Vol 111, No 3 | Circulation

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Background— Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death as a result of ventricular fibrillation. Controversy exists with regard to risk stratification and therapeutic management, particularly in asymptomatic individuals. Methods and Results— A total of 212 individuals (mean age, 45±6 years) with a type 1 Brugada ECG pattern were studied. Of these, 123 (58%) were asymptomatic, 65 (31%) had ≥1 syncope of unknown origin, and 24 (11%) had to be resuscitated because of ventricular fibrillation. In 125 individuals (59%), a spontaneous type 1 ECG was recorded. In the remaining, drug challenge with a class I antiarrhythmic agent unmasked a Brugada ECG. The mean ST elevation was 2.3±1.2 mm in symptomatic patients and 1.9±1.5 mm in asymptomatic individuals (P=0.04). During a mean follow-up of 40±50 months, 4 of the 24 patients (17%) with aborted sudden cardiac death and 4 of 65 (6%) with a prior syncope had a recurrent arrhythmic event, whereas only 1 of 123 asymptomatic individuals (0.8%) had a first arrhythmic event. Four of 9 patients with arrhythmic events during follow-up were not inducible during programmed electrical stimulation. A previous history of aborted sudden death or syncope and the presence of a spontaneous type 1 ECG were predictors of adverse outcome. Conclusions— The present study reports data on a large population of individuals with a type 1 Brugada ECG pattern with the longest follow-up reported so far. A very low incidence of severe arrhythmic events, particularly in asymptomatic individuals, was found during follow-up. In the presence of very few arrhythmic events on follow-up, programmed electrical stimulation showed very little accuracy in predicting outcome.

Targeted Modification of Atrial Electrophysiology by Homogeneous Transmural Atrial Gene Transfer

Circulation. 2005 | Volume 111, Issue 3: 264–270,

originally publishedJanuary 10, 2005,

https://doi.org/10.1161/01.CIR.0000153338.47507.83

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Background— Safe and effective myocardial gene transfer remains elusive. Heterogeneous ventricular gene delivery has been achieved in small mammals but generally with methods not readily transferable to the clinic. Atrium-specific gene transfer has not yet been reported. We hypothesized that homogeneous atrial gene transfer could be achieved by direct application of adenoviral vectors to the epicardial surface, use of poloxamer gel to increase virus contact time, and mild trypsinization to increase virus penetration. Methods and Results— We “painted” recombinant adenovirus encoding the reporter gene Escherichia coli β-galactosidase directly onto porcine atria. Investigational variables included poloxamer use, trypsin concentration, and safety. Using the painting method, we modified the atrial phenotype with an adenovirus expressing HERG-G628S, a long-QT-syndrome mutant. Our results showed that application of virus with poloxamer alone resulted in diffuse epicardial gene transfer with negligible penetration into the myocardium. Dilute trypsin concentrations allowed complete transmural gene transfer. After trypsin exposure, echocardiographic left atrial diameter did not change. Left atrial function decreased on postoperative day 3 but returned to baseline by day 7. Tissue tensile strength was affected only in the 1% trypsin group. HERG-G628S gene transfer prolonged atrial action potential duration and refractory period without affecting ventricular electrophysiology. Conclusions— We show complete transmural atrial gene transfer by this novel painting method. Adaptation of the method could allow application to other tissue targets. Use with functional proteins in the atria could cure or even prevent diseases such as atrial fibrillation or sinus node dysfunction.

Patients With Depressive Symptoms Have Lower Health Status Benefits After Coronary Artery Bypass Surgery

Circulation. 2005 | Volume 111, Issue 3: 271–277,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000152102.29293.D7

