bluuebunny/crossref_metadata_2025 huggingface dataset:
Preconditioning of Human Myocardium With Adenosine During Coronary Angioplasty
Authors: Leesar Massoud A. , Stoddard Marcus , Ahmed Mirza , Broadbent John , Bolli Roberto
Published: June 2012

Background
It is unknown whether adenosine can precondition human myocardium against ischemia in vivo.

Methods and Results
Thirty patients were randomized to receive a 10-minute intracoronary infusion of adenosine (2 mg/min) or normal saline; 10 minutes later, they underwent percutaneous transluminal coronary angioplasty (PTCA; three 2-minute balloon inflations 5 minutes apart). In control patients, the ST-segment shift on the intracoronary ECG was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic preconditioning. In contrast, in adenosine-treated patients, there were no differences in ST-segment shift during the three inflations. The ST-segment shift was significantly smaller in the adenosine-treated group compared with the control group during all three inflations. The reduction in ST-segment shift afforded by adenosine during the first inflation (−72% versus first inflation in control subjects) was greater than that afforded by ischemic preconditioning in control subjects (−52% during the third versus first inflation). Measurements of chest pain score paralleled those of ST-segment shift. Adenosine had no effect on baseline regional wall motion as determined by quantitative two-dimensional echocardiography. Thus, intracoronary infusion of adenosine before PTCA rendered the myocardium remarkably resistant to subsequent ischemia. Judging from the intracoronary ECG, the protection provided by adenosine was even superior to that provided in control subjects by the ischemia associated with the first two balloon inflations. Infusion of adenosine had no major adverse effects in patients undergoing PTCA of the left anterior descending or circumflex arteries.

Conclusions
Adenosine preconditions human myocardium against ischemia in vivo. Pretreatment with adenosine is remarkably effective (even more effective than ischemic preconditioning) and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA of the left anterior descending coronary artery. Whether adenosine can be safely infused into the right or the circumflex coronary artery in the presence of a temporary pacemaker remains to be established.
Incidence and Predictors of Bleeding After Contemporary Thrombolytic Therapy for Myocardial Infarction
Authors: Berkowitz Scott D. , Granger Christopher B. , Pieper Karen S. , Lee Kerry L. , Gore Joel M. , Simoons Maarten , Armstrong Paul W. , Topol Eric J. , Califf Robert M.
Published: June 2012

Background
Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials.

Methods and Results
We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41 021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40 903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke).

Conclusions
Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.
Changes in Ischemic Tolerance and Effects of Ischemic Preconditioning in Middle-aged Rat Hearts
Authors: Tani Masato , Suganuma Yukako , Hasegawa Hiroshi , Shinmura Ken , Hayashi Yoko , Guo Xiao-dong , Nakamura Yoshiro
Published: June 2012

Background
Although both clinical and animal studies have shown that ischemic tolerance is reduced in the senescent myocardium, it has not been clarified when myocardium becomes more vulnerable to ischemia. Preconditioning protects the hearts of young adult animals of various species, but its effects are not identical in human studies. We investigated whether ischemic tolerance and the effect of preconditioning decreased in isolated hearts of middle-aged rats.

Methods and Results
The hearts of young adult rats (12 weeks old: group Y, n=44) and middle-aged rats (50 weeks old: group M, n=44) were subjected to global ischemia for 15, 20, or 25 minutes followed by reperfusion. Hearts were also subjected to preconditioning and then to 20 (group Y, n=22) or 15 (group M, n=22) minutes of ischemia followed by reperfusion. Left ventricular developed pressure (LVDP) was decreased by 40% to 60%, and the level of ATP was decreased by 60% to 70% in group M compared with group Y. Preconditioning increased LVDP (% LVDP, 40.5% to 72.4%) and levels of high-energy phosphates (ATP, 11.8 to 14.1; creatine phosphate, 17.0 to 23.1 μmol/g dry wt) and reduced left ventricular end-diastolic pressure (LVEDP, 32.8 to 10.3 mm Hg), creatine kinase release (257 to 132 U/g dry wt), and ryanodine-sensitive sarcoplasmic reticulum Ca
2+
release after ischemia in group Y. Preconditioning exerted opposite effects in group M (% LVDP, 45.9% to 15.8%; LVEDP, 21.0 to 28.5 mm Hg; ATP, 14.1 to 8.5 μmol/g dry wt; and CK release, 176 to 332 U/g dry wt). Preconditioning was associated with increases in the incidence of reperfusion-induced ventricular fibrillation (0% to 62.5%) and the rate of sarcoplasmic reticulum Ca
2+
release in group M.

Conclusions
These results indicate that hearts became more vulnerable to ischemia with age and that the beneficial effects of preconditioning were reversed in middle-aged rat hearts.
Postresuscitation Left Ventricular Systolic and Diastolic Dysfunction
Authors: Kern Karl B. , Hilwig Ronald W. , Berg Robert A. , Rhee Kyoo H. , Sanders Arthur B. , Otto Charles W. , Ewy Gordon A.
Published: June 2012

Background
Global left ventricular dysfunction after successful resuscitation is well documented and appears to be a major contributing factor in limiting long-term survival after initial recovery from out-of-hospital sudden cardiac death. Treatment of such postresuscitation myocardial dysfunction has not been examined previously.

