Prognostic markers of all-cause mortality in patients with atrial fibrillation: data from the prospective long-term registry of the German Atrial Fibrillation NETwork (AFNET).

AIMS: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients. METHODS AND RESULTS: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality. CONCLUSION: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort.

Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.

BACKGROUND: Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD. METHODS: Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. FINDINGS: Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13-0.24] mmol/L, p = 1.5x10(-10)). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1x10(-7)). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. CONCLUSION: A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.

Association of echocardiographic atrial size and atrial fibrosis in a sequential model of congestive heart failure and atrial fibrillation.

BACKGROUND: Cardioversion (CV) success of atrial fibrillation (AF) inversely correlates to the size of the left atrium (LA). Atrial fibrillation and its most important risk factor, congestive heart failure (CHF), both induce atrial structural enlargement and fibrosis. To investigate the effect of AF and CHF on atrial dilatation and fibrosis, and to estimate whether echocardiographically determined atrial size may be used as a marker for atrial fibrosis. METHODS: In six dogs, pacemakers were implanted followed by HIS bundle ablation. After 4 weeks of rapid ventricular stimulation (185 bpm) for CHF induction, additional rapid atrial stimulation (500 bpm) was maintained for 7 weeks to induce AF. Serial determinations of echocardiographic atrial size were performed. Seven dogs with sinus rhythm served as histological controls. Postmortem tissue was obtained to determine the degree and composition of atrial fibrosis. RESULTS: While the ejection fraction of the AF/CHF dogs decreased significantly from 57+/-5% to 19+/-7% (P<.01), an increased degree of atrial fibrosis was found (right atrium [RA], 4.9+/-2.0% to 19.9+/-5.4%; LA, 4.4+/-1.6% to 22.2+/-3.2%; P<.01), accompanied by a significant increase of atrial volumes (LA: 21+/-4 to 44+/-4 mm3; P<.01; RA: 10+/-3 to 18+/-6 mm3; P<.05) and LA diameters (34+/-4 to 43+/-2 mm, P<.05). Atrial fibrosis and size significantly correlated. CONCLUSIONS: Atrial fibrillation/CHF leads to a significant atrial fibrosis and dilation. The increased echocardiographic size correlates to the degree of atrial fibrosis and may be used as clinical marker for atrial fibrosis. The fibrosis accompanying atrial dilatation may also explain why LA size, as determined by echocardiography, is a strong predictor of CV success.

Efficacy of transesophageal defibrillation in ventricular fibrillation of long duration.

INTRODUCTION: Increasing duration of ventricular fibrillation (VF) is associated with a higher risk of ineffective resuscitation. In addition, precountershock chest compression can influence defibrillation success. Transesophageal defibrillation may increase defibrillation success because of the proximity of the esophagus to the heart. We evaluated the efficacy of transesophageal defibrillation compared with standard transthoracic defibrillation after long episodes of VF. METHODS: Defibrillation success after 10 minutes of untreated VF was evaluated in 12 sheep randomized into 2 groups: (group A) in 6 sheep, up to 3 transthoracic shocks were applied, followed by up to 3 transesophageal shocks (first shock: 150 J, second and third shocks: 200 J). (group B) In 6 sheep, 2 minutes of precountershock chest compression preceded the defibrillation shocks. Truncated biphasic shocks were delivered between a sternal and an apical patch electrode for transthoracic defibrillation and between an esophageal and a cutaneous patch electrode for transesophageal defibrillation. RESULTS: In group A with no precountershock chest compression, external defibrillation failed despite shocks with maximum energy (200 J) in all 6 sheep. Transesophageal defibrillation was successful in 3 sheep (50%). In group B with precountershock chest compression, external defibrillation failed in all 6 sheep. Transesophageal defibrillation was successful with the first shock in all 6 sheep. CONCLUSIONS: Transesophageal defibrillation may terminate VF of long duration that is refractory to standard defibrillation. Precountershock chest compression may increase transesophageal defibrillation success.

Angiotensin II antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial: rationale and study design.

BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Recent experimental data and retrospective analyses of clinical trials suggest that increased levels of angiotensin II can induce an arrhythmogenic atrial substrate, which favours the occurrence of AF. The purpose of the ANTIPAF (Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation) trial is to prove the principal concept that blockade of angiotensin II type 1 receptors with olmesartan medoxomil 40 mg/day suppresses paroxysmal AF episodes during a 12-month follow-up. The ANTIPAF trial is the first placebo-controlled trial analysing the occurrence of AF as the primary study endpoint. METHODS: Examination of the study hypothesis in a prospective, randomised, placebo-controlled, double-blind group comparison in patients with documented paroxysmal AF (total of 422 patients) stratified by beta-adrenoceptor antagonist use. The primary endpoint of the study is the percentage of days with documented episodes of paroxysmal AF identified on daily transtelephonic tele-ECG recordings. Patients will record and transmit at least one 1-minute ECG per day independent of symptoms. Furthermore, tele-ECG recordings will be transmitted in any case of symptomatic AF. The present paper summarises the rationale and design of the ANTIPAF trial.

Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation.

INTRODUCTION: Atrial fibrosis has been shown to concur with the persistence of atrial fibrillation (AF) and is only incompletely reversible, thus counteracting attempts to restore and maintain sinus rhythm (SR). Besides the angiotensin system, the matrix metalloproteinases (MMP) play a major role in the pathogenesis of fibrosis. Thus, the present study investigated changes of the MMP system during the development of human AF. METHODS AND RESULTS: Right atrial appendages of 146 patients were excised during heart surgery and grouped according to rhythm (SR vs AF) and AF duration. Hydroxyproline as a surrogate for collagen content and morphometrically determined collagen content increased significantly from SR (14.3 +/- 7.7%) to chronic permanent AF (CAF) of 6-24 months (21.2 +/- 9.2%, P = 0.02), and CAF of > 60 months (25.3 +/- 4.7%, P < 0.01). From SR to paroxysmal and chronic persistent AF (CPAF) and to CAF MMP-2 and MMP-9 activity rose, while their mRNA and protein levels were not altered significantly. Plasminogen activator inhibitor (PAI), an inhibitor of a potent activator of many MMPs, was significantly decreased with increasing duration of AF. In parallel, the mRNA levels of the tissue inhibitors of MMPs TIMP-1 and -2 decreased significantly. CONCLUSION: Human atrial fibrogenesis is enhanced with increasing duration of AF: a longer AF duration is associated with elevated atrial interstitial MMP activity, but decreased PAI and TIMP expression.

Single-step atrial thrombus exclusion and transesophageal cardioversion in atrial fibrillation.

Atrial fibrillation (AF), the most common arrhythmia, has a major impact on both patient morbidity and healthcare economics. Hospital admissions due to AF have risen by two-thirds in the last 20 years. This is due mainly to an aging population and an increasing prevalence of chronic heart disease. Strategies for the management of AF include prevention of thromboembolism, rate control and correction of the arrhythmia. Electrical cardioversion as one component of the treatment of AF requires the absence of atrial thrombi. Transesophageal echocardiography is used routinely for exclusion of atrial thrombi prior to cardioversion in many hospitals. This review presents preliminary data on the clinical use of devices for simultaneous transesophageal echocardiography and transesophageal cardioversion.

Simultaneous transesophageal cardioversion and echocardiography: feasibility and safety.

