bluuebunny/crossref_metadata_2025 huggingface dataset:
HDL cholesterol and mortality in Finnish men with special reference to alcohol intake.
Authors: Paunio M , Heinonen O P , Virtamo J , Klag M J , Manninen V , Albanes D , Comstock G W
Published: June 2012

BACKGROUND

There is substantial evidence that a low serum level of HDL cholesterol (HDLC) is a risk factor for coronary deaths. However, data on older people are scarce, and previous studies have not examined this association in relation to alcohol intake.

METHODS AND RESULTS

Coronary mortality, all-cause mortality, and mortality due to alcohol and violence were related to HDLC levels among 7052 male smokers 50 to 69 years old in south and west Finland enrolled from 1984 to 1988 in the ATBC (AT, alpha-tocopherol; BC, beta-carotene) Study placebo group. During the average follow-up period of 4.7 years, 620 men died; 222 of these deaths were from coronary heart disease and 82 from causes related alcohol and violence. HDLC levels were inversely associated with coronary mortality, irrespective of age, whereas high total cholesterol was positively associated with coronary mortality among the younger men, 50 to 59 years of age, but not among the older men, 60 to 69 years old. Correction for temporal variation in HDLC measurement indicated a 43% stronger inverse association between HDLC and coronary mortality compared with that based only on a single value. The inverse association of HDLC and coronary mortality was less marked at higher levels of alcohol intake. All-cause and alcohol- and violence-related mortality were positively associated with HDLC among the younger men. All-cause mortality showed a U-shaped dose response among men > or = 60 years old.

CONCLUSIONS

Previous studies may have underestimated the beneficial effect of high HDLC because of regression-dilution bias and the confounding effect of heavy alcohol intake. This study supports the view that, particularly among older men, lipoprotein fractions may be more appropriate for screening than total cholesterol.
Adenosine receptor involvement in a delayed phase of myocardial protection 24 hours after ischemic preconditioning.
Authors: Baxter G F , Marber M S , Patel V C , Yellon D M
Published: June 2012

BACKGROUND

We previously reported a delayed phase of protection against infarction 24 hours after ischemic preconditioning in the rabbit. In the present study, we investigated the possibility that this "second window of protection," like the well-described early phase of protection in the rabbit, might be associated with adenosine receptor activation.

METHODS AND RESULTS

In the first series of experiments, we examined whether adenosine receptor blockade with 8-(p-sulfophenyl)-theophylline (SPT) during preconditioning could abolish the delayed protection against infarction 24 hours later. Open-chest rabbits were subjected to myocardial preconditioning (PC) with the four 5-minute coronary occlusions or they were sham operated on (SHAM). During these procedures, animals received either SPT (PC + SPT, n = 6; and SHAM + SPT, n = 6) or vehicle (PC + VEH, n = 12; and SHAM + VEH, n = 11). Twenty-four hours later, infarct development after a 30-minute coronary occlusion/120-minute reperfusion insult was assessed with triphenyltetrazolium staining. In vehicle-treated rabbits, the infarct-to-risk ratio (I/R) was reduced from 53.6 +/- 5.7% (SHAM + VEH) to 32.9 +/- 4.6% (PC + VEH) (P < .05), clearly indicating a delayed phase of protection. Although I/R was not significantly different between SHAM + VEH (53.6 +/- 5.7%) and SHAM + SPT (61.7 +/- 5.4%), in PC + SPT the delayed protection was abolished (I/R = 56.8 +/- 3.8%). In the second series of experiments, we examined if pharmacological adenosine A1 receptor stimulation could evoke a delayed phase of protection. Conscious rabbits were pretreated with intravenous boluses of saline or the A1 receptor-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA), and infarct size in response to 30-minute ischemia/120-minute reperfusion was assessed 24 hours later. I/R was 54.5 +/- 2.7% in saline-pretreated controls (n = 12). Pretreatment with 25 micrograms/kg CCPA (n = 6), 50 micrograms/kg CCPA (n = 6), or 100 micrograms/kg CCPA (n = 6) resulted in I/R ratios of 37.1 +/- 4.2% (P < .01), 37.7 +/- 2.2% (P < .01), and 26.3 +/- 5.7% (P < .01), respectively. In both series of experiments, there were no differences in systemic hemodynamics during the infarct protocol, assessed as rate-pressure product, between the different experimental groups.

CONCLUSIONS

Twenty-four hours after repetitive brief coronary occlusions, susceptibility to infarction in rabbit myocardium is reduced, an effect that may have clinical relevance. Results of the present study suggest that this second window of protection following preconditioning may, like the early phase of protection, be initiated by an adenosine-related mechanism.
Effect of chronic dihydropyridine (isradipine) on the large arterial walls of spontaneously hypertensive rats.
Authors: Levy B I , Duriez M , Phillipe M , Poitevin P , Michel J B
Published: June 2012

BACKGROUND

The effect of genetic hypertension and of chronic therapy by calcium entry blocker (CEB, isradipine) on the function and structure of large arteries has been studied in adult spontaneously hypertensive rats (SHR, n = 30) and in their normotensive control Wistar-Kyoto (WKY) rats (n = 30).

METHODS AND RESULTS

Fifteen-week-old rats were randomly allocated to treatment with isradipine (3 mg/kg subcutaneously once a day) or to placebo and followed for 12 weeks. Hemodynamic parameters, including instantaneous pressure and aortic velocity, were recorded under anesthesia at the end of the treatment period. Passive mechanical properties of carotid arteries were measured in situ in the presence or the absence of smooth muscle cell activity (potassium cyanide poisoning). Histomorphometric parameters of the carotid and aortic media, including cross-sectional area, medial thickness, nucleus density and size, and medial contents of proteins of interstitial matrix, were measured by an automated morphometric system. Untreated SHRs had greater peripheral resistance, stiffer and thicker arterial walls because of smooth muscle cell hyperplasia (thoracic aorta and carotid artery) and/or hypertrophy (thoracic aorta), and increased collagen content than did normotensive control rats. SHRs showed a significant left ventricular hypertrophy. For the whole duration of treatment, treatment with CEB normalized the arterial pressure in SHRs. We observed a significant decrease in peripheral resistance, increased cardiac output, and left ventricular contractility without significant reduction in left ventricular hypertrophy. Increases in diuresis and natriuresis were associated during the last week of treatment in both treated strains with marked increase in plasma renin activity; in contrast, urinary aldosterone was increased by treatment in WKY rats but not in SHRs. Arterial compliance was significantly increased by CEB under control and passive conditions. CEB induced a significant reduction in the medial hypertrophy of the aortic walls of SHRs and WKY rats associated with a reduction in medial hyperplasia. In the carotid artery, CEB reduced smooth muscle cell hypertrophy but did not affect the smooth muscle cell hyperplasia. Isradipine significantly reduced the arterial wall collagen contents in both strains, with marked increases in the elastin content in the carotid but not in the aortic wall.

CONCLUSIONS

These results suggest that (1) despite normalization of arterial pressure, chronic treatment with CEB in SHRs does not significantly reduce left ventricular hypertrophy, probably because of increase in myocardial contractility and/or increase in plasma renin activity; (2) mechanical properties of the arterial wall are normalized by treatment; and (3) remodeling of the arterial wall by CEB is not uniform according to the studied vessel.
Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.
Authors: McDonald K M , Garr M , Carlyle P F , Francis G S , Hauer K , Hunter D W , Parish T , Stillman A , Cohn J N
Published: June 2012

BACKGROUND

Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock.

METHODS AND RESULTS

The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007).

CONCLUSIONS

High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.
Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy.
Authors: Mady C , Cardoso R H , Barretto A C , da Luz P L , Bellotti G , Pileggi F
Published: June 2012

BACKGROUND

The fundamental determinant of the natural history of Chagas' disease is cardiac involvement.

METHODS AND RESULTS

We studied 104 male patients with congestive heart failure due to Chagas' disease to estimate the survival distribution function and to evaluate age, functional class (FC), maximal oxygen consumption (VO2max), and ejection fraction (EF) as predictors of survival. Statistical evaluation was performed through univariate (Student's t test and chi 2 test) and multivariate analyses (Cox's regression model). Overall survival was 66% at 1 year, 56% at 3 years, and 48% at 5 years. Ages were not statistically different (P = .9811) between survivor (40.3 +/- 8.7) and nonsurvivor (40.3 +/- 9.4) groups. The ejection fraction(s) were statistically different (P = .0001) between survival (43.6 +/- 9.9) and nonsurvival (30.6 +/- 8.1) groups, as was VO2max (P = .0001) (21.0 +/- 4.7 and 15.0 +/- 4.9, respectively). Most of the surviving patients were in FC II and most of the nonsurvivors were in FC IV (P = .0001). VO2max (P = .0001) and EF (P = .0008) are highly associated with survival time in the multivariate analysis, but FC (P = .0578) is less important. Age (P = .9811) did not influence survival.

CONCLUSIONS

We conclude that 50% of the patients with heart failure due to Chagas' disease die in 47 months and that VO2max and EF are important indices of survival in this group.
Myocardial Fibrosis and Stiffness With Hypertrophy and Heart Failure in the Spontaneously Hypertensive Rat
Authors: Conrad Chester H. , Brooks Wesley W. , Hayes John A. , Sen Subha , Robinson Kathleen G. , Bing Oscar H. L.
Published: June 2012

Background
Fibrosis is commonly found in association with cardiac hypertrophy and failure, but the relation of the connective tissue response to the development of impaired cardiac function remains unclear. We examined passive myocardial stiffness, active contractile function, and fibrosis in the spontaneously hypertensive rat (SHR), a model of chronic pressure overload in which impaired cardiac function follows a long period of stable hypertrophy.

Methods and Results
We studied the passive and active mechanical properties of left ventricular (LV) papillary muscles isolated from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at the ages of 12 months and 20 to 23 months. Seven of 15 SHR between 20 and 23 months of age had findings consistent with heart failure (SHR-F). In comparison to preparations from WKY rats and nonfailing SHR (SHR-NF), papillary muscles from the SHR-F group demonstrated increased passive stiffness (central segment exponential stiffness constant,
k
cs
: SHR-F 95.6±19.8, SHR-NF 42.1±9.7, WKY rats 39.5±9.5 (mean±SD); SHR-F
P
<.01 versus SHR-NF, WKY rats). The increase in stiffness was associated with an increase in LV collagen concentration (SHR-F 8.71±3.14, SHR-NF 5.83±1.20, WKY rats 4.78±0.70 mg hydroxyproline/g dry LV wt; SHR-F
P
<.01 versus SHR-NF, WKY rats); an increase in interstitial fibrosis, as determined histologically (SHR-F 13.5±8.0%, SHR-NF 4.9±2.1%, WKY rats 3.6±0.8%; SHR-F
P
<.01 versus SHR-NF, WKY rats); and impaired tension development (SHR-F 3.18±1.27, SHR-NF 4.41±1.04, WKY rats 4.64±0.85 kdyne/mm
2
; SHR-F
P
<.05 versus SHR-NF;
P
<.01 versus WKY rats).

Conclusions
The development of heart failure in the aging SHR is associated with marked myocardial fibrosis, increased passive stiffness, and impaired contractile function relative to age-matched nonfailing SHR and nonhypertensive control animals. These data suggest that fibrosis or events underlying the connective tissue response are important in the transition from compensated hypertrophy to failure in the SHR.
Vasopressin Improves Vital Organ Blood Flow During Closed-Chest Cardiopulmonary Resuscitation in Pigs
Authors: Lindner Karl H. , Prengel Andreas W. , Pfenninger Ernst G. , Lindner Ingrid M. , Strohmenger Hans-Ulrich , Georgieff Michael , Lurie Keith G.
Published: June 2012

Background
This study was designed to compare the effects of epinephrine with those of vasopressin on vital organ blood flow during closed-chest cardiopulmonary resuscitation (CPR) in a pig model of ventricular fibrillation.

Methods and Results
Vasopressin was compared with epinephrine by randomly allocating 28 pigs to receive either 0.2 mg/kg epinephrine (n=7), 0.2 U/kg vasopressin (low dose) (n=7), 0.4 U/kg vasopressin (medium dose) (n=7), or 0.8 U/kg vasopressin (high dose) (n=7) after 4 minutes of ventricular fibrillation and 3 minutes of closed-chest CPR. Left ventricular myocardial blood flow, determined by use of radiolabeled microspheres during CPR, before and then 90 seconds and 5 minutes after drug administration was 17±2, 43±5, and 22±3 mL · min
−1
· l00 g
−1
(mean±SEM) in the epinephrine group; 18±2, 50±6, and 29±3 mL · min
−1
· 100 g
−1
in the low-dose vasopressin group; 17±3, 52±8, and 52±6 mL · min
−1
· 100 g
−1
in the medium-dose vasopressin group; and 18±2, 95±9, and 57±6 mL · min
−1
· 100 g
−1
in the high-dose vasopressin group (
P
<.001 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin, and
P
<.01 at 5 minutes between epinephrine and medium-dose vasopressin). At the same times, calculated coronary systolic perfusion pressures were 12±2, 36±5, and 18±2 mm Hg in the epinephrine group; 10±1, 39±6, and 26±5 mm Hg in the low-dose vasopressin group; 11±2, 49±6, and 38±5 mm Hg in the medium-dose vasopressin group; and 10±2, 70±5, and 47±6 mm Hg in the high-dose vasopressin group (
P
<.01 at 90 seconds and 5 minutes between epinephrine and high-dose vasopressin); and calculated coronary diastolic perfusion pressures were 15±2, 24±2, and 19±2 mm Hg in the epinephrine group; 13±1, 25±2, and 20±1 mm Hg in the low-dose vasopressin group; 13±2, 25±2, and 21±2 mm Hg in the medium-dose vasopressin group; and 13±2, 35±3, and 24±2 mm Hg in the high-dose vasopressin group (
P
<.05 at 90 seconds between epinephrine and high-dose vasopressin). Total cerebral blood flow was significantly higher after high-dose vasopressin than after epinephrine (
P
<.05 at 90 seconds and
P
<.01 at 5 minutes between groups). Five animals in the epinephrine, 5 in the low-dose vasopressin, 7 in the medium-dose vasopressin, and 6 in the high-dose vasopressin groups were successfully resuscitated and survived the 1-hour observation period.

Conclusions
We conclude that administration of vasopressin leads to a significantly higher coronary perfusion pressure and myocardial blood flow than epinephrine during closed-chest CPR in a pig model of ventricular fibrillation.
Anti-Cardiolipin Antibodies and Risk of Myocardial Infarction in a Prospective Cohort of Middle-Aged Men
Authors: Vaarala Outi , Mänttäri Matti , Manninen Vesa , Tenkanen Leena , Puurunen Marja , Aho Kimmo , Palosuo Timo
Published: June 2012

Background
Data concerning the relation between anti-phospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort.

Methods and Results
The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non–high-density lipoprotein cholesterol, ≥5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361;
P
<.005). Subjects with the antibody level in the highest quartile of distribution had a relative risk for myocardial infarction of 2.0 (95% confidence interval, 1.1 to 3.5) compared with the remainder of the population. This risk was independent of confounding factors, such as age, smoking, systolic blood pressure, low-density lipoprotein (LDL), and high-density lipoprotein. There was a correlation between the levels of aCL antibodies and antibodies to oxidized LDL (
r
=.40,
P
<.001), and their joint effect was additive for the risk.

Conclusions
In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.
Plasmin-Mediated Activation of Contact System in Response to Pharmacological Thrombolysis
Authors: Ewald Gregory A. , Eisenberg Paul R.
Published: June 2012

Background
Thrombin activity increases in patients treated with coronary thrombolysis for acute myocardial infarction, but the mechanisms are not well defined. We have shown that thrombin activity increases in plasma and whole blood incubated with plasminogen activators and appears to be plasmin mediated and dependent on activity of the factor VIIIa/IXa complex.

Methods and Results
In the present study, increases in thrombin activity induced by incubation of recalcified citrated plasma with 0.16 to 0.5 μmol/L plasmin at 37°C were markedly attenuated in recalcified citrated plasma deficient in factors XI or XII, prekallikrein, or high molecular weight kininogen, as well as in plasma incubated with plasmin in the presence of 3.5 μmol/L corn trypsin inhibitor, a specific factor XIIa inhibitor. Increases in thrombin activity also occurred in nonanticoagulated whole blood incubated with pharmacological concentrations of plasminogen activators and were markedly attenuated in the presence of corn trypsin inhibitor. Plasmin-mediated (0.25 μmol/L) activation of purified factor XII occurred in 0.05 mol/L Tris-HCl and 0.012 mol/L NaCl (pH 7.8) at 37°C, resulting in equimolar quantities of two fragments that corresponded to cleavage of factor XII at Arg
353
-Val
354
, the site involved in kallikrein-mediated activation of factor XII, and cleavage at Lys
346
-Ser
347
, an apparently novel site of plasmin-mediated hydrolysis of factor XII. Contact activation was also demonstrated in plasma samples from patients after treatment with fibrinolytic agents for myocardial infarction, by demonstrating cleavage of high molecular weight kininogen from its one-chain to its two-chain form by ligand blotting with
125
I-prekallikrein.

Conclusions
Plasmin-mediated activation of the contact system of coagulation appears to account, at least in part, for increases in procoagulant activity in patients treated with fibrinolytic agents. It may also explain hypotension, by release of bradykinin from high molecular weight kininogen, and complement activation, by activated factor XII, that has been demonstrated in these patients.
Previous Angina Alters In-Hospital Outcome in TIMI 4
Authors: Kloner Robert A. , Shook Thomas , Przyklenk Karin , Davis Vicki G. , Junio Lucille , Matthews Ray V. , Burstein Steven , Gibson C. Michael , Poole W. Kenneth , Cannon Christopher P. , McCabe Carolyn H. , Braunwald Eugene
Published: June 2012

Background
Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction.

Methods and Results
Patients eligible for thrombolytic therapy were enrolled into the study. Data were collected from case report forms regarding previous history of angina, in-hospital outcome and 6-week follow-up. Two hundred eighteen patients had a history of previous angina at any time before acute myocardial infarction, and 198 patients did not have previous angina. Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% versus 8%) (
P
=.03), severe congestive heart failure (CHF) or shock (1% versus 7%,
P
=.006), or the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%,
P
=.004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 versus 154 CK integrated units;
P
=.01) and were less likely to have Q waves on their ECG (57% versus 69%;
P
=.01). In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% versus 6%;
P
=.09), a lower incidence of severe CHF or shock (1% versus 6%
P
=.008), a lower combined end point of death, CHF, or shock (3% versus 10%;
P
=.006), smaller infarct size assessed by CK (115 versus 151 CK units;
P
=.03), and a trend toward fewer Q-wave infarcts. However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals.

Conclusions
Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.
Distinct Patterns of Calcium Transients During Early and Delayed Afterdepolarizations Induced by Isoproterenol in Ventricular Myocytes
Authors: De Ferrari Gaetano M. , Viola MariaCristina , D’Amato Elvira , Antolini Renzo , Forti Stefano
Published: June 2012

Background
The relation between early afterdepolarizations (EADs) and changes in intracellular Ca
2+
concentration ([Ca
2+
]
i
) is still unclear. In the present study, we compared spatiotemporal changes in [Ca
2+
]
i
related to EADs and delayed afterdepolarizations (DADs) induced by isoproterenol.

Methods and Results
Isolated patch-clamped guinea pig ventricular myocytes, loaded with fluo-3 acetoxymethyl ester (fluo-3 AM), were paced at 0.1 to 2 Hz. Isoproterenol (100 nmol/L) caused alterations in both phase 2 and phase 4 of the action potential (AP), consistent with EADs and DADs, respectively. During EADs (n=16), similar to driven APs, increases in [Ca
2+
]
i
occurred simultaneously throughout the cell, whereas during DADs (n=25), they originated in discrete cell sites and propagated as a wave. This difference was confirmed by analysis of eight EADs and DADs coupled to the same beat. Ca
2+
transients linked to EADs reached a peak relative fluorescence level (expressed as percentage of the maximal level reached during the last stimulated beat) that was always higher than that reached during the DADs (77±3% versus 64±2%,
P
<.001). Spatial heterogeneity of Ca
2+
transients was assessed by the maximal time interval between peaks monitored in different cell regions; this time lag was always greater during DADs than during EADs (290 versus 40 milliseconds,
P
=.006).

Conclusions
The present study had two main findings. First, even very modest notches occurring during the plateau of the AP may be accompanied by a marked secondary increase in [Ca
2+
]
i
. Second, these Ca
2+
transients occurring during EADs are synchronous throughout the cell and differ significantly from those observed under identical conditions during DADs.
Morning Sympathetic Nerve Activity Is Not Increased in Humans
Authors: Middlekauff Holly R. , Sontz Eric M.
Published: June 2012

Background
The sympathetic nervous system has been implicated in the circadian pattern of myocardial infarction and sudden death. It has been postulated that sympathetic nerve activity is higher in the morning than at other times of the day and that this increase reflects an endogenous circadian pattern or is triggered by changes in posture and the onset of morning activities.

Methods and Results
To test these two concepts, we made microneurographic recordings of muscle sympathetic nerve activity in the morning (6:30 to 8:30
am
) and afternoon (2:00 to 4:00
pm
) in eight healthy subjects (mean age, 42±4 years), and intraindividual comparisons (paired
t
tests) were made during (1) supine rest, (2) postural changes simulated by lower body negative pressure (LBNP), and (3) activity produced by sustained handgrip. Plasma cortisol, known to follow a circadian pattern, was measured to assess whether normal circadian patterns were present under experimental conditions. Plasma cortisol exhibited a robust circadian variability (plasma cortisol [mean±SEM],
am
versus
pm
: 17±1 versus 9±1 μg/dL,
P
=.008). In contrast, basal muscle sympathetic nerve activity was not higher in the morning compared with the afternoon (group mean sympathetic nerve activity,
am
versus
pm
: 38±6 versus 38±6 bursts per minute,
P
=NS). Similarly, plasma norepinephrine levels were not higher in the morning compared with the afternoon (plasma norepinephrine,
am
versus
pm
: 157±17 versus 173±14 pg/mL,
P
=NS). During postural stress simulated by LBNP, the magnitude of change in sympathetic nerve activity was not higher in the morning compared with the afternoon (LBNP −20 mm Hg,
am
versus
pm
: 103±34% versus 157±31%,
P
=NS). Finally, the magnitude of change in muscle sympathetic nerve activity during the first minute of handgrip exercise (
am
versus
pm
: 11±17% versus 8±11%,
P
=NS) or the second minute of handgrip exercise (
am
versus
pm
: 59±34% versus 60±15%,
P
=NS) was not higher in the morning compared with the afternoon.

Conclusions
These findings challenge the concept that sympathetic nerve activity is higher in the morning either during supine rest or during postural changes and activity. We speculate that if the sympathetic nervous system is involved in the circadian pattern of sudden death, this involvement must reflect exaggerated morning end-organ responsiveness to norepinephrine, not enhanced morning sympathetic outflow.
Dobutamine Echocardiography Predicts Improvement of Hypoperfused Dysfunctional Myocardium After Revascularization in Patients With Coronary Artery Disease
Authors: Perrone-Filardi Pasquale , Pace Leonardo , Prastaro Mariella , Piscione Federico , Betocchi Sandro , Squame Fiorenzo , Vezzuto Pasquale , Soricelli Andrea , Indolfi Ciro , Salvatore Marco , Chiariello Massimo
Published: June 2012

Background
In patients with coronary artery disease, dysfunctional hypoperfused myocardium at rest may represent either necrotic or viable hibernating myocardium. The accuracy of inotropic stimulation in identifying hypoperfused, reversibly dysfunctional myocardium has not been extensively investigated.

Methods and Results
Eighteen patients with stable chronic coronary artery disease underwent, while off drugs, quantitative
201
Tl single-photon emission computed tomography after rest injection (2 to 3 mCi), two-dimensional echocardiography at rest and during dobutamine (5 to 10 μg/kg per minute IV), and radionuclide angiography. Single-photon emission computed tomography and echocardiography at rest were repeated 34±10 days after coronary revascularization, and radionuclide angiography was repeated 45±13 days after revascularization. Resting hypoperfusion was defined as
201
Tl uptake <80% of maximal activity. Systolic function was scored from 1 (normal) to 4 (dyskinesia), and functional improvement was defined as a score change >1 grade. Of 79 dysfunctional hypoperfused segments, 48 (61%) improved function after revascularization. In 42 (88%) of these latter segments, function had improved during dobutamine. Conversely, systolic function after revascularization did not improve in 31 segments, and in 27 (87%), it had not improved during dobutamine. Functional improvement after revascularization was observed in 42 (91%) of 46 segments manifesting an improvement during dobutamine as opposed to 6 (18%) of 33 segments that did not improve during dobutamine. Resting
201
Tl uptake (% of maximal activity) before revascularization (65±9%) significantly increased at follow-up in segments where function improved (70±12%,
P
<.005), whereas it did not change significantly in segments with unchanged systolic function after revascularization (from 57±13% to 60±17%,
P
=NS). In 10 patients with prerevascularization ejection fraction <45%, left ventricular ejection fraction significantly increased from 36±7% before revascularization to 42±7% at follow-up (
P
<.05).

Conclusions
Inotropic stimulation using dobutamine echocardiography identifies hypoperfused reversibly dysfunctional myocardium. Functional improvement during dobutamine is highly predictive of improvement after revascularization.
Apoptosis in Human Atherosclerosis and Restenosis
Authors: Isner Jeffrey M. , Kearney Marianne , Bortman Scott , Passeri Jonathan
Published: June 2012

Background
Apoptosis has been recognized in normal, including rapidly proliferating, cell populations and is inferred to be potentially responsible for the maintenance of stable cell numbers in tissues with various degrees of proliferative activity. Previous studies performed in rats indicated that despite the persistence of a relatively high level of injury-induced proliferative activity, total arterial smooth muscle content at 12 weeks remained unchanged from that measured at 2 weeks, suggesting that accrual of vascular smooth muscle cells is mitigated by cell death. The extent to which apoptosis may be observed in human atherosclerosis and/or restenosis, however, has not been previously established.

Methods and Results
We performed immunohistochemical studies on 56 specimens retrieved from patients undergoing directional atherectomy for primary atherosclerotic lesions or recurrent arterial narrowing after percutaneous revascularization (restenosis). Immunohistochemical staining disclosed evidence of apoptosis in 35 (63%) of the 56 specimens studied. When present, immunohistochemical evidence of apoptosis was typically limited to <2% of cells in the specimen. The finding of apoptosis, however, was not distributed equally among four groups of specimens studied. Specimens retrieved from patients with restenosis were more frequently observed to contain foci of apoptosis than specimens retrieved from patients with primary atherosclerotic lesions. Among 14 peripheral arterial specimens from patients with restenosis, 13 (93%) contained foci of apoptosis; in contrast, apoptosis was observed in only 6 (43%) of 14 peripheral specimens from patients with primary lesions (
P
=.0046). Among coronary arterial specimens, apoptosis was observed in 12 (86%) of 14 specimens from patients with restenosis versus 6 (29%) of 14 specimens from patients with primary obstructions (
P
<.0075).

Conclusions
Apoptosis is a feature of human vascular pathology, including restenotic lesions and, to a lesser extent, primary atherosclerotic lesions. The findings of the present study suggest that apoptosis may modulate the cellularity of lesions that produce human vascular obstruction, particularly those with evidence of more extensive proliferative activity.
Angiotensin-Converting Enzyme
I/D
Polymorphism and Arterial Wall Thickness in a General Population
Authors: Castellano Maurizio , Muiesan Maria Lorenza , Rizzoni Damiano , Beschi Marina , Pasini Gianfranco , Cinelli Angelo , Salvetti Massimo , Porteri Enzo , Bettoni Giorgio , Kreutz Reinhold , Lindpaintner Klaus , Rosei Enrico Agabiti
Published: June 2012

Background
It has been reported that the
D
allele of an insertion/deletion (
I/D
) polymorphism of the angiotensin I–converting enzyme (ACE) gene is associated with conditions of increased cardiovascular risk, including left ventricular hypertrophy.