Methods and Results
Systolic and diastolic parameters of left ventricular function were measured in 27 swine before and after successful resuscitation from prolonged ventricular fibrillation cardiac arrest. Dobutamine infusions (10 μg·kg
−1
·min
−1
in 14 animals or 5 μg·kg
−1
·min
−1
in 5 animals) begun 15 minutes after resuscitation were compared with controls receiving no treatment (8 animals). The marked deterioration in systolic and diastolic left ventricular function seen in the control group after resuscitation was ameliorated in the dobutamine-treated animals. Left ventricular ejection fraction fell from a prearrest 58±3% to 25±3% at 5 hours after resuscitation in the control group but remained unchanged in the dobutamine (10 μg·kg
−1
·min
−1
) group (52±1% prearrest and 55±3% at 5 hours after resuscitation). Measurement of the constant of isovolumic relaxation of the left ventricle (τ) demonstrated a similar benefit of the dobutamine infusion for overcoming postresuscitation diastolic dysfunction. The τ rose in the controls from 28±1 milliseconds (ms) prearrest to 41±3 ms at 5 hours after resuscitation whereas it remained constant in the dobutamine-treated animals (31±1 ms prearrest and 31±5 ms at 5 hours after resuscitation).

Conclusions
Dobutamine begun within 15 minutes of successful resuscitation can successfully overcome the global systolic and diastolic left ventricular dysfunction resulting from prolonged cardiac arrest and cardiopulmonary resuscitation.
Development of Cardiovascular Risk Factors From Ages 8 to 18 in Project HeartBeat!
Authors: Labarthe Darwin R. , Nichaman Milton Z. , Harrist Ronald B. , Grunbaum Jo Anne , Dai Shifan
Published: June 2012

Background
Project HeartBeat! is a longitudinal study of the development of cardiovascular risk factors as growth processes. Patterns of serial change, or trajectories, from ages 8 to 18 years for plasma total cholesterol concentration (TC) and percent body fat illustrate the design and synthetic cohort approach of the study.

Methods and Results
Six hundred seventy-eight children (49.1% female, 20.1% black) entered the study at ages 8, 11, and 14 years and were followed up with examinations every 4 months for ≤4 years. Multilevel analysis demonstrated trajectories for population mean values of TC and percent body fat in sex-specific synthetic cohorts from ages 8 to 18 years. Polyphasic patterns of change in TC were confirmed, with notable sex differences in age patterns and with minimum mean values of TC of 3.85 mmol/L for females and 3.59 for males. As illustrated by data for males, the approximate 75th percentile values of mean TC ranged from 4.78 mmol/L at its early peak to 4.06 at its late-teen nadir. Percent body fat exhibited a trajectory closely parallel with that for TC only for males and appeared to be unrelated for females.

Conclusions
The polyphasic trajectory for TC from ages 8 to 18 years differs between females and males, indicates marked age variation in 75th percentile values and, in males only, closely parallels the trajectory for percent body fat. These and other results indicate the value of both follow-up every 4 months across age intervals to detect rapid risk factor change and the synthetic cohort approach for gaining new insights into the dynamics and possible determinants of this change from ages 8 to 18 years.
Coronary Vasoconstriction During Myocardial Ischemia Induced by Rises in Metabolic Demand in Patients With Coronary Artery Disease
Authors: Sambuceti Gianmario , Marzilli Mario , Marraccini Paolo , Schneider-Eicke Jan , Gliozheni Enri , Parodi Oberdan , L'Abbate Antonio
Published: June 2012

Background
In patients with coronary artery disease, a maximal vasodilation of the coronary microcirculation is generally assumed to occur during myocardial ischemia induced by rises in metabolic demand. However, vasoconstriction has been documented during severe prolonged ischemia in animals. The aim of this study was to investigate coronary vasomotor tone during pacing-induced ischemia in humans.

Methods and Results
The study included 11 patients with exercise-induced ischemia and single-vessel disease of the left anterior descending artery and 7 control subjects with normal coronary arteries. Blood flow velocity was monitored with a Doppler catheter in the left anterior descending artery. Coronary resistance index was calculated as the ratio between mean arterial pressure and flow velocity. Measurements were obtained at baseline, after intracoronary adenosine (2 mg), and during maximal atrial pacing in the absence and presence of adenosine. After adenosine administration at rest, coronary resistance decreased more in control subjects than in patients (25±7% of baseline versus 61±19%;
P
<.01). Coronary resistance decreased in all control subjects (
P
<.01) both at maximal pacing (60±17% of baseline) and after administration of adenosine during tachycardia (31±13% of baseline). By contrast, all 10 ischemic patients displayed increased coronary resistance at maximal heart rate (221±131% of baseline;
P
<.01 versus baseline,
P
<.01 versus control subjects). At this stage, adenosine decreased coronary resistance to 44±20% of values observed before injection. Additionally, it reduced ST-segment depression in 5 of 8 patients.