BACKGROUND: Transesophageal echocardiography (TEE) is routinely used to exclude atrial thrombus prior to cardioversion of atrial fibrillation (AF). Because the TEE probe lies adjacent to the atria, cardioversion using an electrode attached to the TEE probe should allow for immediate low-energy transesophageal cardioversion. OBJECTIVE: The purpose of this study was to evaluate a cardioversion electrode sheath that can be affixed to conventional TEE probes for simultaneous thrombus exclusion and cardioversion of AF. METHODS: A thin electrode was integrated into a latex or polyurethane sheath covering a conventional TEE probe. TEE thrombus exclusion and biphasic transesophageal cardioversion using a step-up protocol were performed during deep sedation. Esophagoscopy was performed immediately after cardioversion and after 1 week. RESULTS: TEE was performed in 27 patients. One patient showed left atrial thrombi. Transesophageal cardioversion was successful in 25 of the remaining 26 patients. Mean atrial cardioversion threshold was 63 +/- 48 J. Transesophageal cardioversion restored sinus rhythm in two patients with unsuccessful transthoracic cardioversion. Transesophageal cardioversion in deep sedation was well tolerated. Esophagoscopy revealed slight mucosal damage in three patients at the site of shock application; two of these patients showed signs of gastroesophageal reflux disease. Mucosal damage unrelated to the site of shock delivery was noted in three patients. CONCLUSION: Atrial thrombus exclusion and transesophageal cardioversion of AF via a disposable cardioversion sheath offers the opportunity to perform transesophageal cardioversion and TEE thrombus exclusion during one sedation. It may not be suitable for use in patients with gastroesophageal reflux disease. Transesophageal cardioversion may establish sinus rhythm in selected patients refractory to transthoracic cardioversion.

Impact of left ventricular lead position on the efficacy of cardiac resynchronisation therapy: a two-dimensional strain echocardiography study.

BACKGROUND: Definition of the optimal left ventricular (LV) lead position in cardiac resynchronisation therapy (CRT) is desirable. OBJECTIVE: To define the optimal LV lead position in CRT and assess the effectiveness of CRT depending on the LV lead position using new myocardial deformation imaging. METHODS: Myocardial deformation imaging based on tracking of acoustic tissue pixels in two-dimensional echocardiographic images (EchoPAC, GE ultrasound) was performed in 47 patients with heart failure at baseline and during CRT. In a 36-segment LV model the segment with the latest peak systolic circumferential strain before CRT was determined. The segment with maximal temporal difference in peak systolic circumferential strain on CRT compared with before CRT was assumed to be the LV lead position. The optimal LV lead position was defined as concurrence or immediate neighbouring of the segment with the latest contraction before CRT and those with assumed LV lead location. RESULTS: 25 patients had optimal and 22 non-optimal LV lead positions. Before CRT, the LV ejection fraction (EF) and peak oxygen consumption (Vo2max) were similar in patients with optimal and non-optimal LV lead positions (mean (SD) EF = 31.4 (6.1)% vs 30.3 (6.5)% and Vo2max = 14.2 (1.8) vs 14.0 (2.1) ml/min/kg, respectively). At 3 months on CRT, EF increased by 9 (2)% vs 5 (3)% and Vo2max by 2.0 (0.8) vs 1.1 (0.5) ml/min/kg in the optimal vs non-optimal LV lead position groups, respectively (both p<0.001). CONCLUSIONS: Concordance of the LV lead site and location of the latest systolic contraction before CRT results in greater improvement in EF and cardiopulmonary workload than the non-optimal LV lead position.

Reduced numbers of circulating endothelial progenitor cells in patients with coronary artery disease associated with long-term statin treatment.

While statin treatment may transiently mobilize endothelial progenitor cells (EPCs), the dose-dependent effects of a continuous statin therapy on EPCs in patients with chronic coronary artery disease (CAD) have not been analyzed. In 209 patients with angiographically documented CAD, 144 of which received 10-40 mg/day of statins for >8 weeks, the EPC number was determined by flow cytometry directly (CD34(+)/KDR(+), n=58) and after in vitro-culture (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled Ac-LDL (DiI-Ac-LDL(+))/lectin(+), n=209). EPC function was assessed by the formation of colony forming units (CFUs). Univariate analysis revealed that the dose of continuous statin therapy inversely correlated with the EPC number. Treatment with 40 mg/day significantly reduced EPC counts. Multivariate analysis unveiled the statin dose and extent of CAD as independent predictors of reduced EPC numbers. Conversely, obesity predicted increased counts, while CFU development was not detectable in all patients and augmented in females and smokers but not in statin-treated patients. Compared with matched controls, statin-treated patients showed significantly reduced absolute and relative EPC counts. In a prospective analysis, initiation of statin therapy significantly diminished the number of circulating and isolated EPCs after 3 but not after 1 month(s). Thus, the statin dose during chronic and continuous treatment independently predicts reduced numbers of circulating as well as isolated EPCs in patients with CAD.

