Reduced norepinephrine reuptake increases the overflow of the neurotransmitter to plasma from the aging heart during stimulation of the cardiac sympathetic outflow. Failure of transmitter inactivation at postjunctional receptors with aging would amplify the neural signal, and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, particularly when accompanied by an age-dependent reduction in vagal tone. Reduction of postsynaptic adrenergic responsiveness with aging, however, might protect against this, as indicated by our finding that in no case was the heart rate increase during stress greater in older men, despite their having larger increases in cardiac norepinephrine spillover.
Comparison of Cardiopulmonary Adaptation During Exercise in Children After the Atriopulmonary and Total Cavopulmonary Connection Fontan Procedures
Authors: Rosenthal Mark , Bush Andrew , Deanfield John , Redington Andrew
Published: June 2012

Background
There are several potential physiological differences between the atriopulmonary (AP) and the total cavopulmonary connection (TCPC) Fontan circulations. Studies suggest that the TCPC reduces energy loss due to turbulence and may have more dependence on respiratory movement for pulmonary blood flow. We compared cardiopulmonary physiology during rest and exercise in patients who had undergone the AP Fontan procedure with those who had undergone the TCPC Fontan procedure.

Methods and Results
Forty-three children were studied more than 6 months after undergoing a Fontan procedure (23 AP and 20 TCPC); 106 healthy children were also studied as a control group. Measurements of effective pulmonary blood flow, stroke volume, arteriovenous oxygen difference, minute ventilation, heart rate, and oxygen and carbon dioxide consumption were made with an Innovision quadrupole mass spectrometer. Data from the control group allowed calculation of
z
scores for the Fontan groups matched for age, sex, pubertal stage, and body surface area. Maximal exercise performance was equal in the two Fontan groups, but it was below normal. However, adaptation to exercise was different in the Fontan groups. After 9 minutes of exercise, pulmonary blood flow rose less in the AP group than in the TCPC group (
P
<.01), and the stroke volume in the AP group also tended to be lower (
P
=.057) and their arteriovenous oxygen difference was significantly greater (
P
<.01). Although minute ventilation per unit of carbon dioxide production was similar in the Fontan groups at this level of exercise, children in the TCPC group breathed faster by approximately 10 breaths per minute (
P
<.005).

Conclusions
At submaximal exercise, children who had undergone the TCPC Fontan procedure had pulmonary hemodynamics superior to those of children who had undergone the AP procedure, largely because of respiratory adaptation that permitted blood to be “sucked” into the lungs. To achieve the same maximal exercise performance, children who had undergone the AP procedure had a superior metabolic adaptation to exercise stress.
Photodynamic Therapy of Normal and Balloon-Injured Rat Carotid Arteries Using 5-Amino-Levulinic Acid
Authors: Nyamekye Isaac , Anglin Sandra , McEwan Jean , MacRobert Alexander , Bown Stephen , Bishop Christopher
Published: June 2012

Background
Although the management of atherosclerotic disease by the use of balloon angioplasty is widespread, the treatment is limited by restenosis in 30% to 50% of cases. Fibrocellular intimal hyperplasia, the main cause of restenosis, arises from proliferation and migration of medial smooth muscle cells (SMC) into the intimal layer. Factors leading to intimal hyperplasia are incompletely understood, and drugs have universally failed to influence clinical restenosis. Photodynamic therapy (PDT), the light activation of photosensitizing drugs to generate cytotoxic mediators, may have potential as prophylaxis for intimal hyperplasia. 5-Amino-levulinic acid–induced protoporphyrin IX (ALA-PPIX), a naturally occurring porphyrin precursor, and its product, -PPIX, offers a novel method of sensitization for PDT. We have investigated the pharmacokinetics of ALA in arteries and the effects of ALA-PPIX–sensitized PDT on normal and balloon-injured arteries.

Methods and Results
ALA (20 to 200 mg/kg) was injected into healthy rats, and PPIX fluorescence was measured in the carotid arteries. In a second group of rats, the exposed carotid artery was laser illuminated (50 J/cm
2
, 630 nm) 30 to 90 minutes after sensitization. Three and 14 days after PDT, histological sections from treated arteries were analyzed by light microscopy. Subsequently, two new groups of rats underwent PDT (ALA, 100 mg/kg; laser, 50 J/cm
2
, 630 nm [at 60 to 90 minutes]). The left carotid arteries underwent balloon angioplasty by intraluminal passage of a Fogarty FG2 catheter immediately before irradiation. These rats were killed at 14 and 28 days together with laser-only, ALA-only, and untreated control rats. The arteries were perfusion-fixed in vivo. ALA-PPIX induced arterial media fluorescence in a dose-dependent manner. In the normal arteries, PDT produced a dose-dependent cellular depletion in the treated arterial segment at 3 days, and this was complete with 100 and 200 mg/kg of ALA. At 14 days, the media remained acellular, although the endothelial lining had regenerated. In the balloon-injured arteries, PDT produced complete inhibition of intimal hyperplasia at both 14 and 28 days (0%). This was significantly greater than that produced by any of the control rats (34% to 69% and 37% to 66% at the two times, respectively). Significance was at 99% using ANOVA and Fisher’s PLSD test. No hemorrhage, thrombosis, or aneurysm formation was seen.