Conclusions
In patients with coronary artery disease, transient myocardial ischemia induced by increased metabolic demand is not associated with maximal vasodilation. Rather, an inappropriate severe microvascular vasoconstriction is present that can be abolished by intracoronary adenosine.
Effect of Cholesterol Reduction on Myocardial Ischemia in Patients With Coronary Disease
Authors: Andrews Thomas C. , Raby Khether , Barry Joan , Naimi Cameron L. , Allred Elizabeth , Ganz Peter , Selwyn Andrew P.
Published: June 2012

Background
Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life.

Methods and Results
We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (
P
<.001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution.

Conclusions
Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients.
Lipoprotein(a) as a Determinant of Coronary Heart Disease in Young Women
Authors: Orth-Gome´r Kristina , Mittleman Murray A. , Schenck-Gustafsson Karin , Wamala Sarah P. , Eriksson Margita , Belkic Karen , Kirkeeide Richard , Svane Bertil , Ryde´n Lars
Published: June 2012

Background
Lipoprotein(a) [Lp(a)] appears to be a risk factor for coronary heart disease (CHD) in men. The role of Lp(a) in women, however, is less clear.

Methods and Results
We examined the ability of Lp(a) to predict CHD in a population-based case-control study of women 65 years of age or younger who lived in the greater Stockholm area. Subjects were all patients hospitalized for an acute CHD event between February 1991 and February 1994. Control subjects were randomly selected from the city census and were matched to patients by age and catchment area. Lp(a) was measured 3 months after hospitalization by use of an immunoturbidometric method (Incstar) calibrated to the Northwest Lipid Research Laboratories (coefficient of variation was <9%). Of the 292 consecutive patients, 110 (37%) were hospitalized for an acute myocardial infarction, and 182 were hospitalized (63%) for angina pectoris. The mean age for both patients and control subjects was 56±7 years. Of participants, 74 patients (25%) and 84 control subjects (29%) were premenopausal. The distributions of Lp(a) were highly skewed in both patients and control subjects, with a range from 0.001 to 1.14 g/L. Age-adjusted odds ratio for CHD in the highest versus the lowest quartile of Lp(a) was 2.3 (95% confidence interval [CI], 1.4 to 3.7). After adjustment for age, smoking, education, body mass index, systolic blood pressure, total cholesterol, triglycerides, and HDL, the odds ratio was 2.9 (95% CI, 1.6 to 5.0). The odds ratios were similar when myocardial infarction and angina patients were compared with their respective control subjects. The odds ratios were 5.1 (95% CI, 1.4 to 18.4) and 2.4 (95% CI, 1.3 to 4.5) in premenopausal and postmenopausal women, respectively.

Conclusions
These results suggest that Lp(a) is a determinant of CHD in both premenopausal and postmenopausal women.
Actuarial Outcome After Catheter Balloon Commissurotomy in Patients With Mitral Stenosis
Authors: Orrange Sharon E. , Kawanishi David T. , Lopez Becky M. , Curry Susan M. , Rahimtoola Shahbudin H.
Published: June 2012

Background
The goal of the present study was to determine the intermediate-term survival and the independent predictors of survival and event-free survival for patients who undergo catheter balloon commissurotomy (CBC).

Methods and Results
CBC for the treatment of mitral stenosis was performed in 132 patients from 1986 through 1994. The use of CBC increased the mitral valve area (MVA) from 1.0±0.3 to 1.9±0.6 cm
2
(
P
<.001). There were six early deaths (4.5%) up to 1 month after CBC (“hospital” deaths). In the past 4.5 years, there have been no hospital deaths. Four late deaths occurred after elective mitral valve replacement (MVR). Actuarial 7-year survival was 95±1%; when mortality after MVR is included, 7-year survival was 83±6%. Actuarial 1-, 3-, 5-, and 7-year event-free survival (survival without MVR or repeat CBC) was 80±4%, 77±4%, 65±6%, and 65±6%. On multivariate analysis, the only two independent predictors (both after CBC) of 7-year event-free survival were MVA of ≥1.5 versus <1.5 cm
2
(75±7% versus 32±12%) and mean pulmonary artery wedge pressure of ≤18 versus >18 mm Hg (84±6% versus 38±11%) (
P
<.001 for both). Patients with MVA of ≥1.5 cm
2
(n=96) could be further subdivided into high- and low-risk subgroups for 7-year event-free survival by two post-CBC variables: mean pulmonary artery wedge pressure of ≤18 versus >18 mm Hg (90±6% versus 48±14%) (
P
=.0002) and cardiac index of ≥2.5 versus <2.5 L·min
−1
·m
−2
(82±8% versus 61±13%) (
P
=.004). Patients with post-CBC MVA of <1.5 cm
2
(n=24) had no additional predictors of event-free survival. Of patients who did not undergo MVR or repeat CBC, 8% were in New York Heart Association functional class III and 92% were in class I or early class II at the last follow-up.

