bluuebunny/crossref_metadata_2025 huggingface dataset:
Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact
Authors: Jordan Jens , Toka Hakan R. , Heusser Karsten , Toka Okan , Shannon John R. , Tank Jens , Diedrich Andre , Stabroth Christine , Stoffels Mandy , Naraghi Ramin , Oelkers Wolfgang , Schuster Herbert , Schobel Hans P. , Haller Hermann , Luft Friedrich C.
Published: June 2012

Background
—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function.

Methods and Results
—In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was 134±4.9/82±4.1 mm Hg and 90±6/49±2.4 mm Hg in patients and in control subjects, respectively. During ganglionic blockade, plasma vasopressin concentration increased 24-fold in control subjects and <2-fold in patients. In patients, cold pressor testing, hand-grip testing, and upright posture all increased blood pressure excessively. In contrast, muscle sympathetic nerve activity was not increased at rest or during cold pressor testing. The phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 8.0±2.0 μg in patients and 135±35 μg in control subjects before ganglionic blockade and 5.4±0.4 μg in patients and 13±4.8 μg in control subjects during ganglionic blockade.

Conclusions
—In patients with monogenic hypertension and neurovascular contact, basal blood pressure was increased even during sympathetic and parasympathetic nerve traffic interruption. However, sympathetic stimuli caused an excessive increase in blood pressure. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that baroreflex buffering and baroreflex-mediated vasopressin release are severely impaired.
In Vivo and In Vitro Evidence for Impaired Arginine Transport in Human Heart Failure
Authors: Kaye David M. , Ahlers Belinda A. , Autelitano Dominic J. , Chin-Dusting Jaye P. F.
Published: June 2012

Background
—The clinical features of congestive heart failure (CHF) result from a complex interaction between reduced ventricular function, neurohormonal activation, and impaired endothelial function. Although endothelial dysfunction has been well documented, the mechanisms that contribute to this abnormality remain unknown. Recent studies, however, indicate a potential therapeutic role for supplemental
l
-arginine, suggesting the presence of an underlying disorder of
l
-arginine metabolism.

Methods and Results
—We used 2 complementary approaches to assess
l
-arginine transport in control subjects and patients with CHF. During a steady-state intra-arterial infusion of [
3
H]
l
-arginine (100 nCi/min), forearm clearance of [
3
H]
l
-arginine was significantly reduced in CHF patients compared with forearm kinetics in control subjects (64±2 versus 133±14 mL/min,
P
=0.002). In conjunction with this, [
3
H]
l
-arginine uptake by peripheral blood mononuclear cells (PBMCs) was also substantially reduced in heart failure patients compared with controls (V
max
10.1±1.3 versus 49.8±7.1 pmol/10
5
cells per 5 minutes,
P
<0.001). In association with this finding, we observed a 76% (
P
<0.01) reduction in mRNA expression for the cationic amino acid transporter CAT-1, as assessed by ribonuclease protection assay.

Conclusions
—These data document both in vivo and in vitro evidence for a marked depression of
l
-arginine transport in human CHF and therefore provide an explanation for the restorative actions of supplemental
l
-arginine on vascular function in CHF.
Chronic Unloading by Left Ventricular Assist Device Reverses Contractile Dysfunction and Alters Gene Expression in End-Stage Heart Failure
Authors: Heerdt Paul M. , Holmes Jeffrey W. , Cai Bolin , Barbone Alessandro , Madigan John D. , Reiken Steven , Lee David L. , Oz Mehmet C. , Marks Andrew R. , Burkhoff Daniel
Published: June 2012

Background
—Left ventricular (LV) assist devices (LVADs) can improve contractile strength and normalize characteristics of the Ca
2+
transient in myocytes isolated from failing human hearts. The purpose of the present study was to determine whether LVAD support also improves contractile strength at different frequencies of contraction (the force-frequency relationship [FFR]) of intact myocardium and alters the expression of genes encoding for proteins involved in Ca
2+
handling.

Methods and Results
—The isometric FFRs of LV trabeculae isolated from 15 patients with end-stage heart failure were compared with those of 7 LVAD-supported patients and demonstrated improved contractile force at 1-Hz stimulation, with reversal of a negative FFR after LVAD implantation. In 20 failing hearts, Northern blot analysis for sarcoplasmic endoreticular Ca
2+
-ATPase subtype 2a (SERCA2a), the ryanodine receptor, and the sarcolemmal Na
+
-Ca
2+
exchanger was performed on LV tissue obtained before and after LVAD implantation. These paired data demonstrated an upregulation of all 3 genes after LVAD support. In tissue obtained from subsets of these patients, Western blot analysis was performed, and oxalate-supported Ca
2+
uptake by isolated sarcoplasmic reticular membranes was determined. Despite higher mRNA for all genes after LVAD support, only SERCA2a protein was increased. Functional significance of increased SERCA2a was confirmed by augmented Ca
2+
uptake by sarcoplasmic reticular membranes isolated from LVAD-supported hearts.