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Background— Depression is an established independent prognostic factor for mortality, readmission, and cardiac events after CABG surgery. However, limited data exist on whether depression influences functional outcomes after CABG. Methods and Results— We followed 963 patients who underwent first CABG between February 1999 and February 2001. At baseline and at 6 months after CABG, we interviewed patients to assess depressive symptoms using the Geriatric Depression Scale (GDS) and physical function using the Short Form-36 Physical Component Scale (PCS). The patient’s physical function was considered improved if the PCS score increased ≥5 points at 6 months. Patients with high GDS scores were younger, were more often female, and had worse physical function and higher comorbidity than patients with low GDS scores. Rates of improvement in physical function were 60.1% for a GDS score <5 (below 75th percentile), 49.8% for a GDS score between 5 and 9 (75th to 90th percentile), and 39.7% for a GDS score ≥10 (≥90th percentile; P=0.002 for the trend). Depressive symptoms remained a significant independent predictor of lack of functional improvement after adjustment for severity of coronary artery disease, angina class, baseline PCS score, and medical history. A GDS score ≥10 was a stronger inverse risk factor for functional improvement after CABG than such traditional measures of disease severity as previous myocardial infarction, heart failure on admission, history of diabetes, and left ventricular ejection fraction. Conclusions— Higher levels of depressive symptoms at the time of CABG are a strong risk factor for lack of functional benefits 6 months after CABG.

Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment

Individual Patient Meta-Analysis of 13 677 Subjects

Circulation. 2005 | Volume 111, Issue 3: 278–287,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153341.46271.40

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Background— Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. Methods and Results— A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. Conclusions— The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

Role of β₂ Adrenergic Receptors in Human Atherosclerotic Coronary Arteries

Circulation. 2005 | Volume 111, Issue 3: 288–294,

originally publishedJanuary 10, 2005,

https://doi.org/10.1161/01.CIR.0000153270.25541.72

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Background— Adrenergic regulation of coronary vasomotion is balanced between α₁-adrenergic–mediated (α₁-AR) constriction and β₂-adrenergic–mediated (β₂-AR) relaxation. This study aimed at assessing the role of β₂-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries. Methods and Results— During intracoronary (IC) infusion of increasing doses of the β₂-AR agonist salbutamol (0.15, 0.3, and 0.6 μg/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 μg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 μg/kg) of the α-adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 μmol/min) of N^G-monomethyl-l-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11±2, P<0.05), APV (APV max %: 53±17, P<0.05), and CBF (CBF max %: 57±17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27±6, P<0.05) and CBF (CBF max %: 29±6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10±2, P<0.05), APV (APV max %: 33±12, P<0.05), and CBF (CBF max %: 37±12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: −6±2, P<0.05), APV (APV max %: −15±9, P<0.05), and CBF (CBF max %: −15±6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14±3, P<0.05), APV (APV max %: 61±20, P<0.05), and CBF (CBF max %: 67±19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: −15±2, P<0.05) and no changes in APV (APV max %: −6±13, P=NS) and CBF (CBF max %: −10±13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: −15±3, P<0.05), APV (APV max %: −15±9, P<0.05), and CBF (CBF max %: −15±6, P<0.05). Conclusions— In severely atherosclerotic coronary arteries, β₂-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.

Heart Failure and Death After Myocardial Infarction in the Community

The Emerging Role of Mitral Regurgitation

Circulation. 2005 | Volume 111, Issue 3: 295–301,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000151097.30779.04

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Background— In case series, mitral regurgitation (MR) increased the risk of death after myocardial infarction (MI), yet the prevalence of MR, its incremental prognostic value over ejection fraction (EF), and its association with heart failure and death after MI in the community is not known. Methods and Results— The prevalence of MR and its association with heart failure and death were examined among 1331 patients within a geographically defined MI incidence cohort between 1988 and 1998. Echocardiography was performed within 30 days after MI in 773 patients (58%), and MR was present in 50% of cases, mild in 38%, and moderate or severe in 12%. Among patients with MR, a murmur was inconsistently detected clinically. After 4.7±3.3 years of follow-up, 109 episodes of heart failure and 335 deaths occurred. There was a graded positive association between the presence and severity of MR and heart failure or death. Moderate or severe MR was associated with a large increase in the risk of heart failure (relative risk 3.44, 95% CI 1.74 to 6.82, P<0.001) and death (relative risk 1.55, 95% CI 1.08 to 2.22, P=0.019) among 30-day survivors independent of age, gender, EF, and Killip class. Conclusions— In the community, MR is frequent and often silent after MI. It carries information to predict heart failure or death among 30-day survivors independently of age, gender, EF, and Killip class. These findings, which are applicable to a large community-based MI cohort, suggest that the assessment of MR should be included in post-MI risk stratification.