Conclusions
The rates for intermediate-term survival and event-free survival after CBC are very encouraging. Most patients without events were asymptomatic or minimally symptomatic. Thus, in selected patients with mitral stenosis who require an interventional procedure, CBC is the procedure of choice at centers with physicians who have experience and skill in performing this procedure.
Sex and Test Verification Bias
Authors: Roger Veronique L. , Pellikka Patricia A. , Bell Malcolm R. , Chow Charles W.H. , Bailey Kent R. , Seward James B
Published: June 2012

Background
The use of exercise echocardiography for the diagnosis of coronary artery disease (CAD) has been validated in pilot studies but is not documented in clinical practice and in women comparatively with men. The objectives of this study were to determine the effects of sex and of test verification bias on the diagnostic performance of exercise echocardiography.

Methods and Results
Three thousand six hundred seventy-nine consecutive patients (1714 women, 1965 men) who underwent an exercise echocardiographic study were studied; the observed sensitivity, specificity, and correct classification rate were calculated among 340 patients (244 men, 96 women) who underwent angiography; to study the effect of test verification bias, sensitivity and specificity were estimated for all patients who underwent exercise echocardiography including those not referred to angiography. In the angiographic group, the prevalence of CAD was 60% in women and 80% in men. The observed sensitivity and specificity of exercise echocardiography was 78% and 44% in men and 79% and 37% in women. After adjustment for test verification bias, the estimated sensitivity was lower in women (32% versus 42% in men), whereas specificity was similar in both sexes. The positive predictive value was lower in women (66%) compared with men (84%).

Conclusions
In clinical practice, test verification bias results in a lower observed specificity and a higher sensitivity of exercise echocardiography. In women, positive predictive value and adjusted sensitivity are lower compared with that in men.
Effect of Verapamil in Intermittent Claudication
Authors: Bagger Jens Peder , Helligsoe Per , Randsbaek Flemming , Kimose Hans Henrik , Jensen Bent Skov
Published: June 2012

Background
The calcium antagonist verapamil is a vasodilator drug that has been shown to increase oxygen extraction of ischemic tissues in coronary and peripheral vascular disease.

Methods and Results
Since the balance between the positive and the negative effects of vasodilation may be delicate in ischemic diseases a dose-response study (dose range, 120 to 480 mg) was established to determine optimal, individual dosages of slow-release verapamil in 44 patients with stable intermittent claudication (Fontaine classification stage II) with respect to walking capacity. A randomized, double-blind, placebo-controlled, cross-over study (4 weeks) was performed to assess clinical and hemodynamic effects of verapamil. The optimal daily dose of verapamil on maximal walking ability was 120 (8 patients), 240 (8 patients), 360 (14 patients), and 480 mg (14 patients). Walking distances were measured at a metronome-controlled speed of 60 steps per minute on level surface. Optimal individual doses of verapamil increased mean pain-free walking distance by 29% from 44.9 to 57.8 meters (
P
<.01) and maximal walking distance by 49% from 100.7 to 149.8 meters (
P
<.001) compared with placebo. The increase in maximal walking distance correlated positively only with initial systolic ankle pressure (
r
=.49,
P
<.001) and ankle/brachial pressure index (
r
=.37,
P
<.013). Verapamil had no effect on systolic ankle pressure, ankle/brachial pressure index, peripheral leg temperature, or blood pressure, which suggests that the drug may have extrahemodynamic effects, possibly brought about through improved oxygen metabolism.

Conclusions
Verapamil showed significant clinical benefits in patients with moderate intermittent claudication in this short-term study. Individual optimization of drug dosage should be considered an option both in trials and in the clinical setting in these patients.
Recombinant Staphylokinase Variants With Altered Immunoreactivity
Authors: Collen De´sire´ , De Cock Frans , Demarsin Eddy , Jenne´ Stephane , Lasters Ignace , Laroche Yves , Warmerdam Petra , Jespers Laurent
Published: June 2012

Background
The “charged cluster–to-alanine” substitution variants SakSTAR(K35A,E38A,K74A,E75A,R77A) and SakSTAR(K74A,E75A,R77A,E80A,D82A), previously identified as SakSTAR.M38 and SakSTAR.M89, respectively, induce less antibody formation in patients than wild-type recombinant staphylokinase (SakSTAR), but their specific activities are reduced by 50%. Therefore, the effect of the reversal of one or more of these substituted amino acids on the ratio of activity to antigenicity was studied.

Methods and Results
Fourteen mutants with one to four “alanine-to–wild-type” reversals were expressed in
Escherichia coli
and highly purified (>95%). In rabbits immunized with wild-type SakSTAR, the combined K35,E38,K74,E75,R77 or K74,E75,R77,E80,E82 epitope accounted for only 30% of antibody absorption from plasma, and no clear immunodominant residue could be identified. In baboons immunized with SakSTAR, the K35,E38 and K74,E75,R77 epitopes or the K74,E75,R77 and E80,D82 epitopes contributed equally to account for 50% of total antibody binding, but no immunodominant residues were apparent. In pooled plasma from patients with peripheral arterial occlusion treated with wild-type SakSTAR, about 40% of the antibodies depended on K74 of epitope K74,E75,R77 for binding, whereas epitopes K35,E38 and E80,D82 had a negligible contribution toward antibody recognition.