Conclusions
—LVAD support can improve contractile strength of intact myocardium and reverse the negative FFR associated with end-stage heart failure. The expression of genes encoding for proteins involved in Ca
2+
cycling is upregulated (reverse molecular remodeling), but only the protein content of SERCA2a is increased.
Increased Plasma P-Selectin and Decreased Thrombomodulin in Pulmonary Arterial Hypertension Were Improved by Continuous Prostacyclin Therapy
Authors: Sakamaki Fumio , Kyotani Shingo , Nagaya Noritoshi , Sato Nagato , Oya Hideo , Satoh Toru , Nakanishi Norifumi
Published: June 2012

Background
—Thrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium.

Methods and Results
—To assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (
P
<0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (
P
<0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (
P
<0.05).

Conclusions
—Decreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury.
One-Year Clinical Outcome After Minimally Invasive Direct Coronary Artery Bypass
Authors: Mehran Roxana , Dangas George , Stamou Sotiris C. , Pfister Albert J. , Dullum Mercedes K. C. , Leon Martin B. , Corso Paul J.
Published: June 2012

Background
—Minimally invasive coronary artery bypass (MIDCAB) is a new surgical technique by which the left internal mammary artery is anastomosed under direct visualization to the left anterior descending artery without cardiopulmonary bypass.

Methods and Results
—We followed all 274 patients who underwent MIDCAB from the time it was introduced at a single center. In-hospital and 1-year clinical events were source-documented and adjudicated. The in-hospital major acute cardiac event rate was 2.2%; this included a 1.1% mortality rate. At 1 year, the respective rates were 7.8% and 2.5%. When compared with the initial 100 procedures, the subsequent 174 procedures had shorter vessel occlusion times (10±5 versus 14±6 minutes;
P
=0.009), times to extubation (6±3 versus 14±10 hours;
P
<0.001), and lengths of hospital stay (2.1±1.9 versus 3.2±3.1 days;
P
=0.04). Cumulative 1-year adverse cardiac events were 11% in the initial 100 cases and 6% in the subsequent 174 cases (
P
=0.17).

Conclusions
—Excellent clinical results can be achieved with the MIDCAB technique. The clinical adverse event rate may decrease with accumulated experience.
Insulin Prevents Cardiomyocytes From Oxidative Stress–Induced Apoptosis Through Activation of PI3 Kinase/
Akt
Authors: Aikawa Ryuichi , Nawano Masao , Gu Yaping , Katagiri Hideki , Asano Tomoichiro , Zhu Weidong , Nagai Ryozo , Komuro Issei
Published: June 2012

Background
—Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress–induced apoptotic death.

Methods and Results
—Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H
2
O
2
). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 μmol/L H
2
O
2
for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, ≈4% versus H
2
O
2
, ≈23%). Pretreatment with 10
−
6
mol/L insulin significantly decreased the number of H
2
O
2
-induced TUNEL-positive cardiac myocytes (≈12%) and DNA fragmentation induced by H
2
O
2
. Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongly activated both PI3K and the putative downstream effector
Akt
. Moreover, a proapoptotic protein,
Bad
, was significantly phosphorylated and inactivated by insulin through PI3K.

Conclusions
—These results suggest that insulin protects cardiomyocytes from oxidative stress–induced apoptosis through the PI3K pathway.
Randomized Comparison of Primary Stenting and Provisional Balloon Angioplasty Guided by Flow Velocity Measurement
Authors: Serruys Patrick W. , de Bruyne Bernard , Carlier Stéphane , Sousa José Eduardo , Piek Jan , Muramatsu Toshiya , Vrints Chris , Probst Peter , Seabra-Gomes Ricardo , Simpson Ian , Voudris Vasilis , Gurné Olivier , Pijls Nico , Belardi Jorge , van Es Gerrit-Anne , Boersma Eric , Morel Marie-Angèle , van Hout Ben
Published: June 2012

Background
—Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive.

Methods and Results
—To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is “optimal.” An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885;
P
=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%;
P
=0.066).

Conclusions
—After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty.
Randomized Comparison of Elective Stent Implantation and Coronary Balloon Angioplasty Guided by Online Quantitative Angiography and Intracoronary Doppler
Authors: Di Mario Carlo , Moses Jeffrey W. , Anderson Todd J. , Bonan Raoul , Muramatsu Toshiya , Jain Abnash Chander , Suarez de Lezo Josè , Cho Seung Yun , Kern Morton , Meredith Ian T. , Cohen David , Moussa Issam , Colombo Antonio
Published: June 2012

Background
—The purpose of this study was to compare long-term outcomes of coronary stenting in all lesions (elective stenting) or only in lesions with inadequate morphological and functional results after balloon angioplasty (guided PTCA).