Conclusions
ALA-PPIX–sensitized PDT applied at the time of angioplasty effectively inhibits experimental intimal hyperplasia development in rats. This may offer a new approach to the management of angioplasty restenosis in patients.
Intake of Mercury From Fish, Lipid Peroxidation, and the Risk of Myocardial Infarction and Coronary, Cardiovascular, and Any Death in Eastern Finnish Men
Authors: Salonen Jukka T. , Seppänen Kari , Nyyssönen Kristiina , Korpela Heikki , Kauhanen Jussi , Kantola Marjatta , Tuomilehto Jaakko , Esterbauer Hermann , Tatzber Franz , Salonen Riitta
Published: June 2012

Background
Even though previous studies have suggested an association between high fish intake and reduced coronary heart disease (CHD) mortality, men in Eastern Finland, who have a high fish intake, have an exceptionally high CHD mortality. We hypothesized that this paradox could be in part explained by high mercury content in fish.

Methods and Results
We studied the relation of the dietary intake of fish and mercury, as well as hair content and urinary excretion of mercury, to the risk of acute myocardial infarction (AMI) and death from CHD, cardiovascular disease (CVD), and any cause in 1833 men aged 42 to 60 years who were free of clinical CHD, stroke, claudication, and cancer. Of these, 73 experienced an AMI in 2 to 7 years. Of the 78 deceased men, 18 died of CHD and 24 died of CVD. Men who had consumed local nonfatty fish species had elevated hair mercury contents. In Cox models with the major cardiovascular risk factors as covariates, dietary intakes of fish and mercury were associated with significantly increased risk of AMI and death from CHD, CVD, and any death. Men in the highest tertile (≥2.0 μg/g) of hair mercury content had a 2.0-fold (95% confidence interval, 1.2 to 3.1;
P
=.005) age- and CHD-adjusted risk of AMI and a 2.9-fold (95% CI, 1.2 to 6.6;
P
=.014) adjusted risk of cardiovascular death compared with those with a lower hair mercury content. In a nested case-control subsample, the 24-hour urinary mercury excretion had a significant (
P
=.042) independent association with the risk of AMI. Both the hair and urinary mercury associated significantly with titers of immune complexes containing oxidized LDL.

Conclusions
These data suggest that a high intake of mercury from nonfatty freshwater fish and the consequent accumulation of mercury in the body are associated with an excess risk of AMI as well as death from CHD, CVD, and any cause in Eastern Finnish men and this increased risk may be due to the promotion of lipid peroxidation by mercury.
Multicenter Validation of a Risk Index for Mortality, Intensive Care Unit Stay, and Overall Hospital Length of Stay After Cardiac Surgery
Authors: Tu Jack V. , Jaglal Susan B. , Naylor C. David
Published: June 2012

Background
A multicenter population-based study was conducted to develop and validate a risk index for mortality, intensive care unit (ICU) length of stay, and postoperative length of stay after cardiac surgery.

Methods and Results
Data were collected from 13 098 patients undergoing cardiac surgery between April 1, 1991, and March 31, 1993, at all nine adult cardiac surgery institutions in Ontario, Canada. A six-variable risk index (age, sex, left ventricular function, type of surgery, urgency of surgery, and repeat operation) was developed using logistic regression analysis to predict in-hospital mortality, ICU stay in days, and postoperative stay in days after cardiac surgery in a derivation set of 6213 patients who had cardiac surgery during fiscal year 1991 (April 1, 1991, to March 31, 1992). The index predicted mortality, prolonged ICU stay (≥6 days), and prolonged postoperative length of stay (≥17 days) after cardiac surgery with areas under the receiver-operating characteristic (ROC) curve of 0.75, 0.66, and 0.69, respectively, in an independent validation set of 6885 patients who had cardiac surgery during fiscal year 1992 (April 1, 1992, to March 31, 1993). Increasing risk scores were associated with greater mortality rates and longer ICU and postoperative stays at all nine institutions.

Conclusions
Mortality, ICU length of stay, and postoperative length of stay after cardiac surgery can be predicted using a simple six-variable risk index. The index has potential application as a risk stratification tool for comparing patient outcomes and resource use among different hospitals and surgeons.