Conclusions
The recognition pattern by SakSTAR variants of antibodies induced with wild-type SakSTAR differs markedly among species. This implies that a systematic evaluation of reduced antigen recognition and antibody induction in humans will require the development of human or humanized systems. Surprisingly, SakSTAR(K
74
), with a single substitution of Lys74 with Ala, had an intact specific activity but did not absorb 40% of the antibodies induced in patients by treatment with wild-type SakSTAR.
Prospective Study of Moderate Alcohol Consumption and Risk of Peripheral Arterial Disease in US Male Physicians
Authors: Camargo Carlos A. , Stampfer Meir J. , Glynn Robert J. , Gaziano J. Michael , Manson JoAnn E. , Goldhaber Samuel Z. , Hennekens Charles H.
Published: June 2012

Background
Moderate alcohol consumption decreases the risk of coronary heart disease, but its relation to peripheral arterial disease (PAD) is uncertain.

Methods and Results
In the Physicians' Health Study, a randomized trial of the use of aspirin and β-carotene in 22 071 apparently healthy men, we documented 433 incident cases of PAD during 11 years of follow-up. After we controlled for age and treatment assignment, daily drinkers (≥7 drinks per week) had a relative risk (RR) of PAD of 0.92 (95% confidence interval, 0.72 to 1.17) compared with the reference group (<1 drink per week). After additional control for smoking, however, the RR was 0.68 (0.52 to 0.89). Further control for exercise, diabetes mellitus, and parental history of myocardial infarction revealed an RR of 0.74 (0.57 to 0.97).

Conclusions
Moderate alcohol consumption appears to decrease the risk of PAD in apparently healthy men.
Role of Superoxide in Angiotensin II–Induced but Not Catecholamine-Induced Hypertension
Authors: Laursen Jørn Bech , Rajagopalan Sanjay , Galis Zorina , Tarpey Margaret , Freeman Bruce A. , Harrison David G.
Published: June 2012

Background
The major source of superoxide (·O
2
−
) in vascular tissues is an NADH/NADPH-dependent, membrane-bound oxidase. We have previously shown that this oxidase is activated in angiotensin II– but not norepinephrine-induced hypertension. We hypothesized that hypertension associated with chronically elevated angiotensin II might be caused in part by vascular ·O
2
−
production.

Methods and Results
We produced hypertension in rats by a 5-day infusion of angiotensin II or norepinephrine. Rats were also treated with liposome-encapsulated superoxide dismutase (SOD) or empty liposomes. Arterial pressure was measured in conscious rats under baseline conditions and during bolus injections of either acetylcholine or nitroprusside. Vascular ·O
2
−
production was assessed by lucigenin chemiluminescence. In vitro vascular relaxations were examined in organ chambers. Norepinephrine infusion increased blood pressure to a similar extent as angiotensin II infusion (179±5 and 189±4 mm Hg, respectively). In contrast, angiotensin II–induced hypertension was associated with increased vascular ·O
2
−
production, whereas norepinephrine-induced hypertension was not. Treatment with liposome-encapsulated SOD reduced blood pressure by 50 mm Hg in angiotensin II–infused rats while having no effect on blood pressure in control rats or rats with norepinephrine-induced hypertension. Similarly, liposome-encapsulated SOD enhanced in vivo hypotensive responses to acetylcholine and in vitro responses to endothelium-dependent vasodilators in angiotensin II–treated rats.

Conclusions
Hypertension caused by chronically elevated angiotensin II is mediated in part by ·O
2
−
, likely via degradation of endothelium-derived NO·. Increased vascular ·O
2
−
may contribute to vascular disease in high renin/angiotensin II states.
Effects of Cardiac Allograft Vasculopathy on Myocardial Blood Flow, Vasodilatory Capacity, and Coronary Vasomotion
Authors: Kofoed Klaus F. , Czernin Johannes , Johnson Jay , Kobashigawa Jon , Phelps Michael E. , Laks Hillel , Schelbert Heinrich R.
Published: June 2012

Background
Coronary vasculopathy is the third leading cause of death 1 year after cardiac allograft transplantation. This study was designed to assess the hemodynamic effects of transplant vasculopathy on myocardial blood flow and vasomotion.