Methods and Results
—Treatment of multivessel disease, with any lesion length and vessel size, was allowed provided that all lesions were suitable for stent implantation. Patients were randomized to elective stent implantation (n=370) or guided PTCA (n=365). An optimal PTCA result (residual diameter stenosis ≤35%, coronary flow reserve measured with a Doppler guidewire >2.0, absence of threatening dissections) was achieved in 166 lesions (43%). The remaining 218 lesions underwent stent implantation (provisional stenting). Final residual diameter stenosis was lower in the elective and provisional stent groups (9.3% and 10.2%) than in the optimal PTCA group (24.8%,
P
<0.00001). On an intention-to-treat analysis, the probability of ≥1 major adverse cardiac event at 12 months was 17.8% in the elective stenting group and 18.9% in the guided PTCA group (20.1% for optimal PTCA and 18.0% for the provisional stenting subgroup,
P
=NS). The incidence of repeat target lesion revascularization at 1 year was 14.9% in the elective stent group and 15.6% in the guided PTCA group (17.6% for optimal PTCA and 14.1% for the provisional stenting subgroup,
P
=NS).

Conclusions
—When balloon angioplasty is guided by online quantitative angiography and Doppler-derived coronary flow reserve, with provisional stenting reserved for suboptimal results, early and late clinical outcomes are comparable to those achieved by elective stenting of all patients.
Percutaneous Coronary Intervention in the Current Era Compared With 1985–1986
Authors: Williams David O. , Holubkov Richard , Yeh Wanlin , Bourassa Martial G. , Al-Bassam Mahdi , Block Peter C. , Coady Paul , Cohen Howard , Cowley Michael , Dorros Gerald , Faxon David , Holmes David R. , Jacobs Alice , Kelsey Sheryl F. , King Spencer B. , Myler Richard , Slater James , Stanek Vladimir , Vlachos Helen A. , Detre Katherine M.
Published: June 2012

Background
—Although refinements have occurred in coronary angioplasty over the past decade, little is known about whether these changes have affected outcomes.

Methods and Results
—Baseline features and in-hospital and 1-year outcomes of 1559 consecutive patients in the 1997–1998 Dynamic Registry who were having first coronary intervention were compared with 2431 patients in the 1985–1986 National Heart, Lung, and Blood Institute Registry. Compared with patients in the 1985–1986 Registry, Dynamic Registry patients were older (mean age, 62 versus 58 years;
P
<0.001) and more often female (32.1% versus 25.5%;
P
<0.001). In the Dynamic Registry, procedures were more often performed for acute myocardial infarction (22.9% versus 9.9%;
P
<0.001) and treated lesions were more severe (84.5% versus 82.5% diameter reduction;
P
<0.001), thrombotic (22.1% versus 11.3%;
P
<0.001) or calcified (29.5% versus 10.8%;
P
<0.001). Stents were used in 70.5% of Dynamic Registry patients, whereas 1985–1986 patients received balloon angioplasty alone. Procedural success was higher in the Dynamic Registry (92.0% versus 81.8%;
P
<0.001) and the rate of in-hospital death, myocardial infarction, and emergency coronary bypass surgery combined was lower (4.9% versus 7.9%;
P
=0.001) than in the 1985–1986 Registry. The 1-year rate for CABG was lower in the Dynamic Registry (6.9% versus 12.6%;
P
<0.001).

Conclusions
—Although Dynamic Registry patients had more unstable and complex coronary disease than those in the 1985–1986 Registry, their rate of procedural success was higher whereas rates of complications and subsequent CABG were lower. Results of percutaneous coronary intervention have improved substantially over the past decade.
Effects of Estrogen Replacement on Infarct Size, Cardiac Remodeling, and the Endothelin System After Myocardial Infarction in Ovariectomized Rats
Authors: Smith Paula J. W. , Ornatsky Olga , Stewart Duncan J. , Picard Pierre , Dawood Fayez , Wen Wen-Hu , Liu Peter P. , Webb David J. , Monge Juan Carlos
Published: June 2012

Background
—Estrogen may increase the long-term survival of women who have suffered from a myocardial infarction (MI). We examined the acute and chronic influence of estrogen on MI in the rat left coronary artery ligation model.

Methods and Results
—Female Sprague-Dawley rats (10 to 12 weeks, n=93), divided into 3 groups (rats with intact ovaries, ovariectomized rats administered 17β-estradiol [17β-E
2
] replacement, and ovariectomized rats administered placebo 2 weeks before MI), were randomized to left coronary artery ligation (n=66) or sham-operated (n=27) groups. Ten to 11 weeks after MI, rats were randomly assigned to either (1) assessment of left ventricular (LV) function and morphometric analysis or (2) measurement of cardiopulmonary mRNA expression of preproendothelin-1 and endothelin A and B receptors. Acutely, estrogen was associated with a trend toward increased mortality. Infarct size was increased in the 17β-E
2
group compared with the placebo group (42±2% versus 26±3%, respectively;
P
=0.01). Chronically, wall tension was normalized through a reduction in LV cavity size with estrogen treatment (419±41 mm Hg/mm for 17β-E
2
versus 946±300 mm Hg/mm for placebo,
P
=0.039). In the LV, there was a 2.5-fold increase in endothelin B mRNA expression after MI in placebo-treated rats (
P
=0.004 versus sham-operated rats) that was prevented in the 17β-E
2
group (
P
=NS versus sham-operated rats).

Conclusions
—These results suggest that estrogen is detrimental at the time of MI or early post-MI period, resulting in an increased size of infarct or infarct expansion, but chronically, it can normalize wall tension and inhibit LV dilatation, which may in turn lead to increased long-term survival. Regulation of the endothelin system, particularly the expression of the endothelin B receptor, may contribute to these estrogenic effects.
Antioxidant Effect of Estrogen on Cytomegalovirus-Induced Gene Expression in Coronary Artery Smooth Muscle Cells
Authors: Speir Edith , Yu Zu-Xi , Takeda Kazuyo , Ferrans Victor J. , Cannon Richard O.
Published: June 2012

Background
—Pathogens infecting the arterial wall with resultant inflammation may contribute to atherogenesis. Human coronary artery smooth muscle cells (SMCs) infected with human cytomegalovirus (CMV) demonstrate a rapid increase in reactive oxygen species (ROSs), with activation of genes involved in viral replication and inflammation. Because estrogen appears to have antioxidant properties, we wished to determine whether this hormone attenuates SMC responses to CMV infection.

Methods and Results
—Using confocal microscopy and an intracellular fluorescent dye activated by ROSs, we found that 17β-estradiol (0.1 to 10 nmol/L) and its stereoisomer 17α-estradiol (which has low affinity for the estrogen receptor) dose-dependently inhibited ROS generation in CMV-infected SMCs. These effects were not blocked by the estrogen receptor inhibitor ICI 182,780. 3-Methoxyestrone, which lacks the phenolic hydroxyl group, did not interfere with ROS generation. We found that 17β-estradiol and 17α-estradiol, but not 3-methoxyestrone, prevented binding of nuclear factor (NF)-κB to DNA. Furthermore, in SMCs transfected with the reporter constructs 3XκB-CAT, MIEP-CAT, or ICAM-CAT, cotransfection with a CMV-IE72 expression plasmid caused promoter and CAT activation. Treatment with 17β-estradiol and 17α-estradiol, but not 3-methoxyestrone, inhibited CAT activity and, in CMV-infected SMCs, prevented IE72 and ICAM-1 protein expression and cytopathic effects.

Conclusions
—These findings indicate that estrogen molecules with an A-ring hydroxyl group have estrogen receptor–independent anti-CMV effects at physiological concentrations by inhibiting ROS generation, NF-κB activation, NF-κB–dependent transcription, and viral replication. To the extent that chronic infection of the vascular wall with CMV contributes to atherogenesis, these antioxidant actions of estrogen may be of therapeutic importance.
Cyclic Nucleotide Phosphodiesterase Type 5 Activity Limits Blood Flow to Hypoperfused Myocardium During Exercise
Authors: Traverse Jay H. , Chen Ying Jie , Du Ruisheng , Bache Robert J.
Published: June 2012

Background
—Nitric oxide (NO) causes vasodilation by stimulation of guanylate cyclase in vascular smooth muscle to produce cGMP. The resultant vasodilator effect is regulated by a family of cGMP phosphodiesterases (PDEs). Sildenafil, a selective inhibitor of PDE5 used for treatment of erectile dysfunction, has been found to cause relaxation of isolated epicardial coronary artery segments. The present study examined the effects of sildenafil on coronary blood flow and hemodynamics during exercise in normal and ischemic heart.

Methods and Results
—In chronically instrumented normal dogs, sildenafil 2 mg/kg PO caused a slight but significant increase in left anterior descending (LAD) coronary blood flow during resting conditions, with a nonsignificant trend toward increased coronary flow during treadmill exercise. Exercise in the presence of LAD stenosis that decreased distal coronary pressure to 57±2 mm Hg reduced LAD flow during exercise from 69±8 to 41±7 mL/min (
P
<0.05), with hypoperfusion most severe in the subendocardium. At the same distal coronary pressure, sildenafil increased LAD flow in the ischemic region to 50±11 mL/min (
P
<0.05). Increase in ischemic region blood flow produced by sildenafil was uniform across the LV wall, given that no change occurred in the transmural distribution of perfusion.

Conclusions
—Inhibition of PDE5 with sildenafil caused vasodilation of coronary resistance vessels with an increase of blood flow into an ischemic myocardial region during exercise in the presence of coronary artery stenosis.
Endogenous Na,K Pump Ligands Are Differentially Regulated During Acute NaCl Loading of Dahl Rats
Authors: Fedorova Olga V. , Lakatta Edward G. , Bagrov Alexei Y.
Published: June 2012

Background
—Two mammalian digitalis-like factors, an ouabain-like compound (OLC) and marinobufagenin (MBG), exhibit specificity to α-3 and α-1 Na
+
,K
+
-ATPase isoforms, respectively. We compared regulation of MBG and OLC by acute NaCl loading in Dahl salt-sensitive (DS) and salt-resistant (DR) rats.

Methods and Results
—An intraperitoneal NaCl load (0.8 g/kg) was given to adult male rats (24 DS and 24 DR). Diuresis, natriuresis, renal excretion, and tissue levels of MBG and OLC were measured. Inhibition of renal Na
+
,K
+
-ATPase by MBG and ouabain was compared in DS, DR, and Wistar rats. DS (versus DR) exhibited a smaller peak (2 hours) natriuretic response (1.34±0.10 versus 2.08±0.14 mmol · kg
−
1
· h
−
1
;
P
<0.01), despite a greater plasma Na
+
(153±2 versus 145±1 mmol/L;
P
<0.01). In DS and DR, pituitary, adrenal, and plasma OLC exhibited transient 2-fold to 3-fold increases, followed by a decrease to baseline levels. Plasma and adrenal MBG doubled in both strains within 1 hour of NaCl loading and remained elevated. Eight-hour MBG excretion in DS was 4-fold greater than in DR (15.8±0.8 versus 3.6±0.4 pmol;
P
<0.01), whereas OLC excretion in DS was only 30% greater than in DR (16.1±1.1 and 11.9±0.8 pmol;
P
<0.05). Kidney Na
+
,K
+
-ATPase (α-1 isoform) from Wistar rats and DS exhibited greater sensitivity to MBG than to ouabain.

Conclusions
—NaCl loading of DS causes transient increase in OLC but sustained increases in MBG tissue levels and excretion. We hypothesize that increased MBG production occurs in an attempt to compensate for genetically impaired pressure-natriuresis mechanisms.
Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations
Authors: Théroux P. , Chaitman B.R. , Danchin N. , Erhardt L. , Meinertz T. , Schroeder J.S. , Tognoni G. , White H.D. , Willerson J.T. , Jessel A.
Published: June 2012

Background
—The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis.

Methods and Results
—A total of 11 590 patients with unstable angina or non–ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%,
P
=0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%,
P
=0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%,
P
=0.03), but the rate of non–Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%,
P
=0.005). There were no increases in clinically serious adverse events.

Conclusions
—No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.
Association of Influenza Vaccination and Reduced Risk of Recurrent Myocardial Infarction
Authors: Naghavi Morteza , Barlas Zeba , Siadaty Said , Naguib Sameh , Madjid Mohammad , Casscells Ward
Published: June 2012

Background
—Numerous studies have suggested that microbial agents may promote atherosclerosis. A smaller body of research has suggested that acute respiratory infection may be a risk factor for myocardial infarction (MI). We hypothesized that influenza vaccine might reduce the risk of recurrent MI in patients with documented coronary heart disease (CHD).

Methods and Results
—A case-control study was performed on 218 CHD patients seen at Memorial Hermann Hospital during the influenza season of October 1997 through March 1998. Patients who experienced new MI were included in the case group, and those who did not experience new MI or unstable angina were assigned to the control group. Data were collected by structured review of patients’ charts and through a subsequent telephone survey. Adjusted for history of influenza vaccination in previous years, multivariate logistic regression revealed risk of MI to be associated with current hypertension (OR 4.96, 95% CI 2.06 to 11.96,
P
<0.0001), hypercholesterolemia (OR 4.08, 95% CI 1.67 to 9.99,
P
=0.002), smoking (OR 3.75, 95% CI 1.76 to 7.98,
P
=0.001), and influenza vaccination (OR 0.33, 95% CI 0.13 to 0.82,
P
=0.017). Despite significant association in univariate analysis, multivitamin therapy and physical exercise were not associated with risk of reinfarction in multivariate analysis.

Conclusions
—In this study in patients with chronic CHD, vaccination against influenza was negatively associated with the development of new MI during the same influenza season. However, to address causal inference, examination of prospective data sets will be needed.
Suppression of Endothelial Nitric Oxide Production After Withdrawal of Statin Treatment Is Mediated by Negative Feedback Regulation of Rho GTPase Gene Transcription
Authors: Laufs Ulrich , Endres Matthias , Custodis Florian , Gertz Karen , Nickenig Georg , Liao James K. , Böhm Michael
Published: June 2012

Background
—Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function.

Methods and Results
—To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production.

Conclusions
—Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.
Trends and Disparities in Coronary Heart Disease, Stroke, and Other Cardiovascular Diseases in the United States
Authors: Cooper Richard , Cutler Jeffrey , Desvigne-Nickens Patrice , Fortmann Stephen P. , Friedman Lawrence , Havlik Richard , Hogelin Gary , Marler John , McGovern Paul , Morosco Gregory , Mosca Lori , Pearson Thomas , Stamler Jeremiah , Stryer Daniel , Thom Thomas
Published: June 2012

Abstract
—A workshop was held September 27 through 29, 1999, to address issues relating to national trends in mortality and morbidity from cardiovascular diseases; the apparent slowing of declines in mortality from cardiovascular diseases; levels and trends in risk factors for cardiovascular diseases; disparities in cardiovascular diseases by race/ethnicity, socioeconomic status, and geography; trends in cardiovascular disease preventive and treatment services; and strategies for efforts to reduce cardiovascular diseases overall and to reduce disparities among subpopulations. The conference concluded that coronary heart disease mortality is still declining in the United States as a whole, although perhaps at a slower rate than in the 1980s; that stroke mortality rates have declined little, if at all, since 1990; and that there are striking differences in cardiovascular death rates by race/ethnicity, socioeconomic status, and geography. Trends in risk factors are consistent with a slowing of the decline in mortality; there has been little recent progress in risk factors such as smoking, physical inactivity, and hypertension control. There are increasing levels of obesity and type 2 diabetes, with major differences among subpopulations. There is considerable activity in population-wide prevention, primary prevention for higher risk people, and secondary prevention, but wide disparities exist among groups on the basis of socioeconomic status and geography, pointing to major gaps in efforts to use available, proven approaches to control cardiovascular diseases. Recommendations for strategies to attain the year 2010 health objectives were made.
Moderate Alcohol Consumption and Risk of Coronary Heart Disease Among Women With Type 2 Diabetes Mellitus
Authors: Solomon Caren G. , Hu Frank B. , Stampfer Meir J. , Colditz Graham A. , Speizer Frank E. , Rimm Eric B. , Willett Walter C. , Manson JoAnn E.
Published: June 2012

Background
—Moderate alcohol consumption is associated with reduced risk for coronary heart disease (CHD) in generally healthy populations. We assessed prospectively the association between moderate alcohol intake and CHD risk in women with type 2 diabetes mellitus, a group at high risk for cardiovascular disease.

Methods and Results
—We studied women in the Nurses’ Health Study who reported a diagnosis of diabetes mellitus at ≥30 years of age. During 39 092 person-years of follow-up from 1980 to 1994, there were 295 CHD events documented among this population, including 194 cases of nonfatal myocardial infarction and 101 cases of fatal CHD. Odds ratios derived from logistic regression were used to estimate relative risks (RRs) for CHD as a function of usual alcohol intake, with adjustment for potential confounders. Compared with diabetic women reporting no alcohol intake, the age-adjusted RR for nonfatal or fatal CHD among diabetic women reporting usual intake of 0.1 to 4.9 g (<0.5 drinks) of alcohol daily was 0.74 (95% CI 0.56 to 0.98), and among those reporting usual intake ≥5 g/d, it was 0.48 (95% CI 0.32 to 0.72) (
P
for trend <0.0001). Inverse associations between alcohol intake and CHD risk remained significant in multivariate analysis adjusting for several other coronary risk factors (0.1 to 4.9 g/d: RR 0.72 [95% CI 0.54 to 0.96]; ≥5 g/d: RR 0.45 [0.29 to 0.68]).

Conclusions
—Although potential risks of alcohol consumption must be considered, these data suggest that moderate alcohol consumption is associated with reduced CHD risk in women with diabetes and should not be routinely discouraged.
Differential Effects of β-Blockers in Patients With Heart Failure
Authors: Metra Marco , Giubbini Raffaele , Nodari Savina , Boldi Emiliano , Modena Maria Grazia , Cas Livio Dei
Published: June 2012

Background
—Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs.

Methods and Results
—We randomized 150 patients with heart failure (left ventricular ejection fraction ≤0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124±55 mg/d), patients treated with carvedilol (49±18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9±11.0 versus +7.2±7.7 U,
P
=0.038) and in left ventricular stroke volume and stroke work during exercise (both
P
<0.05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all
P
<0.05). In contrast, the metoprolol group showed greater increases in maximal exercise capacity than the carvedilol group (
P
=0.035), but the 2 drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. After a mean of 23±11 months of follow-up, 21 patients in the metoprolol group and 17 patients in the carvedilol group died or underwent urgent transplantation.

Conclusions
—The present study demonstrates that during long-term therapy, carvedilol improves cardiac performance to a greater extent than metoprolol when administered to patients with heart failure in the doses shown to be effective in clinical trials. These differences were likely related to a greater antiadrenergic activity of carvedilol.
Favorable Remodeling Enhances Recovery of Regional Myocardial Function in the Weeks After Infarction in Ischemically Preconditioned Hearts
Authors: Cohen Michael V. , Yang Xi-Ming , Neumann Till , Heusch Gerd , Downey James M.
Published: June 2012

Background
—In a previous study, we found that recovery of segment shortening in the ischemic zone of conscious, chronically instrumented rabbits was significantly better in ischemically preconditioned than control animals after 72 hours of reperfusion. However, although this period of reperfusion was felt to be sufficient to allow recovery from stunning, regional function was disproportionately low for the size of the infarcts.

Methods and Results
—To further characterize the recovery of left ventricular regional function, rabbits were chronically instrumented with a balloon occluder around a branch of the left coronary artery and a pair of ultrasonic crystals to monitor segment shortening in the ischemic zone. The preconditioned group had 1 cycle of 5-minute occlusion/10-minute reperfusion before a 30-minute occlusion, whereas control rabbits experienced only the 30-minute occlusion. All monitored segments were either dyskinetic or akinetic during the 30-minute occlusion. There was no difference in function between the 2 groups until 24 hours of reperfusion. At 72 hours, systolic shortening in control hearts averaged only 5% of the preischemic value, whereas shortening was 29% of baseline in preconditioned hearts. By day 21, systolic shortening averaged 26% in control hearts and 65% in preconditioned hearts (
P
<0.02) and appeared to have reached a plateau. Infarct size was 31.4±2.8% and 15.5±2.1% in control and preconditioned hearts, respectively. Moreover, in ischemically preconditioned hearts, the recovery of regional function was better than in controls for any given amount of microinfarction in the myocardial segment between crystals (
P
=0.02).

Conclusions
—The progressive improvement in preconditioned hearts is most consistent with favorable remodeling in the ischemic zone, which the preconditioning process seems to accentuate.
Acute Coronary Findings at Autopsy in Heart Failure Patients With Sudden Death
Authors: Uretsky Barry F. , Thygesen Kristian , Armstrong Paul W. , Cleland John G. , Horowitz John D. , Massie Barry M. , Packer Milton , Poole-Wilson Philip A. , Ryden Lars
Published: June 2012

Background
—Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear.

Methods and Results
—We evaluated at autopsy the prevalence of acute coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction [MI]) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (
P
<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as “sudden unexpected” or “myocardial failure” from clinical information only, the distribution of death causes was similar in the autopsy and nonautopsied groups.

Conclusions
—Acute coronary findings are frequent and usually not clinically diagnosed in heart failure patients with CAD, particularly in those dying suddenly, suggesting the importance of acute coronary events as a trigger for SD in this setting.
Effects of a K
+
Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome
Authors: Shimizu Wataru , Antzelevitch Charles
Published: June 2012

Background
—This study examines the effects of nicorandil, a K
+
channel opener, on transmural dispersion of repolarization (TDR) and induction of torsade de pointes (TdP) under conditions mimicking the LQT1, LQT2, and LQT3 forms of the congenital long-QT syndrome (LQTS).

Methods and Results
—Transmembrane action potentials of epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle together with a transmural ECG. Chromanol 293B (30 μmol/L) was used to block
I
Ks
(LQT1 model). Isoproterenol (50 to 100 nmol/L) was used to mimic an increase in β-adrenergic tone,
d
-sotalol (100 μmol/L) to block
I
Kr
(LQT2 model), and ATX-II (20 nmol/L) to augment late
I
Na
(LQT3 model). Isoproterenol+chromanol 293B,
d
-sotalol, and ATX-II produced preferential prolongation of the action potential duration at 90% repolarization (APD
90
) of the M cell, an increase of TDR, and spontaneous as well as stimulation-induced TdP (LQT1, 3/6; LQT2, 3/6; LQT3, 5/6). Nicorandil (2 to 20 μmol/L) abbreviated the QT interval and APD
90
of the 3 cell types in the 3 models. High concentrations (10 to 20 μmol/L) completely reversed the effects of 293B±isoproterenol and those of
d
-sotalol to increase APD
90
and TDR and to induce TdP in LQT1 and LQT2 models. Nicorandil 20 μmol/L reversed only 50% of the effect of ATX-II and failed to completely suppress TdP in the LQT3 model (5/6 to 3/6).

Conclusions
—Our data suggest that K
+
channel openers may be capable of abbreviating the long QT interval, reducing TDR, and preventing spontaneous and stimulation-induced TdP when congenital or acquired LQTS is secondary to reduced
I
Kr
or
I
Ks
but less so when it is due to augmented late
I
Na
.
Randomized Crossover Comparison of DDDR Versus VDD Pacing After Atrioventricular Junction Ablation for Prevention of Atrial Fibrillation
Authors: Gillis Anne M. , Connolly Stuart J. , Lacombe Pierre , Philippon François , Dubuc Marc , Kerr Charles R. , Yee Raymond , Rose M. Sarah , Newman David , Kavanagh Katherine M. , Gardner Martin J. , Kus Teresa , Wyse D. George ,   (PA) Study Investigators ;
Published: June 2012

Background
—Some clinical data suggest that atrial-based pacing prevents paroxysmal atrial fibrillation (AF). This study tested the hypothesis that DDDR pacing compared with VDD pacing prevents AF after atrioventricular (AV) junction ablation.

Methods and Results
—Patients were randomized to DDDR pacing (n=33) or to VDD pacing (n=34) after AV junction ablation and followed every 2 months for 6 months. Patients then crossed over to the alternate pacing mode and were followed for an additional 6 months. Primary analysis included the time to first recurrence of sustained AF (duration >5 minutes), total AF burden, and the development of permanent AF. The time to first episode of AF was similar in the DDDR group (0.37 days, 95% CI 0.1 to 1.3 days) and the VDD pacing group (0.5 days, 95% CI 0.2 to 1.7 days,
P
=NS). AF burden increased over time in both groups (
P
<0.01). At the 6-month follow-up, AF burden was 6.93 h/d (95% CI 4.37 to 10.96 h/d) in the DDDR group and 6.30 h/d (95% CI 3.99 to 9.94 h/d) in the VDD group (
P
=NS). Twelve (35%) patients in the DDDR group and 11 (32%) patients in the VDD group had permanent AF within 6 months of ablation. Within 1 year of follow-up, 43% of patients had permanent AF.

Conclusions
—DDDR pacing compared with VDD pacing does not prevent paroxysmal AF over the long term in patients in the absence of antiarrhythmic drug therapy after total AV junction ablation. Many patients have permanent AF within the first year after ablation.
Randomized Comparison of Antiarrhythmic Drug Therapy With Implantable Defibrillators in Patients Resuscitated From Cardiac Arrest
Authors: Kuck Karl-Heinz , Cappato Riccardo , Siebels Jürgen , Rüppel Rudolf
Published: June 2012

Background
—We conducted a prospective, multicenter, randomized comparison of implantable cardioverter-defibrillator (ICD) versus antiarrhythmic drug therapy in survivors of cardiac arrest secondary to documented ventricular arrhythmias.

Methods and Results
—From 1987, eligible patients were randomized to an ICD, amiodarone, propafenone, or metoprolol (ICD versus antiarrhythmic agents randomization ratio 1:3). Assignment to propafenone was discontinued in March 1992, after an interim analysis conducted in 58 patients showed a 61% higher all-cause mortality rate than in 61 ICD patients during a follow-up of 11.3 months. The study continued to recruit 288 patients in the remaining 3 study groups; of these, 99 were assigned to ICDs, 92 to amiodarone, and 97 to metoprolol. The primary end point was all-cause mortality. The study was terminated in March 1998, when all patients had concluded a minimum 2-year follow-up. Over a mean follow-up of 57±34 months, the crude death rates were 36.4% (95% CI 26.9% to 46.6%) in the ICD and 44.4% (95% CI 37.2% to 51.8%) in the amiodarone/metoprolol arm. Overall survival was higher, though not significantly, in patients assigned to ICD than in those assigned to drug therapy (1-sided
P
=0.081, hazard ratio 0.766, [97.5% CI upper bound 1.112]). In ICD patients, the percent reductions in all-cause mortality were 41.9%, 39.3%, 28.4%, 27.7%, 22.8%, 11.4%, 9.1%, 10.6%, and 24.7% at years 1 to 9 of follow-up.

Conclusions
—During long-term follow-up of cardiac arrest survivors, therapy with an ICD is associated with a 23% (nonsignificant) reduction of all-cause mortality rates when compared with treatment with amiodarone/metoprolol. The benefit of ICD therapy is more evident during the first 5 years after the index event.
Effect of Dietary Patterns on Serum Homocysteine
Authors: Appel Lawrence J. , Miller Edgar R. , Jee Sun Ha , Stolzenberg-Solomon Rachael , RD  , Lin Pao-Hwa , Erlinger Thomas , Nadeau Marie R. , Selhub Jacob
Published: June 2012

Background
—Elevated blood levels of homocysteine are associated with an increased risk of atherosclerotic cardiovascular disease. Although numerous studies have assessed the impact of vitamin supplements on homocysteine, the effect of dietary patterns on homocysteine has not been well studied.

Methods and Results
—During a 3-week run-in, 118 participants were fed a control diet, low in fruits, vegetables, and dairy products, with a fat content typical of US consumption. During an 8-week intervention phase, participants were then fed 1 of 3 randomly assigned diets: the control diet, a diet rich in fruits and vegetables but otherwise similar to control, or a combination diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Between the end of run-in and intervention periods, mean change in homocysteine was +0.46 μmol/L in the control diet, +0.21 μmol/L in the fruits and vegetables diet (
P
=0.47 compared with control), and −0.34 μmol/L in the combination diet (
P
=0.03 compared with control,
P
=0.12 compared with the fruits and vegetables diet). In multivariable regression models, change in homocysteine was significantly and inversely associated with change in serum folate (
P
=0.03) but not with change in serum vitamin B
12
(
P
=0.64) or pyridoxal 5′ phosphate, the coenzyme form of vitamin B
6
(
P
=0.83).

Conclusions
—Modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine. These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease.