21/02/2010  Endothelial dysfunction and drug-eluting stents   An article from the E-Journal of the ESC Council for Cardiology Practice Authors: Wojakowski W. and Tendera M. First-generation DES produce prolonged endothelial dysfunction in stented artery leading to abnormal endothelium-dependent vasomotor function. However, the clinical and prognostic relevance of this intriguing phenomenon has yet to be established. Background Percutaneous coronary intervention (PCI) with stent implantation is effective treatment in patients with acute coronary syndromes as and stable CAD patients with significant myocardial ischemia. The major limitation of stent implantation effectiveness has been, until the introduction of drug-eluting stents (DES), in-stent restenosis (ISR). DES use however, has led to a significant reduction of ISR, however it was found that DES can cause delayed endothelial healing and endothelial dysfunction in the stented vessels (1). This issue has raised safety concerns because delayed endothelialisation of the stent struts can contribute to in-stent thrombosis in certain patients. The impaired vasomotor endothelial function after DES implantation has recently been described, however the clinical significance of this finding needs to be further evaluated. In addition, the degree of endothelial healing and vasomotor dysfunction seems to depend on whether the old or new generation of DES is used (2) (3). 1 - Assessment Methods In assessing vasomotor function, most investigators have used intracoronary infusion of acetylcholine (Ach) followed by bolus injection of nitrate and angiographic assessment of the artery segments adjacent to the implanted stent. Standard protocol involves withdrawal of antiangial medication for 1-3 days, and infusion of incremental doses of Ach through the coronary catheter or selective infusion catheter (20 - 100 µg) with 2.5 to 5-min intervals between doses. After reaching the maximum dose, intracoronary bolus of nitroglycerin is administered. Acetylcholine infusion leads to dilatation of normal coronary arteries with preserved endothelial integrity, mainly by nitric oxide release (NO). In the setting of endothelial injury Ach induces paradoxical vasoconstriction (4). Some protocols mandate the infusion of increasing doses of sodium nitropruside (10 µg/min) followed by a bolus of nitroglycerin (5). Angiographic images are recorded after each dose of Ach, and finally < 2 min after the bolus of nitroglycerin. Eventually the diameter of the target segment in diastole is measured in two orthogonal views and averaged. Usually segments located within 5 mm proximally and distally of the stent edges are assessed by this method (6) (4). 2 - Mechanisms There are several mechanisms which may contribute to endothelial dysfunction after implantation of DES (2): Reduced bioavailability of vasorelaxants (nitric oxide, NO) • Relative increase of vasoconstictive factor • Inflammatory response • Impaired maturation of endothelial progenitor cells (EPCs) to endothelial cells (EC) • Impaired mobilisation of EPCs and endothelialisation of the stent struts • Direct toxicity of the drug eluted from stent • Polymer toxicity • Hypersensitivity • Increased production of free radicals Proper reendothelialisation of the stented segment is a prerequisite for the formation of functionally mature endothelium which serves as a source of vasoactive, antiinflammatory and antithrombotic substances. Several studies demonstrated that circulating bone marrow-derived EPCs contribute to the repair of the endothelium after injury, most likely by repopulating the site of stent implantation. Stent expansion causes significant injury to the artery wall. The endothelial lining is disrupted and the local inflammatory response is activated. The vessel wall injury also leads to the recruitment of circulating monocytes, EPCs and platelet deposition on the site of endothelial disruption. The ultimate goal of this reaction is to restitute the endothelial integrity over the area of dilated segment (reendothelialisation). The time between the initial endothelial injury caused by stent struts and full endothelialisation is significantly shorter after implantation of bare metal stents (approximately 30 days) than DES (> 6 months) (7). The reparatory mechanism is in part dependent on the recruitment of circulating EPCs, with their subsequent adherence to the struts surface as well as areas of arterial wall located between the struts (8). This mechanism is altered after implantation of drug-eluting stents (DES). For example, mobilisation of EPC is reduced after implantation of paclitaxel (PES) and sirolimus-eluting (SES) stents (Wojakowski et al. AHA 2009, Circulation. 2009;120:S967-S968.). Data from the histopathology studies and in vivo angioscopy show that part of the stent struts are not covered by endothelial cells for as long as 6 months after PCI. The effect is caused by direct inhibitory effects of drug released from the stent. Absence of functional EC on a substantial part of the stent struts could be at least in part responsible for reduction of vasoactive substances secreted normally by the endothelium, such as NO. This effect can be augmented following implantation of long stents or several stents in the same vessel (2). The vasomotor dysfunction can also be attributed to the direct effects of the drug released from the stent. Sirolimus was shown to reduce the production of angiogenic vascular endothelial growth factor (VEGF) and responsiveness of the endothelial cells to VEGF (5). Obata et al. showed that in patients with acute MI sirolimus 2 weeks after implantation SES can be detected in arterial blood and coronary sinus (5). Importantly, several studies showed that segments proximal to the stent show abnormal endothelial-dependent vasoreactivity (9). The presence of endothelial dysfunction in non-stented segments of the vessel can also be explained by the propagation of drug through vasa vasorum. Therefore the endothelial healing and functional recovery can also be suppressed in segments located proximally and distally to the stent (2). Long term influence of sirolimus and paclitaxel cannot be explained solely based on their release kinetics, because most of sirolimus (80%) is eluted from the stent surface within 28 days after implantation. Additionally, PES platforms show biphasic kinetics of drug elution, with rapid release in the first 48 h after implantation and subsequent slow release over 14 days (10). 3 - Data from animal models Several experimental studies in animal models shed some light in patomechanism of the endothelial dysfunction after implantation of DES. Studies carried out in pigs have consistently shown that PES and SES cause impaired endothelium-dependent vasodilation in proximal and distal segments of the stented vessel one month after implantation. In all studies the endothelium-independent vasoreactivity was preserved (11). Shiroto et al. showed that paclitaxel activated the expression and activity of Rho-kinase, which is involved in the coronary vasospasm in vascular smooth muscle cells. The use of a Rho-kinase antagonist abolished the endothelium-dependent vasoconstriction after implantation of SES and PES in porcine coronary arteries (12). Pendyala et al. showed that function of not only the conduit, but also the resistance vessels is negatively affected by implantation of PES. This effect coexists with local inflammatory reaction, increased production of reactive oxygen species and increased sensitivity to vasoconstrictors such as endothelin-1 (11). Murine and rat studies have shown decreased activity of eNOS and increased production of free radicals after implantation of SES (13). A hypersensitivity reaction to the polymer probably could contribute to the endothelial dysfunction (2). 4 - Data from clinical studies Impaired endothelium-dependent vasomotor function after stent implantation in patients was described 10 years ago for the first time, however the finding that this phenomenon is more pronounced in patients receiving DES was published by Hofma et al. in 2005. They showed that 6 months after implantation of SES Ach infusion led to paradoxical vasoconstriction distally to the stented segment. Endothelium independent vasomotor function was not compromised. Implantation of BMS was not associated with such impairment of vasomotor function (4). Kim et al. measured the endothelium-dependent vasoreactivity in 75 patients after DES implantation (SES and PES). Six months after PCI both types of DES produced abnormal vasoconstriction in segments distal to the stent after Ach infusion (9). Vessel occlusion as well as reperfusion injury in acute myocardial infarction (MI) create the milieu which induce profound endothelial dysfunction and abnormal response to vasoactive agents. DES have become widely used in patients with acute MI. Obata et al recently showed that implantation of SES leads to worsening of endothelial vasomotor dysfunction, as well as a lesser increase in coronary blood flow after infusion of Ach into previously recanalised infarct-related artery. The endothelial dysfunction was shown 2 weeks after primary PCI (5). 5 - Differences between stents Recent data from clinical trials using several types of DES suggest that significant endothelial dysfunction appears limited to first generation DES. Comparison of studies in which endothelium-dependent vasorelaxation was assessed using intracoronary infusion of Ach showed that implantation of PES and SES led to significant impairment of this reaction. On the other hand newer DES [zotarolimus eluting (ZES), everolimus-eluting (EES) and biolomus-eluting (BES) stents] do not produce the endothelial dysfunction. Such a difference can be attributed to use of biocompatible polymers or polymer free platforms and less toxic lipophilic drugs. Also the kinetics of drug elution and abluminal strut coverage leading to reduced systemic levels of drug might play an important role in the preservation of endothelial function. Several clinical studies have shown that endothelial dysfunction was absent after 6-9 months following the implantation of ZES (2) (14-15). In vitro studies have also shown a higher expression of eNOS in endothelial cells (2) (15). Lastly, the endothelialisation of the stent struts after implantation of EES is more complete in comparison to ZES, PES and SES (16). 6 - Clinical relevance Abnormal vasomotor response is a sign of endothelial dysfunction and a prognostic factor for adverse cardiac events (17). The consequences of endothelial dysfunction might go beyond the induction of coronary vasospasm because the endothelium secretes anti-thrombotic substances, such as prostacyclin or tissue plasminogen activators. Impaired endothelial secretory function might produce a thrombogenic milieu. So far no data has clearly shown the association between the DES-induced endothelial dysfunction and clinical outcome including the risk of in-stent thrombosis. This issue clearly needs verification in prospective clinical trials. Wojciech Wojakowski and Michał Tendera 3rd Division of Cardiology, Medical University of Silesia, Katowice, Poland References 1. Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents. N Engl J Med 2006;354:483-95. 2. Pendyala LK, Yin X, Li J, Chen JP, Chronos NA, Hou D. The first-generation drug-eluting stents and coronary endothelial dysfunction. JACC Cardiovasc Interv 2009;2:1169-1177. 3. Muhlestein JB. Endothelial dysfunction associated with drug-eluting stents what, where, when, and how? J Am Coll Cardiol 2008;51:2139-40. 4. Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J 2006;27:166-70. 5. Obata JE, Kitta Y, Takano H, et al. Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute myocardial infarction. J Am Coll Cardiol 2007;50:1305-9. 6. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51. 7. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007;115:1051-8. 8. Sata M, Fukuda D, Tanaka K, Kaneda Y, Yashiro H, Shirakawa I. The role of circulating precursors in vascular repair and lesion formation. J Cell Mol Med 2005;9:557-68. 9. Kim JW, Suh SY, Choi CU, et al. Six-month comparison of coronary endothelial dysfunction associated with sirolimus-eluting stent versus Paclitaxel-eluting stent. JACC Cardiovasc Interv 2008;1:65-71. 10. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653-62. 11. Pendyala LK, Li J, Shinke T, et al. Endothelium-dependent vasomotor dysfunction in pig coronary arteries with Paclitaxel-eluting stents is associated with inflammation and oxidative stress. JACC Cardiovasc Interv 2009;2:253-62. 12. Shiroto T, Yasuda S, Tsuburaya R, et al. Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo. J Am Coll Cardiol 2009;54:2321-9. 13. Jabs A, Gobel S, Wenzel P, et al. Sirolimus-induced vascular dysfunction. Increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J Am Coll Cardiol 2008;51:2130-8. 14. Hamilos MI, Ostojic M, Beleslin B, et al. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J Am Coll Cardiol 2008;51:2123-9. 15. Kim JW, Seo HS, Park JH, et al. A prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent: differential recovery of coronary endothelial dysfunction. J Am Coll Cardiol 2009;53:1653-9. 16. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008;52:333-42. 17. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Jr., Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948-54.

 20/02/2010  How long to continue oral anticoaugulation after ablation for atrial fibrillation?   The Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society atrial fibrillation ablation consensus statement recommends: 1. Warfarin is recommended for all patients for at least 2 months after an AF ablation procedure. 2. Decisions regarding the use of warfarin more than 2 months after ablation should be based on the patient’s risk factors for stroke and not on the presence or type of AF. 3. Discontinuation of warfarin therapy post-ablation is generally not recommended in patients who have a CHADS2 score >2. (Jacc Vol. 55, No. 8, 2010)

 30/01/2010   Catheter ablation superior to drugs in refractory atrial fibrillation   27 January 2010 MedWire News: Radiofrequency catheter ablation (RFCA) achieves significantly better outcomes than antiarrhythmic drug therapy (ADT) in patients with atrial fibrillation (AF) who have not responded to at least one prior antiarrhythmic drug, study results demonstrate. Notably RFCA showed a substantial reduction in the risk for recurrent atrial arrhythmias and a clinically meaningful improvement in symptoms and quality of life compared with ADT, report David Wilber (Loyola University Medical Center, Maywood, Illinois, USA) and colleagues. Although antiarrhythmic drugs are generally used as first-line therapy for AF, the rate of symptom recurrence within 6 to 12 months approaches 50% with most drugs. Furthermore, these drugs are also associated with cumulative adverse effects over time. Several recent studies have established RFCA as an alternative therapy, but these investigations were mostly small study populations conducted in a single or limited number of centers. The researchers initiated a prospective, multicenter, randomized study designed to compare RFCA with ADT in patients with symptomatic AF who had not improved with at least one drug (dofetilide, flecainide, propafenone, sotalol, or quinidine). They included 167 patients from 19 hospitals who experienced at least three AF episodes within 6 months before randomization. Patients were then randomized to ADT (n=61), receiving a not previously administered drug based on the discretion of the investigator, or RFCA (n=106). The primary outcome was time to protocol-defined treatment failure, which included documented symptomatic paroxysmal AF during the evaluation period. The researchers found that at the end of the 9-month effectiveness evaluation period, 66% of patients in the RFCA group remained free from treatment failure compared with 16% of patients treated with ADT. Similarly, 70% of patients treated by RFCA remained free of symptomatic recurrent atrial arrhythmia versus 19% of patients treated with ADT. Major 30-day treatment-related adverse events occurred in five (8.8%) of 57 patients treated with ADT and five (4.9%) of 103 patients treated with RFCA. Mean quality of life scores improved significantly in patients treated by RFCA compared with ADT at 3 months and improvement was maintained during the course of the study. “These data strongly support the use of catheter ablation in patients with paroxysmal AF who do not respond to initial ADT,” Wilber and colleagues conclude in the Journal of the American Medical Association. MedWire JAMA 2010; 303: 333–340

 25/01/2010   STROKE   Stroke is the third-leading cause of death among adults in the United States and a major contributor to long-term functional impairment and disability. Despite recent advances in diagnosis and treatment, approximately one fifth of stroke survivors require institutional care 3 months after the index event, and 15% to 30% are permanently disabled. Aggressive measures of primary prevention for at-risk patients are critical, because the majority of strokes are first events. Nevertheless, of the estimated 780 000 strokes that occur in the United States each year, 180 000 are recurrent events. Secondary prevention is equally important for survivors of stroke or transient ischemic attack. The 90-day risk of stroke after transient ischemic attack has been estimated at 3% to 17% and is highest within the first 30 days. The incidence of stroke appears to be increasing, and the associated economic costs are staggering. The 2008 estimated direct and indirect cost of stroke is $65.5 billion, with a mean per capita lifetime cost of $140 048. The majority of strokes are ischemic; of these, approximately 25% to 40% have no identifiable cause despite a thorough evaluation and are designated as cryptogenic stroke (CS). Other causes of ischemic stroke include large-artery atherosclerotic infarction, cardiac embolism, small-vessel disease, or a defined abnormality such as arterial dissection, hypercoagulable state, or sickle cell disease. (Circulation. 2009;119:2743-2747.)

 22/01/2010   Prehospital ECG Speeds STEMI Care   Transmitting ECG results from the field to the emergency department dramatically improved door-to-balloon time for patients with ST-elevation myocardial infarction (STEMI), researchers found. The strategy cut a half hour from the process, from 90.5 minutes to 60.2 minutes (P<0.0001), well within the recommended 90-minute window, according to Shukri David, MD, of Providence Hospital and Medical Center in Southfield, Mich., and colleagues. Nearly all patients who had a prehospital ECG (97.4%) had a door-to-balloon time of less than 90 minutes, compared with only 61.5% of those who had an ECG upon arrival at the hospital (P<0.001), the researchers reported in the January issue of Catheterization and Cardiovascular Interventions. "It's very important that patients who are suffering a myocardial infarction get to a cath lab so that we can establish blood flow to the injured myocardium," David said in an interview. "That will save lives." Guidelines from both the American College of Cardiology and the American Heart Association have called for patients with STEMI to have blocked vessels opened within 90 minutes of arriving at the hospital, citing ECG conducted by emergency medical services personnel as one way to meet this goal. Previous studies, including a pilot study by David's group, have supported this approach. To validate the use of prehospital ECG, David and his colleagues conducted a prospective, observational study at three hospitals in Michigan over a 55-month period. When possible, EMS personnel obtained a 12-lead ECG during the initial assessment of patients with chest pain. The findings were transmitted to the emergency department via cellular link. Once STEMI was confirmed, the physician in the emergency department activated the cardiac catheterization team as the patient was en route to the hospital. This allowed the patient to head directly to the cath lab. Patients with STEMI who did not have prehospital ECGs but were treated at the same hospitals served as the controls. Although both groups of patients were generally similar, blacks were much less likely to get a prehospital ECG than whites -- 15.7% versus 31% (P<0.001) -- primarily because ambulances in Detroit only received ECG capabilities at the end of the study, according to the researchers. Prehospital ECG reduced door-to-balloon time, but did not have a significant effect on either length of hospital stay or inhospital mortality. David and his colleagues said they likely didn't observe a mortality benefit because of the relatively low number of total deaths (2% in controls versus 0% in the intervention group). In the control group, the time of presentation with STEMI affected the door-to-balloon time. Patients treated during working hours had a shorter time to reperfusion than those treated during off-hours (75 versus 98 minutes, P=0.04). However, with the use of prehospital ECG, there was a significant reduction in door-to-balloon time regardless of the time of presentation. "The use of the prehospital ECG is a way of overcoming the obstacle of delay in cardiac catheterization laboratory activation during off-hours," the researchers wrote. "We were able to take the disadvantage out of having a patient show up on off-hours, or weekends, or holidays," David said. The authors did not report any conflicts of interest. Primary source: Catheterization and Cardiovascular Interventions Source reference: Rao A, et al "Impact of the prehospital ECG on door-to-balloon time in ST-elevation myocardial infarction" Catheter Cardiovasc Interv 2010; 75: 174-78.

 17/01/2010   30 days mortality in Acute Myocardial Infarction in LAZIO   Mortalità a 30 giorni dopo ricovero per un episodio di Infarto Miocardico ACuto (IMA) negli anni 2004-2006 nella regione LAZIO La coorte selezionata sulla base dei criteri descritti nel protocollo è costituita da 16263 episodi di IMA (uomini: 10623; donne: 5640), con una mortalità media pari a 10.4% (uomini: 8.7%; donne: 13.7%). Non sono riportati i risultati per le strutture con un volume annuo di IMA < 150. Analisi della mortalità per struttura Riferimento: L’Azienda Ospedaliera S. Filippo Neri, l’Ospedale L. Parodi Delfino e l’Ospedale S. Giacomo sono le strutture scelte come riferimento e presentano un tasso di mortalità medio pari a 8.8%. Il riferimento è stato selezionato sulla base dei risultati ottenuti per la popolazione totale ed è stato utilizzato anche nelle analisi stratificate per genere. Totale: La variazione dei tassi di mortalità aggiustati è compresa tra un minimo di 8.9% (p=0.964) per l’Azienda Ospedaliera S. Andrea ed un massimo di 18.6% (p=0.000) per il Policlinico Umberto I. Uomini: L’Azienda Ospedaliera S. Andrea, gli Ospedali Riuniti Albano-Genzano e l’Ospedale G.B Grassi hanno un tasso di mortalità aggiustato inferiore a quello del riferimento con una p statisticamente non significativa. Per le altre strutture la variazione dei tassi è compresa tra un minimo di 9.0% (p=0.931) per il Presidio Ospedaliero Sud di Formia ed un massimo di 20.1% (p=0.011) per l’Azienda Ospedaliera Universitaria Policlinico Tor Vergata. Donne: La variazione dei tassi di mortalità aggiustati è compresa tra un minimo di 8.9% (p=0.968) per l’Ospedale di Belcolle ed un massimo di 19.8% (p=0.001) per l’Ospedale S. Pietro Fatebenefratelli. (Fonte ASP, www. asplazio.it/)

 15/01/2010   Blood Pressure   Normal – 120/80 mm Hg. Pre-hypertensive – 120-139/80-89 mm Hg. Hypertensive – 140/90 mm Hg.