Methods and Results
Thirty-two patients were studied 1 to 2 years after cardiac transplantation by use of positron emission tomography (n=32), intravascular ultrasound (n=26), coronary angiography (n=32), and endomyocardial biopsy (n=32). Twenty healthy individuals served as control subjects. Quantitative intravascular ultrasound was used to compute coronary lumen area, intimal thickness, and intimal index [Intima Area/(Intima+Lumen Area)]. Myocardial blood flow was quantified with the use of
13
N-ammonia/positron emission tomography. Mean myocardial blood flow was higher in the transplant patients than in control subjects (0.94±0.26 versus 0.68±0.16 mL·min
−1
·g
−1
;
P
<.0005). Cold increased myocardial blood flow to 0.79±0.18 mL·min
−1
·g
−1
in control subjects but not in patients (0.98±0.36 mL·g
−1
·min
−1
). Hyperemic myocardial blood flow was lower in patients than in control subjects (1.69±0.78 versus 2.30±0.32 mL·min
−1
·g
−1
;
P
<.05) and was inversely related to maximal intimal thickness and intimal index (all
P
<.05). The myocardial flow reserve was reduced in patients (1.82±0.55 versus 3.45±1.03;
P
<.0001).

Conclusions
The degree of intimal thickening is correlated with abnormalities in coronary function in patients with diffuse cardiac allograft vasculopathy. The reduction in vasodilatory capacity and the abnormal blood flow response to cold suggest abnormalities in endothelium-dependent and -independent coronary vasodilation in transplant recipients.
Preload Reduction to Unmask the Characteristic Doppler Features of Constrictive Pericarditis
Authors: Oh Jae K. , Tajik A. Jamil , Appleton Christopher P. , Hatle Liv K. , Nishimura Rick A. , Seward James B.
Published: June 2012

Background
Respiratory variation of ≥25% in mitral E velocity is a characteristic Doppler echocardiographic feature in constrictive pericarditis. However, a subset of patients with constriction do not exhibit the typical respiratory change, most likely because of marked increase in the left atrial pressure, and preload reduction may unmask the respiratory variation.

Methods and Results
In 12 patients with surgically confirmed constrictive pericarditis who had <25% respiratory variation in mitral E velocity during an initial preoperative examination, the Doppler study was repeated after an attempt to decrease left ventricular filling pressure. At baseline, mean mitral E velocity was similar after inspiration and expiration (0.81±0.24 and 0.84±0.21 m/s, respectively). On repeat Doppler examination, with the patient in a head-up tilt or sitting position, the decrease in mitral E velocity with inspiration (0.61±0.13 m/s) was significant (
P
<.004), whereas it did not change significantly with expiration. The mean percent respiratory change in E velocity was 5±7% at baseline and 32±28% with preload reduction. Eight (75%) of the 12 patients developed respiratory variation of ≥25%.

Conclusions
When the respiratory variation in Doppler mitral E velocity is blunted or absent during the evaluation of suspected constrictive pericarditis, repeat Doppler recording of mitral flow velocities after maneuvers to decrease preload is recommended to unmask the characteristic respiratory variation in mitral E velocity.
Lipoprotein Oxidation and Progression of Carotid Atherosclerosis
Authors: Salonen Jukka T. , Nyysso¨nen Kristiina , Salonen Riitta , Porkkala-Sarataho Elina , Tuomainen Tomi-Pekka , Diczfalusy Ulf , Bjo¨rkhem Ingemar
Published: June 2012

Background
Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland.

Methods and Results
Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from >400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7β-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution–mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid–reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7β-hydroxycholesterol (β=.47,
P
=.0005), cigarette smoking (β=.35,
P
=.0167), and LDL TBARS (β=.23,
P
=.0862) and an increased oxidation susceptibility of VLDL+LDL (β=.22,
P
=.1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% (
P
=.013) per unit (μg/L) of 7β-hydroxycholesterol.

Conclusions
The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.
Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction
Authors: Ohman E. Magnus , Kleiman Neal S. , Gacioch Gerald , Worley Seth J. , Navetta Frank I. , Talley J. David , Anderson H. Vernon , Ellis Stephen G. , Cohen Mark D. , Spriggs Douglas , Miller Michael , Kereiakes Dean , Yakubov Steven , Kitt Michael M. , Sigmon Kristina N. , Califf Robert M. , Krucoff Mitchell W. , Topol Eric J.
Published: June 2012

Background
Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase.

Methods and Results
We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients;
P
=.006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo;
P
=.05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively).

Conclusions
The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.
Outcome of Reoperative Coronary Bypass Surgery Versus Coronary Angioplasty After Previous Bypass Surgery
Authors: Weintraub William S. , Jones Ellis L. , Morris Douglas C. , King Spencer B. , Guyton Robert A. , Craver Joseph M.
Published: June 2012

Background
The immediate and long-term outcomes of reoperative coronary artery bypass surgery (CABG) (n=1561) and catheter-based coronary intervention (angioplasty) (n=2613) were compared in patients from Emory University Hospitals who had previous CABG.