A new method to investigate the response to the morphology discrimination algorithm in patients with ICD.

BACKGROUND: Inappropriate therapy for supraventricular tachyarrhythmia is still a major problem in implantable cardioverter defibrillators (ICD). The morphology discrimination algorithm compares the morphology of a tachycardia electrogram with a stored template on a beat-to-beat basis. However, algorithm responders could not yet be identified prior to the occurrence of first tachycardia episodes. We analyzed whether rapid atrial pacing and/or exercise testing can be used for identification of responders and compared the results with ICD detected tachycardia. METHODS: 22 patients (16 male, 61+/-14 years) with dual-chamber ICDs have been enrolled. Patients underwent a standardized bicycle exercise testing and an atrial pacing protocol. For both tests, morphology match scores of 8 consecutive beats were analyzed for each 10-bpm-step increment above sinus rhythm. Patients were categorized as responders, if morphology match was > or = 90% of tested heart rates. During follow-up, ICD stored episodes with morphology discrimination activated were evaluated. RESULTS: There were no significant differences between morphology match (85+/-29% vs. 84+/-27%) and linear regression slope B (-0.19+/-0.87 vs. -0.20+/-0.48) during exercise testing and atrial pacing. 16 patients (73%) were classified as responders. During follow-up (739+/-338 days) 121 sustained supraventricular (n=88) and ventricular tachycardia (n=33) were detected in 10 patients (45%). Specificity for tachycardia discrimination was 78% overall, 100% in responders and 22% in non-responders. CONCLUSION: Exercise testing and atrial pacing were equally suitable for identification of patients who seem to respond to the morphology discrimination algorithm with a high specificity for ventricular tachycardia discrimination. Thus, morphology match tests are suggested to optimize tachycardia discrimination and to reduce inadequate therapies.

Quality of anticoagulation with unfractionated heparin plus phenprocoumon for the prevention of thromboembolic complications in cardioversion for non-valvular atrial fibrillation. Sub-analysis from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial.

INTRODUCTION: Anticoagulation in cardioversion for atrial fibrillation is performed using unfractionated heparin and oral anticoagulants. TEE-guided cardioversion, after achievement of therapeutic anticoagulation (1-3 days), may be an alternative to the traditional procedure (3-week anticoagulation followed by cardioversion). The quality of anticoagulation in atrial fibrillation has not been investigated in a randomised trial with TEE-guided cardioversion. We analysed respective data from the ACE trial on the quality of conventional anticoagulation, where most participating centres chose the TEE-guided approach. MATERIALS AND METHODS: In a randomised, prospective, multicentre trial, we analysed the efficacy of unfractionated heparin plus phenprocoumon in 248 patients on an intention-to-treat basis. There were 2373 evaluable anticoagulation measurements (out of 2925 measurements) and 4 categories of anticoagulation quality (under-, target, over- and severe over-anticoagulation). Of patients with evaluable measurements, 88% received short-term anticoagulation (4 weeks) in TEE-guided cardioversion. RESULTS: The median time to achieve therapeutic anticoagulation (aPTT> or =60 and <80 s or INR> or =2 and <3) was 3 days. Anticoagulation values were out of therapeutic range in 69.5% of measurements during 4- or 7-week follow-up, and never within therapeutic range in 10% of patients. Of the 15 primary endpoints observed (death, thromboembolism and major bleeding complications), only 3 were in patients with anticoagulation measurements within therapeutic range. CONCLUSIONS: In this study setting, with predominance of 4 weeks anticoagulation in TEE-guided cardioversion for atrial fibrillation, therapeutic anticoagulation was reached within 3 days using conventional anticoagulation. Despite careful dose adjustments, anticoagulation was out of therapeutic range in almost 70% of total measurements and 80% of primary endpoints.

Endotoxin hypersensitivity in chronic heart failure.

BACKGROUND: Raised concentrations of endotoxin (lipopolysaccharides, LPS) have been demonstrated in patients with chronic heart failure (CHF). Tolerance of monocytes to LPS can be induced by negative feedback mechanism through LPS itself, resulting in a downregulation of cytokine response to LPS challenge. As endotoxin desensitization has also been suggested for CHF, we investigated the response to LPS challenge in CHF patients. METHODS: We prospectively studied 100 patients with CHF (62 +/- 13 years) and 21 controls (58 +/- 10 years, LVEF 60 +/- 3%). HLA-DR expression and TNFalpha generation of monocytes after ex vivo stimulation by LPS (stimulation with LPS 50 and 500 pg/ml) were determined. 46 CHF patients were in NYHA class II (LVEF 29 +/- 8%) and 54 in NYHA class III (LVEF 27 +/- 7%). RESULTS: HLA-DR expression in controls (25,837 +/- 7915 ABS/cell) was comparable to CHF NYHA II patients (23,720 +/- 8488 ABS/cell, n.s.), but lower in patients classified NYHA III (20,327 +/- 5073 ABS/cell, p < 0.01). Stimulated TNFalpha production ex vivo was higher in CHF NYHA III (LPS 50: 437 +/- 284; LPS 500: 946 +/- 500 pg/ml, each p < 0.05) and CHF NYHA II (LPS 50: 397 +/- 277; LPS 500: 933 +/- 483 pg/ml, each p < 0.05) compared to controls (LPS 50: 315 +/- 134; LPS 500: 715 +/- 339 pg/ml). CONCLUSIONS: In chronic heart failure TNFalpha generation capacity increases while HLA-DR expression decreases compared to controls. Thus patients with CHF display enhanced susceptibility to inflammatory stimuli.

Imaging of the coronary venous system: retrograde coronary sinus angiography versus venous phase coronary angiograms.

BACKGROUND: Left ventricular lead implantation for cardiac resynchronization therapy (CRT) usually requires a pre- or intraprocedural occlusion contrast venography of the coronary sinus (CS) in order to identify tributaries to the lateral wall. As many patients undergo a preprocedural coronary angiogram, we investigated the diagnostic accuracy of venous phase imaging of the CS in patients prior to CRT implantation. The aim of this study was to assess the quality of venous phase coronary sinus angiography. METHODS: In 24 CRT patients retrograde occlusion venography and venous phase coronary sinus angiography obtained during coronary angiography were compared with respect to image quality, vessel diameters and the ability to identify a coronary sinus side branch suitable for left ventricular lead placement. RESULTS: Suitable target vessels for left ventricular lead implantation were identified in all patients irrespective of the method (retrograde occlusion venography or venous phase coronary sinus angiography). There was a high concordance in vessel diameters between venous phase and retrograde angiography. Visibility was superior in retrograde venography. CONCLUSIONS: In heart failure patients who are scheduled for coronary angiograms venous phase coronary sinus angiography is a time-saving and easy to perform alternative imaging modality. Radiation exposure and the amount of contrast medium needed is reduced as compared to coronary sinus occlusion angiography. The information obtained thereby may be used to plan subsequent CRT implantation without the need for retrograde coronary sinus angiography.

Advantage of sirolimus-eluting stents compared to intracoronary radiation therapy 30 months after treatment of in-stent restenosis.

AIMS: Sirolimus-eluting stents (SES) have been shown during short follow-up periods to be effective for treatment of in-stent restenosis (ISR). This study evaluated the 30-months clinical efficacy after SES for treatment of ISR in comparison with intracoronary radiation therapy (IRT). METHOD AND RESULTS: Seventy-two consecutive ISR lesions in native coronary arteries (<30 mm lesion length, reference diameter <3.5 mm) of 72 patients were treated with SES. SES were used in 16 lesions after failed IRT and in 56 lesions for first time ISR. Seventy-two patients with 72 lesions from a prospective registry of 141 patients treated with IRT (beta-radiation) were matched for diabetes, reference vessel diameter, lesion length, and pattern of ISR to present the control group. At 6-months in-stent late loss was 0.29+/-0.48 vs 0.53+/-0.63 mm for the SES group compared to the IRT group (p=0.025). Target lesion revascularisation (TLR) at 12 month follow-up was performed in 7 lesions (10%) after SES and in 17 lesions (24%) after IRT (P=0.025). TLR rate at 30-months was 13% in the SES group vs 32% in the IRT group (P=0.008). MACE (death, myocardial infarction, target lesion revascularisation) at 30-months was observed in 13 patients (18%) in the SES group and in 25 patients (35%) in the IRT group (P=0.024). Considering only patients treated with SES for first-time ISR, TLR rate was 3.5% at 30-months. In the 16 patients treated with SES after failed IRT TLR rate was 44% at 30-months. CONCLUSIONS: Thirty month clinical follow-up of patients treated with SES for first time ISR is favourable compared to follow-up after IRT. However, use of SES after IRT failure is associated with a high rate of recurrent and potentially late treatment failure.

Comparison of coronary restenosis rates in matched patients with versus without diabetes mellitus.

Diabetes mellitus (DM) is an established risk factor for stent restenosis, in part as a result of the smaller vessel dimensions and longer lesions. This study compared the magnitude of acute lumen gain and late lumen loss after elective coronary stent implantation in patients with and without DM using a matched-pair analysis. A total of 133 patients with DM and 192 coronary lesions were included in this analysis. A group of 192 lesions in 182 patients without DM were matched in a pairwise fashion, stratifying for reference diameter, minimal luminal diameter, and lesion length. The binary restenosis rate at the 5-month follow-up angiography was 25% in the DM group and 14% in the non-DM group (p <0.01). Acute angiographic lumen gain (1.47 +/- 0.41 vs 1.56 +/- 0.38 mm, p = 0.03) and late lumen loss (0.64 +/- 0.42 vs 0.55 +/- 0.36 mm, p = 0.02) were significantly different between the DM and non-DM groups. In conclusion, suboptimal acute procedural results and an exaggerated neointimal proliferation contributed by about 50% to the lower net lumen gain in the DM group. Patients with DM had a significantly higher restenosis rate even when matched for preprocedural angiographic lesion dimensions. Mechanistically, inferior procedural results, as well as exaggerated neointimal proliferation, are, quantitatively, equally important in this process.

Analysis of myocardial deformation based on ultrasonic pixel tracking to determine transmurality in chronic myocardial infarction.

AIMS: Pixel tracking-derived myocardial deformation imaging is a new echocardiographic modality which allows quantitative analysis of segmental myocardial function on the basis of tracking of natural acoustic markers in 2D echocardiography. This study evaluated whether myocardial deformation parameters calculated from 2D echocardiography allow assessment of transmurality of myocardial infarction as defined by contrast-enhanced cardiac magnetic resonance imaging (ceMRI). Methods In 47 patients with ischaemic left ventricular dysfunction, transmurality of myocardial infarction was assessed using pixel-tracking-derived myocardial deformation imaging and ceMRI. For each left ventricular segment in a 16-segment model, peak systolic radial strain, circumferential strain, radial strain rate, and circumferential strain rate were calculated from parasternal 2D echocardiographic views using an automatic frame-by-frame tracking system of natural acoustic echocardiographic markers (EchoPAC, GE Ultrasound). Myocardial deformation parameters were related to the segmental extent of hyperenhancement by ceMRI. The relative amount of contrast-enhanced myocardial tissue per segment was used to define no infarction (0% hyperenhancement), non-transmural infarction (1-50% hyperenhancement), or transmural infarction (51-100% hyperenhancement). Results Analysis of myocardial deformation parameters was possible in 659 segments (88%). Systolic strain and strain rate parameters decreased with increasing relative hyperenhancement defined by ceMRI. Radial strain was 27.7+/-8.0, 20.5+/-9.7, and 11.6+/-8.5% for segments with no infarction (n=422), non-transmural infarction (n=106), and transmural infarction (n=131), respectively (P<0.0001). Radial strain allowed distinction of non-transmural infarction from transmural infarction with a sensitivity of 70.0% and a specificity of 71.2% (cut-off value for radial strain 16.5%). CONCLUSION: Frame-to-frame tracking of acoustic markers in 2D echocardiographic images for the analysis of myocardial deformation allows discrimination between different transmurality states of myocardial infarction.

A double-blind, randomized, placebo-controlled multicenter clinical trial to evaluate the effects of the angiotensin II receptor blocker candesartan cilexetil on intimal hyperplasia after coronary stent implantation.

BACKGROUND: Preclinical data suggest beneficial effects of angiotensin II receptor blockers (ARBs) on neointima formation after vascular injury. Preliminary clinical data, however, revealed conflicting results. The AACHEN trial was a double-blind, randomized, placebo-controlled clinical multicenter trial to evaluate the effects of candesartan cilexetil on intimal hyperplasia after coronary stent implantation. METHODS: A total of 120 patients (61 +/- 9 years, 83% male) were randomized to receive either 32 mg candesartan cilexetil (active) or placebo starting 7 to 14 days before elective coronary stent implantation. A follow-up angiography including intravascular ultrasound assessment of the target lesion was performed 24 +/- 2 weeks after stent implantation. The primary end point was defined as the difference in neointimal area between groups as assessed by intravascular ultrasound. Secondary end points included differences in angiographic parameters (ie, restenosis rate) and incidence of major cardiac events. RESULTS: The mean stent length measured 15.0 +/- 4.9 mm in the active and 14.6 +/- 5.7 mm in the placebo group (P = .81). There was no significant difference in neointimal area between groups (2.1 +/- 1.0 vs 2.1 +/- 1.5 mm2, P = 1.00), nor were there differences in angiographic end point parameters. Major cardiac event rates were not significantly different between treatment groups (8% vs 11%, P = .75). CONCLUSIONS: High-dose candesartan cilexetil therapy in patients with symptomatic coronary artery disease undergoing coronary stent implantation does not reduce clinical event rates, restenosis rates, or neointimal proliferation after elective stent implantation.

A novel drug-eluting stent coated with an integrin-binding cyclic Arg-Gly-Asp peptide inhibits neointimal hyperplasia by recruiting endothelial progenitor cells.

OBJECTIVES: Novel stents loaded with an integrin-binding cyclic Arg-Gly-Asp peptide (cRGD) were analyzed for their potential to limit coronary neointima formation and to accelerate endothelialization by attracting endothelial progenitor cells (EPCs). BACKGROUND: Re-endothelialization is important for healing after arterial injury. METHODS: Effects of cRGD on EPC number, recruitment in flow, and invasion were analyzed in vitro. A durable polymer coating containing 67 microg cRGD per stent was developed for Guidant Tetra stents. Twelve cRGD-loaded polymer, 12 unloaded polymer, and 12 bare metal stents were deployed in porcine coronary arteries. Quantification of cRGD in peri-stent tissue was established by high-performance liquid chromatography (HPLC) and mass spectrometry (MS). Histomorphometry and immunostaining were performed after 4 and 12 weeks. Recruitment of labeled porcine EPCs was assessed 7 days after intracoronary infusion. RESULTS: The cRGD clearly supported the outgrowth, recruitment, and migration of EPCs in vitro. At 4 weeks, there was no difference for mean neointimal area and percent area stenosis in the cRGD-loaded, polymer, or bare metal stent group. At 12 weeks, neointimal area (2.2 +/- 0.3 mm2) and percent area stenosis (33 +/- 5%) were significantly reduced compared with polymer stents (3.8 +/- 0.4 mm2, 54 +/- 6%; p = 0.010) or bare metal stents (3.8 +/- 0.3 mm2, 53 +/- 3%; p < 0.001). The HPLC/MS confirmed cRGD tissue levels of 1 to 3 mug/stent at 4 weeks, whereas cRGD was not detectable at 12 weeks. Staining for CD34 and scanning electron microscopy indicated enhanced endothelial coverage on cRGD-loaded stents at 4 weeks associated with a significant increase in the early recruitment of infused EPCs. CONCLUSIONS: Stent coating with cRGD may be useful for reducing in-stent restenosis by accelerating endothelialization.