Methods and Results
Considering that a genetically determined overactivity of the renin-angiotensin system may influence cardiac as well as vascular growth, we investigated possible relations between ACE
I/D
genotype and carotid artery wall thickness (B-mode ultrasound) in 199 subjects, 50 to 64 years old, sampled from the general population of Vobarno, a small town in northern Italy. ACE
DD
genotype was associated with significantly higher common carotid artery intima-media thickness (
P
=.003). The occurrence of carotid atherosclerotic plaques was similar in the different genotypes. There was no association of the ACE
I/D
genotype with blood pressure values (either casual or 24-hour ambulatory monitored).

Conclusions
ACE
DD
genotype may be considered a risk factor for the development of common carotid intima-media thickening in our study population.
More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction
Authors: Smalling Richard W. , Bode Christoph , Kalbfleisch John , Sen Semi , Limbourg Peter , Forycki Florian , Habib Gabriel , Feldman Robert , Hohnloser Stefan , Seals Allen
Published: June 2012

Background
Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models.

Methods and Results
The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg IV over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10+10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%],
P
=.019, and 88% [82% to 94%] versus 71% [63% to 79%],
P
<.001, respectively) than the TPA group. The TIMI 3 flow in the 10+10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10+10-MU r-PA group were superior to those of the TPA group at hospital discharge (53±1.3% versus 49±1.3%,
P
=.034; −2.19±0.12 versus −2.61±0.13 SD per chord,
P
=.02, respectively). The 15-MU and 10+5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10+10-MU r-PA group. Bleeding complications were similar between the groups.

Conclusions
r-PA given as a double bolus of 10+10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.
Testosterone Increases Human Platelet Thromboxane A
2
Receptor Density and Aggregation Responses
Authors: Ajayi Adesuyi A. L. , Mathur Rajesh , Halushka Perry V.
Published: June 2012

Background
The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acute myocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A
2
(TXA
2
) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA
2
receptors.

Methods and Results
In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA
2
receptor density (B
max
) and dissociation constant (
K
d
) were measured by use of the TXA
2
mimetic
125
I-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment (pretreatment phase), at 2 and 4 weeks (active phase), and again at 8 weeks (recovery phase). Treatment with testosterone was associated with an increase in the B
max
value from 0.95±0.13 to 2.10±0.4 pmol/mg protein (n=9), with a peak effect at 4 weeks (
P
=.001), returning to baseline by 8 weeks. There was no significant change in B
max
values in the saline-treated group. The
K
d
values were unchanged. Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP (
P
<.001) at 4 weeks and returned to baseline at 8 weeks. The EC
50
values were not significantly changed. Platelet TXA
2
receptor density was positively correlated (
r
=.56,
P
<.001, n=32 measurements) with pretreatment (endogenous) plasma testosterone levels (range, 215 to 883 ng/dL) but not
K
d
.

Conclusions
Testosterone regulates the expression of platelet TXA
2
receptors in humans. This may contribute to the thrombogenicity of androgenic steroids.
Sex Differences in Patient Acceptance of Cardiac Transplant Candidacy
Authors: Aaronson Keith D. , Schwartz J. Sanford , Goin James E. , Mancini Donna M.
Published: June 2012

Background
The overwhelming majority of cardiac transplant recipients are men. This can be partially explained by the earlier age at which heart failure develops in men. However, an underrepresentation of women also may reflect physician referral or selection biases or differences in patients’ access to or acceptance of heart transplantation.

Methods and Results
We investigated whether sex bias occurred in the transplant candidate selection process at a single cardiac transplant center. We prospectively evaluated 386 individuals <70 years of age (295 men, 91 women) referred for management of moderate to severe heart failure and/or cardiac transplant evaluation. Age, race, sex, heart failure type, New York Heart Association class, left ventricular ejection fraction, peak exercise oxygen consumption, disease duration, resting hemodynamic measurements, comorbidity index score, health insurance coverage, and estimated household income were recorded. For patients not accepted for transplantation, the reason for rejection was also obtained. Univariable and multivariable (logistic regression) analyses were performed comparing men and women and patients accepted and those not accepted for cardiac transplantation. Female sex was independently associated with rejection for cardiac transplantation (odds ratio, 2.57;
P
=.01). However, the reason for rejection was more likely to be patient self-refusal for women than for men (29% versus 9%), and female sex was independently associated with patient self-refusal (odds ratio, 4.68;
P
=.003). When patients who refused transplant were reclassified as accepted for transplant, female sex was no longer associated with nonacceptance. However, lower patient income was associated with nonacceptance for transplant.

Conclusions
We found no evidence of sex bias in the selection of cardiac transplant recipients at our center. These findings suggest that the underrepresentation of women among cardiac transplant recipients may result, in part, from a sex difference in treatment preference, with a decreased willingness of women to undergo transplantation. The reasons for the difference in acceptance rates between men and women need to be elucidated.
Aspirin Enhances the Benefits of Late Reperfusion on Infarct Shape
Authors: Alhaddad Imad A. , Tkaczevski Lidia , Siddiqui Faizi , Mir Rabia , Brown Edward J.
Published: June 2012

Background
The time window of the benefits of late reperfusion on infarct shape is limited. In rats, these benefits diminish in a wave front over time, with minimal benefits when reperfusion follows 16 hours of coronary occlusion. The mechanism of the benefits of aspirin on survival after acute myocardial infarction is unknown. The purpose of this study was to test the ability of aspirin to enhance the benefits of late coronary artery reperfusion on infarct shape and to examine the mechanism of the benefits of aspirin on infarct shape.

Methods and Results
Rats were entered into two different protocols, the morphometric and the histological protocols. In the morphometric protocol, rats were randomized into two groups: the aspirin group, in which rats underwent left coronary artery occlusion followed by treatment with aspirin (12 mg/kg IV), and the control group, in which rats underwent left coronary artery occlusion followed by treatment with placebo. Rats in both groups were reperfused 8 hours after coronary occlusion. Rats in the aspirin group received aspirin in the drinking water (12±2 mg/kg daily). Morphometric analysis was performed 2 weeks after acute myocardial infarction. In the histological protocol, rats underwent the same randomization, coronary occlusion, and reperfusion protocols. Hearts were removed 24 hours after coronary occlusion, and microvessels were assessed for patency. Infarct size expressed as a percent of circumference was similar in the aspirin and placebo treatment groups (28±2% versus 33±3%,
P
=NS). Septal thickness was also similar in both groups (1.8±0.1 versus 2.1±0.1 mm,
P
=NS for aspirin versus placebo). The aspirin-treated group had thicker infarcts compared with the placebo-treated group (0.8±0.1 versus 0.5±0.1 mm,
P
<.05) and less expanded infarcts (expansion index, 1.2±0.1 versus 2.0±0.2,
P
<.05). Aspirin was associated with increased patency of the microvessels in the infarcted area compared with the placebo group (96% versus 64% of microvessels patent,
P
<.001).

Conclusions
Aspirin enhances the benefit of late coronary artery reperfusion on infarct shape after 8 hours of coronary occlusion. The benefits of aspirin on infarct shape after late reperfusion are related to increased patency of the microvessels in the infarcted area.
Bleeding Complications With the Chimeric Antibody to Platelet Glycoprotein IIb/IIIa Integrin in Patients Undergoing Percutaneous Coronary Intervention
Authors: Aguirre Frank V. , Topol Eric J. , Ferguson James J. , Anderson Keaven , Blankenship James C. , Heuser Richard R. , Sigmon Kristina , Taylor Marc , Gottlieb Ronald , Hanovich Gary , Rosenberg Michael , Donohue Thomas J. , Weisman Harlan F. , Califf Robert M.
Published: June 2012

Background
The potential for novel antiplatelet and antithrombin agents to contribute to periprocedural bleeding complications of percutaneous coronary revascularization is poorly defined. In the Evaluation of c7E3 Fab in Preventing Ischemic Complications of High-Risk Angioplasty (EPIC) trial, the periprocedural use of aspirin, heparin, and a chimeric antibody to the platelet glycoprotein IIb/IIIa integrin c7E3 Fab in 2099 patients significantly reduced postprocedural ischemic complications and 6-month clinical restenosis but was associated with increased procedural bleeding complications. We review these complications and describe clinical and procedural variables associated with increased bleeding complications in the EPIC trial.

Methods and Results
Patients with high-risk clinical or lesion morphological characteristics were randomized to receive placebo bolus plus placebo infusion, c7E3 Fab bolus plus placebo infusion, or c7E3 Fab bolus plus c7E3 Fab infusion. Patients received periprocedural aspirin and intravenous heparin continued for a minimum of 12 hours after the procedure. Outcomes reflecting bleeding complications were measured: transfusions, decreased hemoglobin, and an index including both parameters. Major bleeding complications unrelated to bypass surgery occurred in 3.3%, 8.6%, and 10.6%, and blood product transfusions were used in 7.5%, 14.0%, and 16.8% of patients treated with placebo, bolus c7E3 Fab, and bolus plus infusion c7E3 Fab, respectively (both
P
<.001). Most major bleeding complications occurred at the femoral access site, regardless of treatment. Intracranial hemorrhage (0.3%) and death (0.09%) attributable to major bleeding complications were rare. Multivariable regression analyses identified several variables significantly and independently related to major bleeding complications or greater blood loss, including greater age, female sex, lower weight, c7E3 Fab therapy, and duration and complexity of the index procedure. Major bleeding complications and blood loss in patients receiving bolus plus infusion were not significantly greater than in those receiving bolus alone (
P
=.38 and
P
=.14, respectively).

Conclusions
Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving c7E3 Fab than in those receiving placebo, but most were transient and well tolerated. Risk-factor analysis and modification of concomitant antithrombotic and antiplatelet treatment strategies may aid in reducing bleeding complications and enhancing clinical benefit in patients receiving c7E3 Fab during percutaneous coronary revascularization.