Methods and Results
The surgical and angioplasty procedures and statistical methods were standard. Data were collected prospectively and entered into a computerized database. Follow-up was by letter, telephone, or additional events resulting in readmission. In the angioplasty group, 2.9% required in-hospital CABG. Hospital mortality was 1.2% after angioplasty versus 6.8% after repeat CABG (
P
<.0001). Recurrent angina was noted frequently at about 4 years and was more common after angioplasty. One-, 5-, and 10-year mortalities were 11%, 24%, and 49% after CABG versus 6%, 22%, and 38% after angioplasty. Survival corrected for baseline differences did not vary with the choice of procedure. There were more additional procedures after angioplasty. Patients undergoing angioplasty may be divided into those with procedures only in native coronary arteries (n=1545), only in vein grafts (n=869), and a mixture (n=199), with respective 10-year survivals of 66%, 56%, and 65% (
P
<.0001).

Conclusions
These patients have a high incidence of events both in-hospital and in the long term. Although initial mortality was higher after CABG, after baseline differences were accounted for, there was no difference in the long term. Patients more frequently have additional procedures after angioplasty. Choice of therapy should consider clinical and angiographic suitability and patient preference.
Preoperative Renal Risk Stratification
Authors: Chertow Glenn M. , Lazarus J. Michael , Christiansen Cindy L. , Cook E. Francis , Hammermeister Karl E. , Grover Frederick , Daley Jennifer
Published: June 2012

Background
After cardiac surgery, acute renal failure (ARF) requiring dialysis develops in 1% to 5% of patients and is strongly associated with perioperative morbidity and mortality. Prior studies have attempted to identify predictors of ARF but have had insufficient power to perform multivariable analyses or to develop risk stratification algorithms.

Methods and Results
We conducted a prospective cohort study of 43 642 patients who underwent coronary artery bypass or valvular heart surgery in 43 Department of Veterans Affairs medical centers between April 1987 and March 1994. Logistic regression analysis was used to identify independent predictors of ARF requiring dialysis. A risk stratification algorithm derived from recursive partitioning was constructed and was validated on an independent sample of 3795 patients operated on between April and December 1994. The overall risk of ARF requiring dialysis was 1.1%. Thirty-day mortality in patients with ARF was 63.7%, compared with 4.3% in patients without ARF. Ten clinical variables related to baseline cardiovascular disease and renal function were independently associated with the risk of ARF. A risk stratification algorithm partitioned patients into low-risk (0.4%), medium-risk (0.9% to 2.8%), and high-risk (≥5.0%) groups on the basis of several of these factors and their interactions.

Conclusions
The risk of ARF after cardiac surgery can be accurately quantified on the basis of readily available preoperative data. These findings may be used by physicians and surgeons to provide patients with improved risk estimates and to target high-risk subgroups for interventions aimed at reducing the risk and ameliorating the consequences of this serious complication.
Time-Related Changes in Left Ventricular Function After Double Valve Replacement for Combined Aortic and Mitral Regurgitation in a Young Rheumatic Population
Authors: Skudicky Daniel , Essop Mohammed R. , Sareli Pinhas
Published: June 2012

Background
The long-term effects of double valve replacement on left ventricular function in patients with combined severe rheumatic aortic and mitral regurgitation have not been reported previously. Furthermore, the importance of chordal preservation in this group of patients is unknown.

Methods and Results
Serial clinical and echocardiographic evaluations were performed prospectively in 44 patients who underwent double valve replacement for combined aortic and mitral regurgitation. Chordae to the posterior mitral leaflet were preserved in 27 patients. Mean follow-up was 40±19 months. Left ventricular end-diastolic diameter decreased significantly 3 months after surgery (from 66±10 to 52±11 mm;
P
<.001) without a substantial change in end-systolic diameter, resulting in a significant decline in ejection fraction (from 60±9% to 48±15%;
P
<.001). At 1 year, a significant reduction in end-systolic dimension was observed without a concomitant decline in end-diastolic diameter, thus normalizing the ejection fraction (55±12%;
P
=.17 versus baseline). No further changes were seen at latest follow-up. Multivariate regression analysis identified baseline end-systolic diameter and ejection fraction as independent predictors of postoperative systolic performance. Chordal preservation did not emerge as a univariate or multivariate predictor.

Conclusions
After an initial postoperative decline in ejection fraction, normalization in left ventricular systolic function may be expected 1 year after double valve replacement for combined rheumatic mitral and aortic regurgitation. End-systolic diameter and ejection fraction are the only independent predictors of postoperative left ventricular performance.
Chronic Congestive Heart Failure Elicits Adaptations of Endurance Exercise in Diaphragmatic Muscle
Authors: Tikunov Boris , Levine Sanford , Mancini Donna
Published: June 2012

Background
During rest and exercise, patients with heart failure hyperventilate; therefore, the diaphragm can be viewed as undergoing constant moderate-intensity exercise. Accordingly, we hypothesized that heart failure elicits adaptations in the diaphragm similar to those elicited by endurance exercise in the limb muscles of normal subjects.