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

Circulation. 2005 | Volume 111, Issue 3: 302–309,

originally publishedJanuary 10, 2005,

https://doi.org/10.1161/01.CIR.0000153351.86708.F7

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Background— Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion–induced NE overflow and cardiac dysfunction using a selective ET_A receptor antagonist (ABT-627), a selective ET_B receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET_B receptor gene. Methods and Results— According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion–induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET_B receptor–deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na⁺/H⁺ exchanger (NHE). Conclusions— Pharmacological blockade or genetic deficiency of ET_B receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET_A receptor activation. ET_A/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure

Circulation. 2005 | Volume 111, Issue 3: 310–314,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153349.77489.CF

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Background— Endothelial function is known to be impaired in subjects with chronic heart failure (CHF), but the association between endothelial function and subsequent mortality risk in CHF has not been previously reported. Methods and Results— Biomarkers of endothelial function in the systemic arterial circulation (flow-mediated dilation [FMD] in the brachial artery) and the pulmonary circulation (exhaled nitric oxide [NO] production during submaximal exercise) were prospectively assessed in 259 subjects with New York Heart Association class II–III CHF. In subjects with FMD measurements (n=149), there were 12 deaths and 5 urgent transplantations over a median follow-up period of 841 days. In subjects with exhaled NO production measurements (n=110), there were 18 deaths and 1 urgent transplantation over a median follow-up period of 396 days. Both decreased FMD and decreased exhaled NO production were associated with increased risk of death or urgent transplantation after adjustment for other known CHF prognostic factors (age, etiology of CHF, functional class, left ventricular ejection fraction) in Cox multivariate proportional-hazards models (adjusted hazard ratio [HR] estimate for a 1% decrease in FMD=1.20; 95% confidence interval [CI], 1.03 to 1.45; P=0.027; adjusted HR estimate for a 1-ppb/min decrease in exhaled NO production=1.31, 95% CI, 1.01 to 1.69, P=0.04). Conclusions— Endothelial dysfunction in CHF, as assessed by FMD in the brachial artery and exhaled NO production during submaximal exercise, is associated with an increased mortality risk in subjects with both ischemic and nonischemic CHF.

Losartan Increases Bradykinin Levels in Hypertensive Humans

Circulation. 2005 | Volume 111, Issue 3: 315–320,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153269.07762.3B

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Background— Studies in animals and humans indicate a role for kinins in the actions of angiotensin type 1 (AT₁) receptor blockers. However, the effect of these compounds on kinin levels in humans is unknown. Methods and Results— We measured angiotensin (Ang), bradykinin (BK), and kallidin peptides in subjects with essential hypertension administered placebo, losartan (50 mg OD), and eprosartan (600 mg OD) in randomized order in a double-blind, 3-period, 3-treatment, crossover trial. Peptides were measured in arterial blood using high-performance liquid chromatography–based radioimmunoassays. Losartan increased blood levels of BK-(1–9) and hydroxylated BK-(1–9) by ≈2-fold and reduced the BK-(1–7)/BK-(1–9) ratio by 55%. There was a trend for eprosartan to produce similar changes in bradykinin levels. There were no changes in blood kallidin levels. Both losartan and eprosartan increased plasma levels of Ang I, Ang II, and Ang-(2–8), and eprosartan increased Ang-(3–8) levels. Ang-(1–7) and Ang-(1–9) levels were unchanged. There was an associated 30% to 35% reduction in Ang II/Ang I ratio and 63% to 69% reduction in Ang-(1–7)/Ang I ratio. Plasma ACE activity was unchanged. Conclusions— Losartan increases bradykinin levels. The reductions in BK-(1–7)/BK-(1–9), Ang II/Ang I, and Ang-(1–7)/Ang I ratios suggest that the increased bradykinin levels were the result of reduced metabolism by ACE and neutral endopeptidase. Increased bradykinin levels may represent a class effect of AT₁ receptor blockers that contributes to their therapeutic actions and may also contribute to the angioedema that may accompany this therapy.

Relationship of Late Loss in Lumen Diameter to Coronary Restenosis in Sirolimus-Eluting Stents

Circulation. 2005 | Volume 111, Issue 3: 321–327,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153356.72810.97

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Background— Observed rates of restenosis after drug-eluting stenting are low (<10%). Identification of a reliable and powerful angiographic end point will be useful in future trials. Methods and Results— Late loss (postprocedural minimum lumen diameter minus 8-month minimum lumen diameter) was measured in the angiographic cohorts of the SIRIUS (n=703) and E-SIRIUS (n=308) trials. Two techniques, the standard normal approximation and an optimized power transformation, were used to predict binary angiographic restenosis rates and compare them with observed restenosis rates. The mean in-stent late loss observed in the SIRIUS trial was 0.17±0.45 mm (sirolimus) versus 1.00±0.70 mm (control). If a normal distribution was assumed, late loss accurately estimated in-stent binary angiographic restenosis for the control arm (predicted 35.4% versus observed 35.4%) but underestimated it in the sirolimus arm (predicted 0.6% versus observed 3.2%). Power transformation improved the reliability of the estimate in the sirolimus arm (predicted 3.2% [CI 1.0% to 6.7%]) with similar improvements in the E-SIRIUS trial (predicted 4.0% [CI 1.2% to 7.0%] versus observed 3.9%). In the sirolimus-eluting stent arm, in-stent late loss correlated better with target-lesion revascularization than in-segment late loss (c-statistic=0.915 versus 0.665). Conclusions— Because distributions of late loss with a low mean are right-skewed, the use of a transformation improves the accuracy of predicting low binary restenosis rates. Late loss is monotonically correlated with the probability of restenosis and yields a more efficient estimate of the restenosis process in the era of lower binary restenosis rates.

Elevated Brain Natriuretic Peptide Predicts Blood Pressure Response After Stent Revascularization in Patients With Renal Artery Stenosis

Circulation. 2005 | Volume 111, Issue 3: 328–333,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153271.77341.9F

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Background— A significant number (20% to 40%) of hypertensive patients with renal artery stenosis will not have blood pressure improvement after successful percutaneous revascularization. Identifying a group of patients with refractory hypertension and renal artery stenosis who are likely to respond to renal stent placement would be beneficial. Methods and Results— Brain natriuretic peptide (BNP) was measured in 27 patients with refractory hypertension and significant renal artery stenosis before and after successful renal artery stent placement. This neuropeptide was elevated (median, 187 pg/mL; 25th to 75th percentiles, 89 to 306 pg/mL) before stent placement and fell within 24 hours of the successful stent procedure (96 pg/mL; 25th to 75th percentiles, 61 to 182 pg/mL; P=0.002), remaining low (85 pg/mL; 25th to 75th percentiles, 43 to 171 pg/mL) at follow-up. Clinical improvement in hypertension was observed in the patients with a baseline BNP >80 pg/mL (n=22) in 17 patients (77%) compared with 0% of the patients with a baseline BNP ≤80 pg/mL (n=5) (P=0.001). After correction for glomerular filtration rate, BNP was strongly correlated with improvement in hypertension. Conclusions— BNP is increased in patients with severe renal artery stenosis and decreases after successful stent revascularization. In addition, an elevated baseline BNP level of >80 pg/mL appears to be a good predictor of a blood pressure response after successful stent revascularization.

Cyclooxygenases, Thromboxane, and Atherosclerosis

Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism

Circulation. 2005 | Volume 111, Issue 3: 334–342,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153386.95356.78

- Correction
  - Volume 111Issue 18Circulation
  - 10 May 2005

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Background— Antagonism or deletion of the receptor (the TP) for the cyclooxygenase (COX) product thromboxane (Tx)A₂, retards atherogenesis in apolipoprotein E knockout (ApoE KO) mice. Although inhibition or deletion of COX-1 retards atherogenesis in ApoE and LDL receptor (LDLR) KOs, the role of COX-2 in atherogenesis remains controversial. Other products of COX-2, such as prostaglandin (PG) I₂ and PGE₂, may both promote inflammation and restrain the effects of TxA₂. Thus, combination with a TP antagonist might reveal an antiinflammatory effect of a COX-2 inhibitor in this disease. We addressed this issue and the role of TxA₂ in the promotion and regression of diffuse, established atherosclerosis in Apobec-1/LDLR double KOs (DKOs). Methods and Results— TP antagonism with S18886, but not combined inhibition of COX-1 and COX-2 with indomethacin or selective inhibition of COX-2 with Merck Frosst (MF) tricyclic, retards significantly atherogenesis in DKOs. Although indomethacin depressed urinary excretion of major metabolites of both TxA₂, 2,3-dinor TxB₂ (Tx-M), and PGI₂, 2,3-dinor 6-keto PGF_1α (PGI-M), only PGI-M was depressed by the COX-2 inhibitor. None of the treatments modified significantly the increase in lipid peroxidation during atherogenesis, reflected by urinary 8,12-iso-iPF_2α-VI. Combination with the COX-2 inhibitor failed to augment the impact of TP antagonism alone on lesion area. Rather, analysis of plaque morphology reflected changes consistent with destabilization of the lesion coincident with augmented formation of TxA₂. Despite a marked effect on disease progression, TP antagonism failed to induce regression of established atherosclerotic disease in this model. Conclusions— TP antagonism is more effective than combined inhibition of COX-1 and COX-2 in retarding atherogenesis in Apobec-1/LDLR DKO mice, which perhaps reflects activation of the receptor by multiple ligands during disease initiation and early progression. Despite early intervention, selective inhibition of COX-2, alone or in combination with a TP antagonist, failed to modify disease progression but may undermine plaque stability when combined with the antagonist. TP antagonism failed to induce regression of established atherosclerotic disease. TP ligands, including COX-1 (but not COX-2)–derived TxA₂, promote initiation and early progression of atherogenesis in Apobec-1/LDLR DKOs but appear unimportant in the maintenance of established disease.

Irbesartan and Lipoic Acid Improve Endothelial Function and Reduce Markers of Inflammation in the Metabolic Syndrome

Results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) Study

Circulation. 2005 | Volume 111, Issue 3: 343–348,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153272.48711.B9

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Background— The metabolic syndrome is associated with increased angiotensin II activity, induction of a proinflammatory and oxidative state, and endothelial dysfunction. We evaluated the ability of irbesartan, an angiotensin receptor blocker, and lipoic acid, an antioxidant, to affect endothelial function and inflammation in patients with the metabolic syndrome. Methods and Results— We randomized 58 subjects with the metabolic syndrome in a double-blinded manner to irbesartan 150 mg/d (n=14), lipoic acid 300 mg/d (n=15), both irbesartan and lipoic acid (n=15), or matching placebo (n=14) for 4 weeks. Endothelium-dependent and -independent flow-mediated vasodilation was determined under standard conditions. Plasma levels of interleukin-6, plasminogen activator-1, and 8-isoprostane were measured. After 4 weeks of therapy, endothelium-dependent flow-mediated vasodilation of the brachial artery was increased by 67%, 44%, and 75% in the irbesartan, lipoic acid, and irbesartan plus lipoic acid groups, respectively, compared with the placebo group. Treatment with irbesartan and/or lipoic acid was associated with statistically significant reductions in plasma levels of interleukin-6 and plasminogen activator-1. In addition, treatment with irbesartan or irbesartan plus lipoic acid decreased 8-isoprostane levels. No significant changes in blood pressure were noted in any of the study groups. Conclusions— Administration of irbesartan and/or lipoic acid to patients with the metabolic syndrome improves endothelial function and reduces proinflammatory markers, factors that are implicated in the pathogenesis of atherosclerosis.

Tissue Factor Cytoplasmic Domain Stimulates Migration by Activation of the GTPase Rac1 and the Mitogen-Activated Protein Kinase p38

Circulation. 2005 | Volume 111, Issue 3: 349–355,

originally publishedJanuary 10, 2005,

https://doi.org/10.1161/01.CIR.0000153333.52294.42

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Background— Tissue factor (TF), the surface receptor for the serine protease factor VIIa (FVIIa) and the initiator of the extrinsic coagulation cascade, supports vessel development and tumor metastasis by activation of extracellular, protease-dependent signaling pathways. The molecular mechanisms that do not require proteolytic activity of FVIIa are not yet known. The aim of the study, therefore, was to investigate the effects of active-site–inhibited FVIIa (FFR-FVIIa) on TF-mediated signaling. Methods and Results— After stimulation with FVIIa and FFR-FVIIa, migration and activation of the GTPase Rac (Rac1) or the mitogen-activated protein kinase p38 (p38) were analyzed in J82 cells. FVIIa and FFR-FVIIa stimulated migration and activation of Rac1 and p38 in a TF-specific, dose- and time-dependent manner. Enhancement of migration required activation of Rac1 and p38, because it was abolished after inhibition with SB203580 or overexpression of dominant negative p38 and Rac1. The cytoplasmic domain of TF was necessary because no effects of FFR-FVIIa could be detected after transfection of a TF deletion mutant lacking the cytoplasmic domain. Conclusions— We identified a novel signaling pathway through which TF stimulates migration by activation of p38 and Rac1 independent of the proteolytic activity of FVIIa but dependent on the cytoplasmic domain of TF. Binding of FFR-VIIa to TF may stimulate vessel wall remodeling by enhancement of migration through activation of Rac1 and p38. This novel link may provide an insight into the understanding of the nonhemostatic functions of TF.

Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia

Circulation. 2005 | Volume 111, Issue 3: 356–362,

originally publishedJanuary 17, 2005,

https://doi.org/10.1161/01.CIR.0000153352.29335.B9

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Background— Previous studies have shown that adrenomedullin (AM) inhibits vascular endothelial cell apoptosis and induces angiogenesis. We investigated whether AM enhances bone marrow cell–induced angiogenesis. Methods and Results— Immediately after hindlimb ischemia was created, rats were randomized to receive AM infusion plus bone marrow–derived mononuclear cell (MNC) transplantation (AM+MNC group), AM infusion alone (AM group), MNC transplantation alone (MNC group), or vehicle infusion (control group). The laser Doppler perfusion index was significantly higher in the AM and MNC groups than in the control group (0.74±0.11 and 0.69±0.07 versus 0.59±0.07, respectively, P<0.01), which suggests the angiogenic potency of AM and MNC. Importantly, improvement in blood perfusion was marked in the AM+MNC group (0.84±0.08). Capillary density was highest in the AM+MNC group, followed by the AM and MNC groups. In vitro, AM inhibited MNC apoptosis, promoted MNC adhesiveness to a human umbilical vein endothelial cell monolayer, and increased the number of MNC-derived endothelial progenitor cells. In vivo, AM administration not only enhanced the differentiation of MNC into endothelial cells but also produced mature vessels that included smooth muscle cells. Conclusions— A combination of AM infusion and MNC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation alone. This effect may be mediated in part by the angiogenic potency of AM itself and the beneficial effects of AM on the survival, adhesion, and differentiation of transplanted MNCs.

Endothelial Function

Cardiac Events

Amir Lerman and
Andreas M. Zeiher

Circulation. 2005 | Volume 111, Issue 3: 363–368,

originally publishedJanuary 25, 2005,

https://doi.org/10.1161/01.CIR.0000153339.27064.14

Cardiac Rehabilitation and Secondary Prevention of Coronary Heart Disease

An American Heart Association Scientific Statement From the Council on Clinical Cardiology (Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity), in Collaboration With the American Association of Cardiovascular and Pulmonary Rehabilitation

Circulation. 2005 | Volume 111, Issue 3: 369–376,

originally publishedJanuary 25, 2005,

https://doi.org/10.1161/01.CIR.0000151788.08740.5C

- Correction
  - Volume 111Issue 13Circulation
  - 5 April 2005

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This article updates the 1994 American Heart Association scientific statement on cardiac rehabilitation. It provides a review of recommended components for an effective cardiac rehabilitation/secondary prevention program, alternative ways to deliver these services, recommended future research directions, and the rationale for each component of the rehabilitation/secondary prevention program, with emphasis on the exercise training component.