Methods and Results
Costal diaphragmatic biopsy samples were obtained from 7 normal subjects (age, 36±20 years) and 10 patients (age, 50±6 years; left ventricular ejection fraction, 18±8%) at the time of transplant or left ventricular assist-device placement. We measured the distribution of myosin heavy chain isoforms I, IIa, and IIb by SDS gel electrophoresis. We also measured the activities of the following enzymes: citrate synthase, a marker of oxidative metabolism; β-hydroxyacyl-CoA dehydrogenase, a marker of lipolytic metabolism; and lactate dehydrogenase, a marker of glycolytic metabolism. In normal subjects, the distribution of myosin heavy chain isoforms I, IIa, and IIb was 43±2%, 40±2%, and 17±1%, respectively. In contrast, in heart failure subjects, the fiber distribution was 55±2%, 38±2%, and 7±2% for types I, IIa, and IIb, respectively. Therefore, in heart failure, myosin heavy chain I is increased (
P
<.0001) and myosin heavy chain IIb decreased from normal levels (
P
<.001). Additionally, citrate synthase activity (normal, 0.33±0.14; heart failure, 0.54±0.21 μmol·min
−1
·mg protein
−1
;
P
<.05) and β-hydroxyacyl-CoA dehydrogenase activity (normal, 0.27±0.04; heart failure, 0.38±0.02 μmol·min
−1
·mg protein
−1
;
P
<.05) were greater in heart failure patients than in normal subjects, whereas lactate dehydrogenase activity was significantly less in heart failure patients than in normal subjects (normal, 11.6±4.6; heart failure,: 4.3±2.2 μmol·min
−1
·mg protein
−1
;
P
<.01).

Conclusions
In the diaphragm in heart failure, there is a shift from fast to slow myosin heavy chain isoforms with an increase in oxidative capacity and a decrease in glycolytic capacity. These diaphragmatic muscle changes are consistent with those elicited by endurance training of the limb muscles in normal subjects.
Hyperhomocyst(e)inemia Is Associated With Impaired Endothelium-Dependent Vasodilation in Humans
Authors: Tawakol Ahmed , Omland Torbjørn , Gerhard Marie , Wu James T. , Creager Mark A.
Published: June 2012

Background
Hyperhomocyst(e)inemia is a risk factor for atherosclerosis and is prevalent in the elderly. The objective of this study was to determine whether hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.

Methods and Results
High-resolution vascular ultrasonography was used to study endothelium-dependent and -independent vasodilation in a nonatherosclerotic peripheral conduit artery of 26 elderly hyperhomocyst(e)inemic subjects and 15 age- and sex-matched subjects with normal homocysteine levels. Flow-mediated, endothelium-dependent (nitric oxide–mediated) vasodilation was assessed by measuring the percent change in brachial artery diameter during reactive hyperemia. Endothelium-independent vasodilation was assessed after the administration of 0.4 mg sublingual nitroglycerin. Endothelium-dependent vasodilation was significantly impaired in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7±0.6% versus 8.1±1.2%;
P
=.004), whereas endothelium-independent vasodilation was not different between the two groups (10.1±1.6% versus 9.3±1.5%;
P
=NS). In a linear regression analysis with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation.

Conclusions
These data indicate that hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans and suggest that the bioavailability of nitric oxide is decreased in hyperhomocyst(e)inemic humans.
(
. 1997;95:1119-1121.)
Vasopressin Deficiency Contributes to the Vasodilation of Septic Shock
Authors: Landry Donald W. , Levin Howard R. , Gallant Ellen M. , Ashton Robert C. , Seo Susan , D'Alessandro David , Oz Mehmet C. , Oliver Juan A.
Published: June 2012

Background
The hypotension of septic shock is due to systemic vasodilation. On the basis of a clinical observation, we investigated the possibility that a deficiency in vasopressin contributes to the vasodilation of septic shock.

Methods and Results
In 19 patients with vasodilatory septic shock (systolic arterial pressure [SAP] of 92±2 mm Hg [mean±SE], cardiac output [CO] of 6.8±0.7 L/min) who were receiving catecholamines, plasma vasopressin averaged 3.1±1.0 pg/mL. In 12 patients with cardiogenic shock (SAP, 99±7 mm Hg; CO, 3.5±0.9 L/min) who were also receiving catecholamines, it averaged 22.7±2.2 pg/mL (
P
<.001). A constant infusion of exogenous vasopressin to 2 patients with septic shock resulted in the expected plasma concentration, indicating that catabolism of vasopressin is not increased in this condition. Although vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to 10 patients with septic shock who were receiving catecholamines increased arterial pressure (systolic/diastolic) from 92/52 to 146/66 mm Hg (
P
<.001/
P
<.05) due to peripheral vasoconstriction (systemic vascular resistance increased from 644 to 1187 dyne·s/cm
5
;
P
<.001). Furthermore, in 6 patients with septic shock who were receiving vasopressin as the sole pressor, vasopressin withdrawal resulted in hypotension (SAP, 83±3 mm Hg), and vasopressin administration at 0.01 U/min, which resulted in a plasma concentration (≈30 pg/mL) expected for the level of hypotension, increased SAP from 83 to 115 mm Hg (
P
<.01).

Conclusions
Vasopressin plasma levels are inappropriately low in vasodilatory shock, most likely because of impaired baroreflex-mediated secretion. The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock.