New Research and New Guidelines in Cardiovascular Therapy: A report from the European Society of Cardiology Congress 2007

INTRODUCTION

The landmark wheel in Prater was spinning and music was blaring throughout the park as cardiologist and cardiology-related health professionals walked toward Wiener Messe, the site for this year’s congress of the European Society of Cardiology (ESC). Among the exciting new discussions held there, this year’s congress included the presentation of the new European guidelines for the treatment of non-ST segment-elevated myocardial infarction, valvular heart disease, cardiac arrhythmia, coronary artery disease, hypertension and cardiovascular prevention, which are now available through the European Society of Cardiology as full publication or pocket guidelines. Compliance with the new guidelines has translated into benefits on morbidity and mortality [Gierlotka, M. et al., Abst P4826]. However, many other discussions were held during the meeting, including a wealth of new clinical trials that are briefly reviewed in the following sections of this report. Further information is also available on selected clinical trials and experimental findings directly related with cardiovascular therapy in other areas of this website and the organizing society’s website, the official highlights CD-ROM of the meeting, and webcast files from the most important sessions and discussions. Specific, itemized information on clinical trials presented at this and other meetings is also available in the Clinical Studies section of Integrity® at integrity.prous.com.

HEART FAILURE

β-Blockers

β-Blockers are now established as a major asset in the treatment of heart failure (HF), with new studies confirming that they also benefit outcomes in patients starting therapy during the acute phase of heart failure [Orso, F. et al., Abst 295], and that they prolong survival in patients with chronic obstructive pulmonary disease (COPD) undergoing abdominal aortic surgery [Van Gestel, Y.R.B.M. et al., Abst P1371]. Improvements in survival brought about by β-Blockers in heart failure patients with concomitant depression increased when selective serotonin reuptake inhibitor antidepressants were added to the treatment [Tousoulis, D. et al., Abst 296], while these antidepressants exhibited antiinflammatory activity in vitro in endothelial cells [Lekakis, J. et al., Abst P4192].

Among these agents, carvedilol and metoprolol were well tolerated in patients with concomitant heart failure and COPD [Dan, G.A. et al., Abst 3196], but carvedilol was more effective than metoprolol in preventing atrial fibrillation after on-pump coronary artery surgery [Haghjoo, M. et al., Abst P3305] (Fig. 1). While new data from clinical studies have confirmed the benefits of carvedilol on quality of life in subjects with chronic HF [Bennis, A. et al., Abst P453] and hemodynamics in patients with congestive heart failure [Nessler, J. et al., Abst P445], with better mortality outcomes when treatment is initiated by cardiologists compared to general physicians [Bernier, M. et al., Abst P446], mechanistic data in patients with coronary artery disease showed decreases in tumor necrosis factor-α, interleukin-6 and endothelin-1, with overall improvements in endothelial function [Lutay, M.I. et al., Abst P4184]. Greater improvements in left ventricular function and hemodynamic parameters were noted on carvedilol among 183 patients with the Glu27 β₂-adrenergic receptor gene variant [Metra, M. et al., Abst 293]. Overall, carvedilol induced profound electrophysiological effects supposed to be of benefit to patients with dilated cardiomyopathy [Kanoupakis, E.M. et al., Abst P2539]. Experimental studies with the agent revealed sensitization of β₁ and β₂ receptors through inhibition of the phosphatidylinositol-3 kinase pathway [Boehmer, P. et al., Abst P479].

Fig. 1. Postoperative atrial fibrillation rates after coronary artery bypass graft surgery in patients receiving carvedilol or metoprolol [Haghjoo, M. et al., Abst P3305].

Metoprolol is another well studied β-blocker for the treatment of heart failure. Although no new clinical data was presented during the meeting, the results of experimental studies suggested improvements in cardiac reverse remodeling [Bueno Junior, C.R. et al., Abst P2527], while pretreatment before coronary reperfusion proved effective in reducing infarct size [Ibanez, B. et al., Abst P2685]. Controlled-release metoprolol brought about only meaningless changes in pulmonary artery pressure after slow uptitration [Shah, H.A. et al., Abst 3198].

Bisoprolol is a further extensively studied β-blocker for heart failure. New studies have revealed improvements in hospitalization rates, diastolic function and ischemia compared to verapamil in 185 patients with diastolic HF [Adamyan, K.G. et al., Abst P454] (Fig. 2). Furthermore, bisoprolol improved ventilatory responses and oxygen consumption during exercise compared to placebo in a crossover study in 14 healthy volunteers [Beloka, S. et al., Abst 3231].

Fig. 2. Hospitalization rates in patients with diastolic heart failure treated with bisoprolol or verapamil [Adamyan, K.G. et al., Abst P454].

Part of the benefit of nebivolol in the treatment of elderly patients with heart failure was related to a reduction in heart rate, with data from 22,618 patients suggesting a 10% drop in mortality for each reduction of 5 beats [Kjekshus, J.K., Abst 292]. However, nebivolol offered other benefits, including improvements in endothelial function that were not demonstrated with metoprolol in a comparison in experimental animals [Sorrentino, S.A. et al., Abst P451]. Furthermore, nebivolol improved sleep quality, an effect that could not be demonstrated with metoprolol in a comparative study of 43 mildly hypertensive patients [Yilmaz, M.B. et al., Abst P1400].

A transdermal tape for delivering tulobuterol has been developed and proved effective in improving inotropism and offering cardioprotection in experimental models of chronic heart failure [Komamura, K. et al., Abst P448].

Other β-Blockers that have been tested related to putative benefits in heart failure include clenbuterol, which depressed contractility of normal ventricular myocytes [Siedlecka, U. et al., Abst P478], and the α/β blocker isoeugenodilol, which inhibited muscle cell proliferation and neointimal thickening after experimental balloon injury [Wu, J.R. et al., Abst P1394].

Digitalis

Data to suggest no beneficial effects of digitalis on morbidity and mortality in patients with systolic heart failure was presented during the ESC meeting in Vienna, based on analysis of the A-HeFT study [Ghali, J.K. et al., Abst P443]. A Digitalis Investigation Group trial in 6,800 patients with chronic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme (ACE) inhibitors and diuretics suggested reductions in early all-cause death with add-on digoxin compared to placebo [Ahmed, A. et al., Abst 463] (Fig. 3).

Fig. 3. One-year death rates in patients receiving digoxin or placebo [Ahmed, A. et al., Abst P463].

Aldosterone blockers

Addition of spironolactone and canreonate to standard therapy further attenuated left ventricular remodeling in 170 patients with chronic heart failure, offering improvements in systolic and diastolic function [Nodari, S. et al., Abst P450]. Similarly, addition of spironolactone to candesartan therapy improved myocardial strain and induced regression of fibrosis and adverse remodeling in 48 patients with chronic heart failure and low left ventricular ejection fraction [Wang, M. et al., Abst P483].

Eplerenone is a further mineralocorticosteroid receptor blocker, the efficacy of which was demonstrated in the EPHESUS trial. New analyses have confirmed the superiority of early versus delayed treatment initiation in preventing adverse cardiovascular outcomes in heart failure, including sudden cardiac death [Zannad, F. et al., Abst P484]. Experimental studies revealed a potent antifibrotic effect of the compound, which led to improvements in left ventricular function during acute- and chronic-stage myocarditis [Jaeger, S. et al., Abst P3569]. In a mechanistic experimental study, eplerenone showed higher potency than progesterone and spironolactone in competing for aldosterone against mineralocorticosteroid receptor, without agonist activity, while it was somewhat less potent against S810L mutant receptor and exhibited potent agonistic activity. However, the nonsteroidal antagonist BR-4628 showed higher affinity for the receptor [Kolkhof, P. et al., Abst 4420].

Calcium sensitizers

Levosimendan therapy brought about improvements in endothelial function [Karavidas, A. et al., Abst P4179], quality of life and emotional stress in advanced heart failure patients [Papadopoulos, K. et al., Abst P1393], prolonged survival in acute failure after ST segment-elevated myocardial infarction [Brasolin, B. et al., Abst 2443] and reduced beat-to-beat alterations in patients with systolic heart failure compared to dobutamine [Yilmaz, M.B. et al., Abst P441]. The agent was superior to dobutamine in improving left atrial active and passive function in subjects with ischemic heart failure [Duygu, H. et al., Abst P474], while data from the SURVIVE study demonstrated reduced mortality with levosimendan compared to dobutamine, though levosimendan tended to increase the rate of worsening renal function [Cohen-Solal, A. et al., Abst P464] (Fig. 4); general superiority of levosimendan over dobutamine was documented in a number of additional studies, including trials in patients with moderate to severe right ventricular dysfunction [Yilmaz, M.B. et al., Abst P476; Bergh, C.H. et al., Abst 2444]. Furthermore, levosimendan improved coronary flow in a study including 42 patients [Ikonomidis, I. et al., Abst P449]. Use of levosimendan in patients with cardiogenic shock also resulted in rapid and consistent stabilization [Greif, M. et al., Abst P447] and improvements in organ perfusion [Wimmer, R. et al., Abst P4708], although the results in 110 patients suggested no improvement or worsening in mortality in case of cardiogenic shock [Omerovic, E. et al., Abst P4625]. However, mechanistic data from human subjects suggested increased myocardial excitability resulting in complex ventricular arrhythmogenesis [Mavrakis, H.E. et al., Abst P456].

Fig. 4. Death rates at 180 days in patients on levosimendan or dobutamine with or without worsening renal function (WRF) [Cohen-Solal, A. et al., Abst P464].

Vasodilators

According to the A-HeFT trial results, concomitant use of isosorbide dinitrate and hydralazine improved outcomes in adult and elderly subjects with heart failure [Taylor, A. et al., Abst P475]. However, compared to nitrates administration of carperitide was associated with a low readmission rate in 350 patients with acute decompensated heart failure [Mizuno, M. et al., Abst P1907].

ACE inhibitors and angiotensin receptor blockers

Further analyses of the A-HeFT trial suggested limited benefits of angiotensin-converting enzyme (ACE) inhibitors compared to placebo in patients with heart failure and β-Blockers [Ghali, J.K. et al., Abst P473], and the cardioprotective effects of perindopril in 12,056 patients with stable coronary artery disease were independent of renal function [Brugts, J.J. et al., Abst P1370].

While high-dose losartan improved blockade of myocardial sympathetic activity compared to regular clinical doses in patients with moderate heart failure [Ruzicka, M. et al., Abst P1918], new data from the CHANCE study has established that candesartan significantly regressed left ventricular hypertrophy, improving function and exercise tolerance, in patients with hypertrophic, nonobstructive cardiomyopathy [Penicka, M. et al., Abst P461]. Similarly, data from 43 hypertensive patients suggested attenuated myocardial fibrosis and improved diastolic function with valsartan [Mizuta, Y. et al., Abst P470], the benefit of which was independent from changes in systolic blood pressure in the Val-HeFT trial [Anand, I.S. et al., Abst 3201], while combinations of irbesartan or ramipril with a diuretic improved systolic and diastolic left ventricular function more than diuretics alone in 150 patients with heart failure and normal ejection fraction [Sanderson, J.E. et al., Abst P472].

Anticoagulants

Antithrombotic strategies are in use in patients undergoing percutaneous coronary interventions [Yu, C.W. et al., Abst P3996]. The ARTEMIS trial suggested reduced risk of symptomatic pulmonary embolism and death during hospitalization for congestive heart failure in patients receiving fondaparinux [Eikelboom, J. et al., Abst P477] (Fig. 5). A novel antithrombotic, FT-011 reduced postmyocardial infarction cardiac fibrosis and improved cardiac function in experimental animal models [Elsik, M. et al., Abst 462], while the experimental compound AZD-0837 showed extensive absorption and high but smooth plasma levels with a low potential for cytochrome-based drug-drug interactions when administered in an extended-release formulation to healthy volunteers [Johansson, S. et al., Abst P4564].

Fig. 5. Symptomatic pulmonary embolism and death rates in patients with congestive heart failure receiving fondaparinux or placebo [Eikelboom, J. et al., Abst P477].

Other drugs

Beneficial effects of ivabradine on heart rate and angina frequency across various subpopulations of patients with stable angina [Tendera, M. Et al., Abst 4426] were accompanied by benefits on electrophysiological, regional and global systolic function and structural remodeling in experimental models of postmyocardial infarction heart failure [Ceconi, C. et al., Abst P444; Couvreur, N. et al., Abst P4702] and protection against ventricular fibrillation during myocardial ischemia [Vaillant, F. et al., Abst P2687], which were related to improvements in systolic and diastolic cardiac function in animals with established chronic HF [Mellin, V. et al., Abst 2441]. While further experimental results demonstrated attenuation of the renin-angiotensin system after treatment with ivabradine during postinfarction in middle-aged animals, thus reducing periarteriolar fibrosis and improving myocardial perfusion [Dedkov, E.I. et al., Abst P4023], mechanistic data demonstrated the safety of heart rate reduction with ivabradine, which was related to the multiple channels that contribute to cardiac automaticity [Marger, L. et al., Abst P1412]. The compound was associated with a low incidence of severe bradycardia in 1,328 patients, an effect that was limited by baseline heart rate [Savelieva, I. et al., Abst P1390]. Compared to bisoprolol, ivabradine was better tolerated and devoid of negative inotropic effects, preventing the functional mitral regurgitation that could develop through coaptation force reduction in 107 patients with postmyocardial infarction heart failure [Adamyan, K.G: et al., Abst P442]. In the experimental arena, studies were presented that demonstrated protection of endothelial function in chronic heart failure [Vercauteren, M. et al., Abst P468].

Benefits were also reported with the interleukin-1 receptor blocker anakinra, which improved endothelial function, left ventricular function and coronary flow reserve compared to placebo in 23 patients with rheumatoid arthritis [Ikonomidis, I. et al., Abst 1051; Ikonomidis, I. et al., Abst 4332] and inhibited apoptosis in an experimental model of postinfarction remodeling [Abbate, A. et al., Abst P2675]; pentoxifylline, which in 102 patients with chronic heart failure reduced tumor necrosis factor-α levels and improved left ventricular ejection fraction compared to placebo, while increasing hemoglobin levels in anemic subjects but not individuals with chronic inflammation and elevated C-reactive protein levels [Lainscak, M. et al., Abst P485]; bromocriptine, which improved peripartum cardiomyopathy in 11 women [Forster, O. et al., Abst 2436]; and testosterone, which improved exercise capacity, muscle strength and glucose metabolism in 70 men with stable chronic heart failure [Caminiti, G. et al., Abst 2437]. A pilot study suggested feasibility for recombinant human relaxin in the treatment of decompensated chronic congestive heart failure with worsening renal function [Dschietzig, T. et al., Abst 2438]. On the other hand, cibenzoline proved more effective in reducing the left ventricular pressure gradient in patients with hypertrophic obstructive cardiomyopathy carrying the D allele in the angiotensin-converting enzyme gene [Nagai, T. et al., Abst P2841]. In the specific case of patients with chronic heart failure and low triiodothyronine syndrome, liothyronine replacement therapy significantly improved the neuroendocrine profile, in addition to biventricular function [Pingitore, A. et al., Abst P3933], and in fact an effect was reported for thyroid hormone in attenuating cardiac remodeling and improving hemodynamics after experimental myocardial infarction [Mourouzis, I. et al., Abst P3934].

Treatment of anemia with darbepoetin alfa or epoetin alfa induced regression of left ventricular hypertrophy in patients with chronic kidney disease [Akaishi, M. et al., Abst P1369]. Darbepoetin alfa was also associated with improved quality of life in chronic heart failure patients with anemia [Kourea, K. et al., Abst 1737], benefits that were similarly obtained with intravenous iron saccharose therapy [Toblli, J. et al., Abst 1738]. A more complex study suggested beneficial effects of epoetin and granulocyte colony-stimulating factor on left ventricular mechanics during ischemia-reperfusion injury [Yeghiazarians, Y. et al., Abst P1195], while mechanistic data supported a role for erythropoietin in improving endothelial progenitor cell-mediated neovascularization [Westenbrink, B.D. et al., Abst 2440]. Further assays revealed that darbepoetin stimulated endothelial cell proliferation but not angiogenesis after myocardial ischemia [Mansson-Broberg, A. et al., Abst 3011].

Statins were also reported beneficial in subjects with HF, with reduced mortality except in subjects with concomitant anemia [Roik, M. et al., Abst P4626], and a review of 573 cases of hospitalization for acute heart failure from the FINN-AKVA study documented lower one-year death rates among those receiving statin therapy [Lassus, J.P.E. et al., Abst P2597]; these drugs have been noted to improve outcomes in patients who develop moderate to severe left ventricular dysfunction after myocardial infarction [Maini, S. et al., Abst 3192]. While simvastatin improved cardiac sympathetic nerve activity compared to placebo in 54 patients with heart failure [Tsutamoto, T. et al., Abst 3193], atorvastatin prevented sudden cardiac death in 110 patients with class III chronic heart failure in a randomized study [Vrtovec, B. et al., Abst 3195]. Use of rosuvastatin in 42 patients with chronic heart failure was associated with benefits on oxidative stress, endothelial regenerative capacity and endothelial function [Erbs, S. et al., Abst 3191].

In the experimental setting, the poly(ADP-ribose) polymerase inhibitor L-2286 decreased postmyocardial infarction remodeling and prevented heart failure more effectively than enalapril [Bartha, E. et al., Abst P471] and the calcium channel blocker K-201 improved diastolic dysfunction and preserved ejection fraction after norepinephrine exposure [Matsuda, R. et al., Abst 1053], effects that were related to improvements in calcium handling during diastole [Otani, N. et al., Abst P1228]. Though available for other indications, sapropterin was noted to reverse established HF via normalization of calcium cycling in cardiomyocytes [Tocchetti, C.G. et al., Abst P1833], while in a similar manner cilostazol conferred cardioprotection by opening mitochondrial calcium-activated potassium channels [Nishida, H. et al., Abst P2153] and ilodecakin via regulation of the caspase-3 and Akt pathways [Chu, S.Y. et al., Abst P2157].

Regarding untoward drug effects, a survey of 107,092 patients surviving a heart failure hospitalization revealed significant increases in the risk of mortality and cardiovascular risk in subjects receiving nonselective nonsteroidal antiinflammatory drugs or selective cyclooxygenase-2 inhibitors [Gislason, G.H. et al., Abst P459].

Stem cell therapy

New advances have been attained in the research of stem cell-based therapies for heart failure, but one report during the Vienna meeting suggested no impact of bone marrow cell treatment on left ventricular ejection fraction or infarct size in 100 patients [Lunde, K. et al., Abst P1211].

Nonpharmacologic therapies

According to a number of clinical and experimental studies presented during the meeting in Vienna, exercise training was reported as beneficial for diabetic and nondiabetic patients with chronic heart failure, hypertension, dyslipidemia, coronary artery disease, pulmonary hypertension and atrial fibrillation and in postmenopausal women, resulting in benefits on food intake, skeletal muscle tropism, catabolism, contractile function, endothelial function, lipid and glucose profiles and other parameters, including quality of life, while also improving ischemia tolerance and offering myocardial protection [Bueno Junior, C.R. et al., Abst P2527; Gielen, S. et al., Abst P2528; Villa Nova Bacurau, A. et al., Abst P2529; Miche, E. et al., Abst P2532; Galvao, T.F.G. et al., Abst P2692; Tjonna, A.E. et al., Abst 3226; Ribeiro, J.P. et al., Abst 3227; Iurciuc, M. et al., Abst 3228; Such-Miquel, L. et al., Abst 3229; Liakos, C. et al., Abst 3230; Haager, G. et al., Abst P3318; Pandele, G.I. et al., Abst P3869; Casella-Filho, A. et al., Abst P4169; Stolen, T. et al., Abst 4311; Ribeiro, J.P. et al., Abst 4312; Syrseloudis, D. et al., Abst 4314; Moreira-Goncalves, D. et al., Abst 4315; Sandri, M. et al., Abst 4316; Santos, M.H.H. et al., Abst 4317; Santos, M.H.H. et al., Abst 4318; Figueroa, D. et al., Abst 4319; Hoellriegel, R. et al., Abst 4320; Santos, M.H.H. et al., Abst 4322].

CORONARY ARTERY DISEASE

Antianginal drugs

An isolated experimental report contributed to the meeting revealed direct antithrombotic effects of the ATP-sensitive potassium channel opener and nitric oxide donor nicorandil in experimental animals [Ishida, H. et al., Abst P1273], while the compound was shown to restore preconditioning during ischemia through effects on cyclic GMP, protein kinase C and phosphorylated p38 mitogen-activated protein kinase pathways [Iliodromitis, E.K. et al., Abst P2159]. A further nitrate donor, pentaerythrityl tetranitrate reduced vascular guanylyl cyclase activity [Suvorava, T. et al., Abst P4185] and upregulated extracellular superoxide dismutase in experimental animals leading to overexpression of endothelial nitric oxide synthase and antiatherosclerotic effects [Oppermann, M. et al., Abst P2873]. Results were reported with a modified-release formulation of trimetazidine that appeared as more effective and preferred over isosorbide dinitrate, both combined with β-Blockers, in a cohort of 903 patients with stable angina in the PARALLEL study [Glezer, M.G. & Deev, A.D., Abst 4425] (Fig. 6). The novel potassium channel blocker F-15845 was shown to abolish ischemia-induced ST segment elevation in experimental models, without direct hemodynamic cardiac effects [Pignier, C. et al., Abst P1384].

Fig. 6. Change in angina attack frequency during 12 weeks of treatment with trimetazidine or isosorbide dinitrate [Glezer, M.G. & Deev, A.D., Abst 4425].

Antiplatelet therapy

Aspirin is the mainstay in antiplatelet therapy for primary and secondary prevention and treatment of many forms of coronary artery disease. Resistance and underresponse have been reported to aspirin [Marcucci, R. et al., Abst P1256; Hoffmann, S. et al., Abst P1281; Zairis, M. et al., Abst 1708; Acikel, S. et al., Abst P3995; Mardikar, H. et al., Abst P3997; Lev, E.I. et al., Abst P3998; Dominiak, M.T. et al., Abst P4000; Acikel, S. et al., Abst 4002; Pamukcu, B. et al., Abst P4196], according to one report related to hypertriglyceridemia [Wcislo, T. et al., Abst P1401], but effective inhibition of platelet aggregation has been obtained in patients not sufficiently responding to low- and standard-dose aspirin by using higher doses [Dogan, Y. et al., Abst P1255]; furthermore, activity lasting less than 24 hours was noted in type 2 diabetic individuals with standard, 75- to 100-mg doses [Sideris, G. et al., Abst 1705]. On the other hand, aspirin reactions have been documented in a number of individuals, but desensitization protocols have been implemented that safely and effectively prevent cutaneous and respiratory reactions and allow patients to receive aspirin to avoid thrombosis [Rossini, R. et al., Abst P1261]. Regarding gastrointestinal toxicity, a higher incidence of gastric and duodenal damage was noted in 51 patients with enteric-coated compared to buccal aspirin [Kucheriavaya, N. et al., Abst P1392].

Clopidogrel is an effective antiplatelet agent that significantly inhibits ADP-induced platelet aggregation, as previously known and confirmed in new assays using multiple electrode platelet aggregometry or point-of-care systems [Sibbing, D. et al., Abst P1253; Trenk, D. et al., Abst P1275], and has been associated with significant improvements in the TIMI perfusion grade and reductions in reinfarction rates in patients undergoing primary percutaneous interventions for acute myocardial infarction [Lev, E.I. et al., Abst P1293] (Fig. 7). Clopidogrel is commonly used combined with aspirin as dual antiplatelet therapy [Mccollam, P. et al., Abst P1294; Waksman, R. et al., Abst P2010], which according to calculations from the CHARISMA trial carries an acceptable cost-effectiveness ratio while improving outcomes at modest life expectancy benefits [Bakhai, A. et al., Abst P4805] (Figs. 8 and 9). However, underuse seems to persist in women, elderly patients, diabetic individuals and subjects undergoing drug-eluting stent implantation [Valencia, J. et al., Abst P4751] after an acute myocardial infarction [Sorensen, R. et al., Abst P1292]. Though dual antiplatelet therapy has been associated with an increase in the risk of major and minor bleeding [Serebruany, V.L. et al., Abst P4769], new data from the CURE and CHARISMA trials has confirmed the need for prolonged clopidogrel maintenance, as discontinuation within one year was associated with increased rates of major adverse cardiovascular events [Bertrand, M.E. et al., Abst P1288; Collet, J.P. et al., Abst 3164], and prolonged therapy has been more and more commonly used during the last years, in accordance with current guideline recommendations [Sorensen, R. et al., Abst P1296], resulting in benefits on one-year mortality also in patients receiving treatment for unprotected left main coronary artery stenosis [Palmerini, T. et al., Abst P4732]. Furthermore, clopidogrel alone or with aspirin proved safe in patients undergoing stent implantation with oral anticoagulation, as documented in a series of 475 patients [Kraemer, J. et al., Abst P3469], and dual clopidogrel/aspirin therapy was superior to aspirin alone in attenuating fibrinolysis and inhibiting platelet activation during radiofrequency ablation for atrial arrhythmia [Polymeropoulos, K. et al., Abst P3919]. On the other hand, degree of residual platelet aggregation after clopidogrel loading was related to the risk of death and myocardial infarction within one year after elective coronary stenting in the EXCELSIOR study [Hochholzer, W. et al., Abst 3096]. Furthermore, even temporary interruption of antiplatelet therapy within one year of a coronary stent implantation was associated with an increased likelihood for stent thrombosis, further confirming the need for prolonged therapy [Wells, T.A. et al., Abst P2014; Dangas, G. et al., Abst P2028]. While advances in research have confirmed the benefits of treatment with clopidogrel at a loading dose of 300 mg followed by daily doses of 75 mg for 12 months, as reflected in the new guidelines for the treatment of non-ST segment-elevated acute coronary syndrome, according to an EXCELSIOR substudy, response to clopidogrel was substantially reduced in patients with the CYP2C19*2 polymorphic variant; this fact was confirmed in further studies [Trenk, D. et al., Abst 265; Cuisset, T. et al., Abst 266]. In fact, resistance to clopidogrel has been reported in a number of patients, especially in smokers and according to some data is related to either CYP2C19 or P2Y₁₂ receptor gene polymorphisms [Malek, L.A. et al., Abst 793; Toth Zsamboki, E. et al., Abst P1278; Letocart, V. et al., Abst P1295; Gurbel, P.A. et al., Abst P1298]. Platelet hyperreactivity after clopidogrel has been related to poorer prognosis over the long term, at least in patients with non-ST segment-elevated myocardial infarction [Samaniego, B. et al., Abst P531; De Miguel, A. et al., Abst P1277; Diego, A. et al., Abst P3460] or those undergoing drug-eluting stent implantation [Antoniucci, D. et al. Abst P1286; Aradi, D. et al., Abst P4005]. Higher loading and maintenance doses of clopidogrel or reloading with standard doses in patients already on maintenance clopidogrel have been advocated to overcome resistance and to obtain faster and greater antiplatelet effects based on a number of small trials [Neubauer, H. et al., Abst P1274; Hoffmann, S. et al., Abst P1279; Angiolillo, D.J. et al., Abst P1283; Trenk, D. et al., Abst P1284; Biondi-Zoccai, G. et al., Abst P1374; Lakkis, N. et al., Abst P1992; Patti, G. et al., Abst P2007]. Detailed analysis from 106 patients suggested no negative effect of low- and standard-dose atorvastatin on clopidogrel’s antiplatelet efficacy [Hong, S.J. et al., Abst P1290], but coadministration of omeprazole significantly decreased the antiplatelet activity of clopidogrel in the OCLA study [Gilard, M. et al., Abst P4012]. On the other hand, clopidogrel was shown to significantly reduce platelet activation without affecting thrombin generation, regardless of glycoprotein IIIa PIA2 polymorphisms, when administered with low-dose aspirin [Undas, A. et al., Abst 267], but high-dose clopidogrel maintenance therapy did reduce thrombin generation in 30 patients with type 2 diabetes from the OPTIMUS study [Angiolillo, D.J. et al., Abst P1280].

Fig. 7. Death, reinfarction and stent thrombosis rates at 30 days in patients undergoing primary percutaneous interventions receiving or not (control group) clopidogrel [Lev, E.I. et al., Abst P1293].

Fig. 8. Outcomes in patients with established cardiovascular disease (subgroup analysis from the CHARISMA trial) receiving aspirin alone or combined with clopidogrel [Bakhai, A. et al., Abst P4805].

Fig. 9. Costs per quality-adjusted year gained in patients with established cardiovascular disease subgroup analysis from the CHARISMA trial) receiving aspirin alone or combined with clopidogrel [Bakhai, A. et al., Abst P4805].

Greater and faster inhibition of platelet aggregation was reported with prasugrel compared to high-dose clopidogrel loading in healthy volunteers and aspirin-treated patients with coronary artery disease [Varenhorst, C. et al., Abst P1271; Winters, K.J. et al., Abst P1386].

Aspirin- and clopidogrel-based triple therapies have been also tested in patients undergoing percutaneous coronary interventions (PCI), but the addition of vitamin K antagonists resulted in an increase in the risk of major bleeding complications [Rogacka, R. et al., Abst P4729]. Addition of glycoprotein (gp) IIb/IIIa inhibitors to clopidogrel and aspirin was related to a significant reduction in 30-day death and myocardial infarction rates in patients undergoing PCI for acute coronary syndromes [Loma-osorio, P. et al., Abst P1287]. Abciximab is one such compound which improved epicardial and myocardial perfusion after primary angioplasty when administered early after an ST segment-elevated myocardial infarction [Angioi, M. et al., Abst P4020], while in the LIPSIA-STEMI trial it proved more effective when intracoronarily compared to intravenously administered to patients undergoing primary PCI [Thiele, H. et al., Abst P4019]. A comparative trial in 3,112 patients undergoing percutaneous coronary interventions demonstrated no differences in one-year death/myocardial infarction rates after treatment with abciximab or eptifibatide [Dery, J.P. et al., Abst P1251], and a meta-analysis of four trials confirmed the benefits of adding abciximab to clopidogrel and aspirin in patients with elevated troponin levels undergoing PCI [Mehilli, J. et al., Abst P1289]. Complementation of clopidogrel with eptifibatide also enhanced the effect of the antiplatelet agent on inflammatory biomarker expression in 106 patients undergoing percutaneous interventions [Gurbel, P.A. et al., Abst P1297], and addition of eptifibatide to bivalirudin was reported to enhance antiplatelet activity, reducing myocardial infarction rates compared to bivalirudin alone in 150 patients undergoing elective coronary stenting [Gurbel, P.A. et al., Abst P1264]. Use of tirofiban in patients undergoing percutaneous coronary intervention was also associated with near-normalization of myocardial perfusion reserve indices, further documenting the efficacy of these compounds as adjuvant therapy [Rolf, A. et al., Abst P1446]. However, gpIIb/IIIa inhibitors added to warfarin in patients undergoing PCI resulted in common bleeding complications [Karjalainen, P.P. et al., Abst P3497]. In a mechanistic study, abciximab potentiated platelet α-granule release through activity on P2Y₁₂ receptors, as the effect was inhibited by the selective blocker cangrelor [Judge, H.M. & Storey, R.F., Abst P4003].

A novel antiplatelet approach, blockade of protease-activated receptor-1, resulted in E-5555, a compound currently in phase II studies that was well tolerated and effectively inhibited thrombin-induced platelet aggregation without any effect on ADP-induced aggregation, coagulation time or bleeding time in healthy volunteers [Takeuchi, M. et al., Abst 264] and SCH-602539, a potent inhibitor that inhibited thrombosis in experimental animal models [Chintala, M. et al., Abst P1269]. Inhibition of platelet aggregation was also noted in patients with metabolic syndrome treated with escitalopram [Atar, D. et al., Abst P2047], or after coffee consumption, although the effect was also noted after drinking decaffeinated coffee, suggesting components other than caffeine as mediators [Renda, G. et al., Abst P1254]. Furthermore, consumption of caffeine following clopidogrel loading enhanced the antiplatelet activity of clopidogrel in healthy volunteers [Lev, E.I. et al., Abst P1285].

Anticoagulants

Anticoagulant therapy may be required in patients with coronary artery disease, and the triple combination of oral anticoagulants, aspirin and clopidogrel was reported as feasible and effective, though associated with an increase in nonsevere bleeding, in patients with intracoronary stents [Guasch, E. et al., Abst P1282]. However, such increase in the risk of bleeding was deemed unacceptable in further patient series and required the use of oral vitamin K antagonists [Banaszewski, M. et al., Abst P4006]. Low-molecular-weight heparins have been developed with a safer profile compared to unfractionated heparin [Kodumuri, V. et al., Abst 3165] and, at least in the case of enoxaparin, are associated with the same relationship between age and outcomes compared to heparin [Lopes, R.D. et al., Abst P1387], and in fact the latter agent safely reduced in-hospital death and nonfatal reinfarction rates compared to heparin with no relevant increase in the risk of severe bleeding complications in 6,299 patients with ST segment-elevated myocardial infarction treated or not with early reperfusion therapy [Zeymer, U. et al., Abst P4018] (Fig. 10). Among the advantages of low-molecular-weight heparins, which include lower risk of major bleeding complications during PCI [Dumaine, R. et al., Abst P1266], use of these drugs or addition of gpIIb/IIIa inhibitors to heparin proved superior to heparin alone in patients with acute coronary syndromes already receiving aspirin [Jain, H. et al., Abst P1262] and was safely maintained during PCI, as demonstrated in 254 patients [Karjalainen, P.P. et al., Abst P3485; Abd El Kader, M. et al., Abst P3494] (Fig. 11), while the discontinuation of oral anticoagulants during percutaneous interventions in patients with clear-cut indication for such drugs was associated with an increased risk of complications, including stent thrombosis [Layegh, F. et al., Abst P3495]. Using fondaparinux, the results of the OASIS 5 study did not reveal increases in the risk of major bleeding with more prolonged duration of therapy, the drug offering equiefficacy to enoxaparin but a better safety profile [Jolly, S. et al., Abst P1265; Jolly, S. et al., Abst 3161], while a cost-effectiveness analysis suggested reduced costs for fondaparinux [Sculpher, M.J. et al., Abst P4804]. A meta-analysis of fondaparinux trials confirmed the benefits on all-cause death compared to placebo or unfractionated heparin [Turpie, A.G.G. & Eikelboom, J., Abst P1267]. On the other hand, the effectiveness of protamine in reversing heparin after sheath removal for stenting was documented in a series of 350 patients [Rossi, M.L. et al., Abst P1327].

Fig. 10. In-hospital death, nonfatal reinfarction and major bleeding rates in patients receiving enoxaparin or unfractionated heparin [Zeymer, U. et al., Abst P4018].

Fig. 11. Major adverse cardiovascular event, bleeding and access site complication rates during hospitalization in patients undergoing percutaneous coronary interventions during interrupted or uninterrupted oral anticoagulation [Karjalainen, P.P. et al., Abst P3485].

Direct thrombin inhibition is a further anticoagulant strategy, and results with bivalirudin in 17,375 patients with non-ST segment-elevated acute coronary syndrome undergoing PCI revealed no increase in the risk of ischemic events compared to heparin with or without gpIIb/IIIa inhibitors [Varma, A. et al., Abst P1268]. Another anticoagulant option is inhibition of factor Xa, and clinical data support its combination with clopidogrel in healthy volunteers [Kubitza, D. et al., Abst P1272], while experimental data support the use of rivaroxaban combined with clopidogrel and aspirin to enhance the antithrombotic effect of the individual drugs [Perzborn, E. et al., Abst P1270].

Fibrinolytic agents

New data reported during the meeting confirmed the benefits of prehospital half-dose thrombolysis followed by urgent percutaneous coronary intervention regarding death, reinfarction and stroke after ST segment-elevated myocardial infarction [Denktas, A. et al., Abst P3984]. In fact, prehospital thrombolysis with early PCI offered excellent early and mid-term outcomes in 1,714 subjects from the real-world FAST-MI registry [Danchin, N. et al., Abst P3452], and results from a study in 151 patients suggested significantly higher target vessel flow rates after alteplase-based fibrinolysis with tirofiban followed by percutaneous coronary intervention compared to acute PCI with upstream tirofiban [Peters, S. et al., Abst P3986]. According to new analyses of the ASSENT-4 PCI electrocardiographic substudy, benefits of tenecteplase-facilitated percutaneous coronary intervention were limited to patients with Q waves or presenting within three hours of symptom onset [McDonald, M.A. et al., Abst P513].

Adjuvant therapies

Along with statins, which improve short-term outcomes, including mortality, after acute coronary syndromes [Zahger, D. et al., Abst P4709; Ferrieres, J. et al., Abst P4794], β-Blockers have offered generalized improvements in survival in patients with coronary artery disease, including the very elderly [Danchin, N. et al., Abst 4423]. Angiotensin receptor blockers are also effective, as exemplified by improvements in endothelial function and prevention of nitrate tolerance with telmisartan in patients with stable coronary artery disease and metabolic syndrome [Watanabe, H. et al., Abst P4698].

Nonpharmacologic therapies

Many approaches to the nonpharmacologic management of coronary artery disease have been developed, but a particular one, spinal cord stimulation, was discussed in the state of the art session on stable angina during the meeting. The results of the European Registry for Refractory Angina suggested relief of angina symptoms and increase in the quality of life by this technique in 236 patients [Andrell, P. et al., Abst 4424].

Other approaches and experimental therapies

Negative results with pexelizumab regarding benefit in patients undergoing percutaneous coronary interventions for acute myocardial infarction in the APEX-AMI and other studies [Testa, L. et al., Abst P3982] were discussed and related to the complex inflammatory situation during ST segment-elevated syndromes [Theroux, P. et al., Abst 2410]. As adjuvant therapy, pluripotent stem cell mobilization with granulocyte colony-stimulating factor did not induce excessive in-stent neointimal hyperplasia or restenosis after percutaneous stent implantation for ST segment-elevated myocardial infarction [Baldazzi, F. et al., Abst 4346], while such treatment was described as safe after ST segment-elevated myocardial infarction, though devoid of benefits on left ventricular ejection fraction [Ferrante, G. et al., Abst P4674]. Regarding novel targets and approaches, inhibition of protein kinase C_δ with δV1-1 preserved vasodilator capacity of epicardial coronary arteries during experimental acute myocardial infarction [Kaneda, H. et al., Abst P2706]. A study in experimental animals suggested protection with an erythropoietin gelatin hydrogel against myocardial infarction through activation of erythropoietin receptor, Akt, ERK and angiogenesis [Kobayashi, H. et al., Abst P2139]. Similarly, vincristine was demonstrated to protect cardiomyocytes from oxidative stress, reduce apoptosis and enhance survival signals [Chatterjee, K. et al., Abst P2141], while the contrary was noted with epirubicin, which induced systolic dysfunction albeit without an effect on biochemical markers [Cadeddu Dessalvi, C. et al., Abst P2178].

Drug-eluting stents

News continue to be reported in major congresses confirming the safety, efficacy and effectiveness of drug-eluting stents, even in high-risk and elderly patients or subjects with complex or bifurcation lesions, subjects with diabetes (although diabetes remains a significant risk factor for unfavorable outcomes) and/or chronic kidney disease, heart transplant recipients and stenting of safenous vein grafts or in-stent restenosis [Dirksen, M.T. et al., Abst 194; Mehran, R. et al., Abst 923; Thomas, M. et al., Abst 924; Werner, G.S. et al., Abst 925; Vaquerizo, B. et al., Abst 928; Routledge, H. et al., Abst P1303; Radke, P.W. et al., Abst P1305; Kishi, K. et al., Abst P1307; Carrie, D. et al., Abst P1308; Suarez De Lezo, J. et al., Abst P1309; Routledge, H. et al. Abst P1310; Jeger, R. et al., Abst P1315; Miyazawa, A. et al., Abst P1316; Tanigawa, J. et al., Abst P1317; Sadaka, M.A. et al., Abst P1318; Mazuelos, F. et al., Abst P1319; Romero, M. et al., Abst P1320; Nathoe, H.M. et al., Abst P1321; Falsini, G. et al., Abst P1322; Ikeno, K. et al., Abst P1323; Yamaguchi, K. & Watatsuki, T., Abst P1331; Barlocco, F. et al., Abst P1333; Pitt, J.E. et al., Abst P1337; Van Der Hoeven, B.L. et al., Abst P1339; Buszman, P. et al., Abst 1635; Mehran, R. et al., Abst 1638; Hoffmann, R. et al., Abst P1995; Costa, M.A. et al., Abst P1996; De La Torre Hernandez, J.M. et al., Abst P2000; Balachandran, K.P. et al., Abst P2003; Daemen, J. et al., Abst P2004; Voudris, V. et al., Abst P2006; Kaplan, S. et al., Abst P2008; Dawkins, K.D. et al., Abst P2009; Menozzi, A. et al., Abst P2011; De La Torre Hernandez, J.M. et al., Abst P2012; Solinas, E. et al., Abst P2013; Qian, J.Y. et al., Abst P2016; De La Torre Hernandez, J.M. et al., Abst P2017; Kelbaek, H. et al., Abst P2018; Mishkel, G. et al., Abst P2020; Biondi-Zoccai, G. et al., Abst P2021; Moreno, R. et al., Abst P2022; Patti, G. et al., Abst P2023; Pucelikova, T. et al., Abst P2024; Shirai, K. et al., Abst P2025; Sheiban, I. et al., Abst P2026; Alahmar, A.E. et al., Abst P2027; Mishkel, G. et al., Abst P2031; Qasim, A. et al., Abst P2033; Schiele, T.M. et al., Abst P2034; Wakatsuki, T. et al., Abst P2035; Vaquerizo, B. et al., Abst 2348; Biondi-Zoccai, G. et al., Abst 2350; Maeng, M. et al., Abst 2351; Hoffmann, R. et al., Abst 2352; Waksman, R. et al., Abst 2353; Hosogi, S., Abst P2519; Ozaki, Y. et al., Abst P2520; Schiele, T.M. et al., Abst P2522; Siegel, R.M. et al., Abst P2523; Ge, L. et al., Abst P2524; Andron, M. et al., Abst P2770; Dominguez Franco, A.J. et al., Abst P2795; Willich, S.N. et al., Abst 3094; Nordmann, A.J. et al., Abst 3095; Colombo, A. et al., Abst 3097; Daemen, J. et al., Abst 3098; Machecourt, J. et al., Abst 3099; Jensen, J.S. et al., Abst 3100; Serruys, P.W. et al., Abst 3101; Moreno, R. et al., Abst 3103; Beygui, F. et al., Abst P3352; Stabile, E. et al., Abst P3459; Chattopadhyay, S. et al., Abst P3461; Flores Rios, X. et al., Abst P3642; Krucoff, M.W. et al., Abst P3464; Ranjbar, K. et al., Abst P3466; Shirai, K. et al., Abst P3470; Bertel, O. et al., Abst P3472; Wijns, W. et al., Abst P3473; Vaquerizo, B. et al., Abst P3477; Dzavik, V. et al., Abst P3478; Minocha, G. et al., Abst P3486; Ochala, A. et al., Abst P3462; Mahemuti, A. et al., Abst P4007; Alfonso Manterola, F. et al., Abst P4035; Harada, M. et al., Abst P4064; Yamamoto, H. et al., Abst 4345; Dommke, C. et al., Abst 4348; Faurie, B. et al., Abst P4715; De Marco, F. et al., Abst P4716; Routledge, H. et al., Abst P4719; Costa, M.A. et al., Abst P4722; Lefevre, T. et al., Abst P4723; Mishkel, G. et al., Abst P4726; Khattab, A.A. et al., Abst P4730; Kim, Y.H. et al., Abst P4735; Togni, M. et al., Abst P4736; Blanchard, D. et al., Abst P4739; Trabattoni, D. et al., Abst P4740; Mikhail, G.W. et al., Abst P4741; Chieffo, A. et al., Abst P4742; Amador, C. et al., Abst P4744; Eberli, F. et al., Abst P4746; Kim, Y.H. et al., Abst P4756; Behan, M. et al., Abst P4758; Routledge, H. et al., Abst P4761]. Some data suggest the superiority of sirolimus- over paclitaxel-eluting stents in specific situations, such as acute ST segment-elevated myocardial infarction [Kim, H.S. et al., Abst 192], while other studies revealed no meaningful differences between the two stents [Nakamura, S. et al., Abst 193; Ferenc, M. et al., Abst P1301; Guagliumi, G. et al., Abst 3102]. However, data from the SHAKESPEARE European registry of 13,441 patients revealed double one-year death rates after drug-eluting compared to bare metal stent implantation for acute coronary syndrome [Gitt, A.K. et al., Abst P2037], while other studies, such as ERACI III, demonstrated no advantage or disadvantage of one versus the other [Mieres, J. et al., Abst P2038; Pedersen, S. et al., Abst P3468; Kelly, P. et al., Abst P3474]. Furthermore, the ORAR II study results suggested that a bare stent combined with oral sirolimus is more cost-effective than a sirolimus-eluting stent, at similar safety and efficacy outcomes [Rodriguez, A.E. et al., Abst P2517], while iterative reports of drug-eluting stent thrombosis despite dual antiplatelet therapy or after dual therapy discontinuation have been disclosed [Venugopal, V. et al., Abst P3479; Rivero, F. et al., Abst P3480; Carlsson, J. & Eriksson, P., Abst P3481; Tan, J.W.C. et al., Abst P3482; Mishkel, G. et al., Abst P4725], which could be matched to reports of sustained increases in platelet activation after sirolimus-eluting compared to bare metal stent implantation [Marketou, M. et al., Abst P3483]. Other drug-eluting stents have been developed and tested favorable in initial studies, including notably tacrolimus [Van Der Giessen, W.J. et al., Abst P3489], everolimus [Ormiston, J.A. et al., Abst 1634; Kukreja, N. et al., Abst 1636; Garcia-Garcia, H.M. et al., Abst 1637] and biolimus A9 [Christians, U. et al., Abst P1377; Christians, U. et al., Abst P1382]. A titanium-nitric oxide-coated stent was also reported safe and effective [Planer, D. et al., Abst P2029], while experimental data suggested feasibility of α-lipoic acid-coated stents [Jeong, M.H. et al., Abst P2672]. However, a comparison of sirolimus-, paclitaxel-, zotarolimus- and tacrolimus-eluting stents in 977 patients with chronic total occlusion suggested lower restenosis rates with the sirolimus-based approach [Nakamura, S. et al., Abst P3476] (Fig. 12).

Fig. 12. Major adverse cardiovascular event (MACE), target lesion revascularization (TLR) and restenosis rates at 9 months in patients receiving sirolimus-, paclitaxel-, zotarolimus- or tacrolimus-eluting stents [Nakamura, S. et al., Abst P3476].

Gene therapy

In the experimental setting, vascular endothelial growth factor-B gene delivered through adenoviral vectors proved a feasible approach to sustain cardiomyocyte contractility and metabolism after myocardial infarction [Zentilin, L. et al., Abst 1588]. The feasibility of liposome-mediated vascular endothelial growth factor-165 transfection was also demonstrated [Ye, L. et al., Abst 1589]. With an alternative approach, enhanced endothelial regeneration and reduction in neointimal formation was demonstrated with endothelial nitric oxide gene-eluting stents [Sharif, F. et al., Abst 1590].

Stem cell therapies

New clinical and experimental studies on stem cell therapies were reported in Vienna and demonstrated improvements in ischemic myocardial injuries after treatment with a number of progenitor cells, including bone marrow-derived mononuclear cells [Silva, G.V. et al., Abst P1425; Krause, K. et al., Abst P1429; Huang, R. et al., Abst P1430; Huang, R. et al., Abst P1431; Yao, K. et al., Abst P1432; Meluzin, J. et al., Abst P1434; Beeres, S.L.M.A. et al., Abst P2200; Arnold, R. et al., Abst P2518; Piepoli, M.F. et al., Abst P2704; Chojnowska, L. et al., Abst P2705], human fetal cardiomyocyte progenitor cells [Grauss, R.W. et al., Abst P1420; Bystrup, A. et al., Abst P1820], adipose tissue-derived stem cells [Cardoso, C.O. et al., Abst P1423; Kharlamov, A.N. et al., Abst 4419], mesenchymal stem cells [Schuleri, K.H. et al., Abst P1818], myocardin-overexpressing human mesenchymal stem cells [Grauss, R.W. et al., Abst 1534], tumor necrosis factor-α-pretreated mesenchymal stem cells [Ahn, Y. et al., Abst P1424] and CD133-positive endothelial progenitor cells [Iwasaki, H. et al., Abst 4352]. A study suggested better improvements in left ventricular function and contractility in an experimental model of chronic myocardial infarction after direct intramyocardial injection of bone marrow-derived mononuclear cells compared to mesenchymal stem cells [Mathieu, M. et al., Abst P1419].

Regarding collection of cells, a comparative study in experimental animals suggested effective mobilization of bone marrow-derived stem cells by parathyroid hormone, which was as effective as filgrastim but devoid of bone marrow depletion [Brunner, S. et al., Abst P1442], while the granulocyte colony-stimulating factor mobilized progenitor cells but induced leukocytosis, resulting in increases in asymmetric dimethylarginine levels and hence impairing endothelial nitric oxide synthase activity [Goette, A. et al., Abst 3063].

On the other hand, a bioartificial collagen-based matrix was also effectively used in five patients with left ventricular postischemic myocardial scars [Barisani, J.L. et al., Abst P1428], while in experimental animals with myocardial infarction benefits were reported with transcoronary injection of an alginate-based biomaterial [Leor, J. et al., Abst 1537].

CARDIAC ARRHYTHMIA

Flecainide is an established antiarrhythmic compound, the activity of which was extended to the treatment of supraventricular tachycardia in the newborn according to a series of 19 cases [Ferlini, M. et al., Abst P2541]. The activity of another classical drug, propafenone, against premature ventricular complexes was predicted by response to single oral doses in 50 patients [Stec, S. et al., Abst P2542], and the compound was deemed safe and effective compared to placebo for conversion of recent-onset atrial fibrillation/flutter in 115 patients not responding to ibutilide [Lazaros, G. et al., Abst P2543] although electrocardiographic changes consistent with Brugada’s syndrome were induced by the drug when used to treat paroxysmal atrial fibrillation in 128 patients [Lanzotti, M.E. et al., Abst P2548]. Data was also presented on sotalol, which proved safe and effective in maintaining sinus rhythm in patients with atrial fibrillation [Konietzko, A. et al., Abst P2547]; amiodarone, which combined with enalapril showed enhanced activity against paroxysmal atrial fibrillation in 58 patients [Ozawa, M. et al., Abst P2544] and in the BIFAC study prevented subacute and late arrhythmia recurrence after successful cardioversion for persistent atrial fibrillation [Botto, G.L. et al., Abst P3303] while in the MEDAB study it improved the efficacy of pacing for atrial fibrillation [Huegl, B. et al., Abst P3325]; and nibentan, with which efficacy against persistent atrial fibrillation and flutter was demonstrated in 64 subjects upon combination with magnesium sulfate [Bregvadze, I.N. et al., Abst P2549]. In a similar way, a combination of bepridil and candesartan offered usefulness in the maintenance treatment of atrial fibrillation in 125 patients [Kawamura, M. et al., Abst P2545], while a combination of nifekalant and nicorandil induced favorable electrocardiographic changes in experimental animals [Ito, H. et al., Abst P2546]. The SOS-KANTO study supported the use of the class II antiarrhythmic agent nifekalant in the treatment of out-of-hospital ventricular fibrillation, as it markedly reduced the likelihood of intensive care unit admission and shortened total hospital stay [Igarashi, M. et al., Abst P429]. A related compound, vernakalant demonstrated in vivo antiarrhythmic activity mediated through blockade of sodium and potassium channels [Wettwer, E. et al., Abst P2536] and prevented recurrence of atrial fibrillation after cardioversion in 73 patients [Torp-Pedersen, C. et al., Abst P2538], while being well tolerated in 236 subjects with atrial fibrillation lasting 3 hours to 45 days [Stiell, I.G. et al., Abst P4606]. In a similar manner, the potassium K_V1.5 channel blocker AR-H65522 converted to sinus rhythm as effectively as cardioversion 167 patients with atrial fibrillation [Geller, J.C. et al., Abst P3289].

Regarding other mechanistic studies, the mechanism of action of ranolazine was assessed and suggested to act on a site located in the inner vestibule of the cardiac sodium channel, blocking it through direct interaction with the inactivated state [Rajamani, S. et al., Abst P2535]. While disopyramide was confirmed effective in prolonging the QT interval in two patients with short QT-1 syndrome [Schimpf, R. et al., Abst P2540], the potassium IKr channel blocker E-4031 was used to demonstrate the role of inhomogeneous distribution of repolarization reserve in the proarrhythmic activity of class III antiarrhythmic drugs [Kamiya, K. et al., Abst P396]. On the other hand, experimental data from animals suggested improvement in beat-to-beat variability with flunarizine resulting in protection against dofetilide-induced torsades de pointes [Oros, A. et al., Abst P2537].

Adjuvant therapies for cardiac arrhythmias include notably anticoagulants and antiplatelet drugs to reduce the risk of thrombotic and thromboembolic events [Ruiz Nodar, J.M. et al., Abst P4718], along with a number of other compounds, such as candesartan, which during a four-year follow-up was effective in preventing relapses of atrial fibrillation, with additional benefits on ventricular remodeling [Cavarra, M.L. et al., Abst 835]. Statins have also been shown useful in the prevention of atrial fibrillation, particularly in the postoperative setting [Liu, T. et al., Abst P3307], and a study demonstrated benefits in sinus rhythm maintenance upon treatment with pravastatin and enalapril [Komatsu, T. et al., Abst P3310]. Atorvastatin was also shown to improve outcomes after early percutaneous coronary interventions [Patti, G. et al., Abst 4260] or electrical cardioversion [Can, I. Et al., Abst P4607] and inhibit the immune response to increased circulating oxidized LDL markers during acute coronary syndromes [Papathanasiou, A. et al., Abst P3633]. On the other hand, substitution of other β-Blockers for nadolol was associated with severe cardiac events in three patients with ventricular arrhythmias [Hermida, J.S. et al., Abst P3336].

According to new analyses from the ATTICA study, long-term fish consumption offered protection against arrhythmia in healthy individuals, adding new benefits to the known antiinflammatory properties of a fish-rich diet [Chrysohoou, C. et al., Abst 328]; the lipoprotein(a)-lowering effect of fish intake was more pronounced in carriers of the LPA ⁹³C→T gene variant [Sofi, F. et al., Abst P3562]. Furthermore, consumption of fish oil decreased the susceptibility to ventricular fibrillation in experimental animals with hypertriglycerylemia [Tribulova, N. et al., Abst P391]. On the issue of ethanol, regular moderate consumption was related with a lower prevalence of metabolic syndrome, coronary heart disease and diabetes in the METS-GREECE registry [Athyros, V. et al., Abst P4776], while abrupt withdrawal in experimental animals potentiated the arrhythmogenic effects of adrenaline, resulting in ventricular arrhythmias [Liu, J. & Fujimiya, T., Abst P3337].

VALVULAR HEART DISEASE

A reduced number of presentations on pharmacotherapeutic issues related to valvular disease were contributed to the meeting this year in Vienna. According to observations from the BRAVE registry, enoxaparin bridging during prosthetic valve procedures was relatively safe with an acceptable risks of bleeding [Hammerstingl, C. et al., Abst P3399]. An experimental study suggested decreased aortic sclerosis lesion size and improved valve function after treatment with amlodipine [Richardson, M. et al., Abst P3956].

CARDIOVASCULAR RISK FACTORS

Hypertension

Despite the availability of effective drugs for treating high blood pressure, early discontinuation and noncompliance are common in outpatients and are frequent sources of undercontrol [Burnier, M. et al., Abst 3125].

Few presentations on diuretic-based therapies were reported this year, but a meta-analysis confirming the blood pressure-lowering effect of indapamide depending on baseline values was discussed, during which the drug was suggested as effective in the treatment of isolated systolic hypertension, especially in elderly subjects with ischemic heart disease [Nagy, V.L. et al., Abst P4843].

Among the β-Blockers, nebivolol preserved renal blood flow and cardiac output better than atenolol [Van De Borne, P. et al., Abst P4850], and was shown to reduce vascular cell adhesion molecule-1 and monocyte chemoattracting protein-1 expression in endothelial cells, preventing foam cell formation and the atherosclerogenic process [Kuroedov, A. et al., Abst P714]. Both nebivolol and carvedilol attenuated increases in blood pressure and heart rate during hypoxia at high altitude [Bilo, G. et al., Abst P4853], while carvedilol and bisoprolol reduced blood pressure without worsening insulin sensitivity in a further study in patients with hypertension and metabolic syndrome, and patients on atenolol showed impaired glycemic profile [Pavlyuk, E.A. et al., Abst P4854]. Compared to no use of β-Blockers, treatment with β-Blockers was associated with effective prevention of atrial fibrillation in hypertension according to a systematic review and meta-analysis [Abi Nasr, I. et al., Abst P4855].

Though less frequently used, α-blockers are also among the antihypertensive drugs recommended by the current guidelines. One such compound, doxazosin, was reported this year to decrease platelet activity through an effect on mean platelet volume, an effect not seen with amlodipine, while both agents improved metabolic abnormalities in 38 patients with metabolic syndrome [Duman, D. et al., Abst P2101] (Fig. 13).

Fig. 13. Change in mean platelet volume after treatment with doxazosin or amlodipine [Duman, D. et al., Abst P2101].

Scarce news was reported on calcium channel blockers, but a randomized study was discussed which suggested improvements in endothelial function and endothelial progenitor cell counts in 35 hypertensive males treated with nifedipine [Sugiura, T. et al., Abst 4330], which was also reported to inhibit vascular remodeling and improve vascular function in experimental animals by restoring copper/zinc-dependent superoxide dismutase activity and reducing oxidative stress [Umemoto, S. et al., Abst P4839]. In a placebo-controlled study efonidipine improved blood pressure as well as endothelial function and metabolic parameters such as insulin sensitivity, adiponectin leptin and resistin [Koh, K. et al., Abst P4831]. The fixed combination of amlodipine and atorvastatin was reported to be less costly and slightly more effective than a two-pill combination on a real-world horizon [Smith, T.W. et al., Abst P4800], being cost-effective compared to atenolol/atorvastatin, amlodipine monotherapy or atenolol alone based on the results of the ASCOT trial [Lindgren, P. et al., Abst P4801].

Though with a risk of angioedema related to bradykinin, which is reversible and not worsening by angiotensin receptor blockers (ARBs) [Beltrami, L. et al., Abst P4832], ACE inhibitors are extensively used in the treatment of hypertension, and along with ARBs have been reported superior to β-Blockers in preventing cardiovascular and total mortality in hypertensive individuals with concomitant diabetes [Balamuthusamy, S. et al., Abst 4415]. Experimental data with ramipril suggested improved myocardial capillarization, endothelial progenitor cell migration and attenuation of intracardiac cellular proliferation during myocardial hypertrophy [Mueller, P. et al., Abst P1427]. The agent also delayed progression of aortic valve stenosis via preservation of nitric oxide effects [Ngo, D.T.M. et al., Abst 3152]. On the other hand, addition of enalapril to torasemide showed promise as a treatment for hypertensive emergencies complicated by acute pulmonary edema, as suggested by the results in 52 patients from a randomized trial [Dyadyk, A.I. et al., Abst P4836].

Angiotensin receptor blockers continued to be the center of most of the new research on hypertension presented at the ESC meeting in Vienna this year. Compared to amlodipine, valsartan improved postprandial inflammation in hypertensive patients with diabetes [Fogari, R. et al., Abst P2790] (Fig. 14). Furthermore, as opposed to amlodipine, both valsartan and ramipril also reduced P-wave dispersion in 208 mildly hypertensive subjects with a history of atrial fibrillation [Fogari, R. et al., Abst P3304]. While showing a favorable impact on cardiovascular markers in patients with non-ST segment-elevated acute coronary syndrome in the ARCHIPELAGO study [Bhatt, D. et al., Abst 4382], irbesartan improved brain perfusion in hypertensive patients with or without metabolic syndrome and type 2 diabetes [Mamyrbaeva, K.M. et al., Abst P4833] and exhibited beneficial effects on cholesterol-dependent oxidative stress and atherosclerosis-related gene expression, which in the EPAS study were increased by coadministration of pravastatin [Morawietz, H. et al., Abst P1396]. Studies in experimental animal models and high-risk patients with metabolic syndrome demonstrated improvements in erectile dysfunction with irbesartan [Baumhaekel, M. et al., Abst P559]. The compound was also shown to prevent atrial fibrillation-induced microvascular flow abnormalities in the ventricles [Goette, A. et al., Abst P3302]. An alternative “sartan”, telmisartan offered maintained 24-hour blood pressure-lowering activity even during the last 8 hours of the dosing interval, but offered additional activity in improving insulin sensitivity and lipid profiles, effects that were not shared by enalapril in a comparative study in 80 mildly to moderately hypertensive patients with metabolic disturbances [Demin, A. et al., Abst P4842]. Telmisartan also proved more effective than carvedilol in preventing recurrent atrial fibrillation in hypertensive patients, suggesting superiority of renin-angiotensin system blockade in favorably affecting electrical and structural atrial remodeling during hypertension [Galzerano, D. et al., Abst P1488] (Fig. 15), while in a study of 26 patients with metabolic syndrome, the ARB improved hemodynamic and metabolic abnormalities, namely insulin resistance, adipocytokine levels and visceral obesity, more effectively than amlodipine [Shimabukuro, M. et al., Abst P2096]. Furthermore, telmisartan inhibited CD4-positive lymphocyte migration through an effect on peroxisome proliferator-activated receptor-γ (PPARγ) [Marx, N. et al., Abst P3637] and attenuated endothelial inflammation and oxidative damage through mechanisms independent of angiotensin receptor blockade or PPARγ agonism [Del Fiorentino, A. et al., Abst P2844; Bode-Boeger, S.M. et al., Abst P2861]. Being as effective as amlodipine in preventing cardiovascular events in hypertensive patients in the CASE-J study, although with greater benefits on left ventricular hypertrophy, renal events and new-onset diabetes [Saruta, T. et al., Abst 4413; Yasuno, S. et al., Abst P4846] (Fig. 16), results from the SARA study with candesartan suggested marked regression of electrocardiographic left ventricular hypertrophy in 202 patients with hypertension, effect being more pronounced in subjects with metabolic syndrome [Calderon, A. et al., Abst P1489].

Fig. 14. Change in postprandial C-reactive protein levels after treatment with amlodipine and valsartan [Fogari, R. et al., Abst P2790].

Fig. 15. Symptomatic or asymptomatic atrial fibrillation rates during 12 months of treatment with telmisartan or carvedilol [Galzerano, D. et al., Abst P1488].

Fig. 16. Change in left ventricular mass index after three years of treatment with candesartan or amlodipine [Saruta, T. et al., Abst 4413].

As an alternative for blocking the renin-angiotensin system, the direct renin inhibitor aliskiren offered effective, sustained 24-hour blood pressure control in hypertensive patients either alone or, if necessary, combined with valsartan or ramipril, both combinations resulting in nonsignificantly higher smooth indices compared to aliskiren monotherapy [Ruilope, L.M. et al., Abst P4844]. The compound was reported to lower blood pressure and suppress plasma renin activity in obese patients with hypertension not responding to diuretic therapy [Jordan, J. t al., Abst 4417].

Alternative targets for intervention may include the retinoid X receptor, as the selective agonist LGD-1069 brought about cardiovascular protective effects in experimental hypertensive animals [Pu, J. et al., Abst 4421], or the parathyroid hormone-related protein receptor, as the selective blocker PTHrP(7-36) prevented pressure overload-related ventricular functional loss in a pressure-dependent manner [Schlueter, K.D. et al., Abst 4422].

DYSLIPIDEMIA

Despite the demonstrated benefits of intensive statin therapy in patients with acute myocardial infarction, as confirmed in new substudies from the TNT trial [Waters, D.D. et al., Abst P2005], real-world data suggest uncommon and variable use of such treatment [Ferrieres, J. et al., Abst P1348]. However, marked reduction in the risk of death has been attributed to statin therapy in patients with increased cardiovascular risk in a number of studies [Winkler, R. et al., Abst 3194], and according to the DEBATE study, this extended to very elderly subjects aged over 75 years with comorbidities and patients with metabolic syndrome and perfusion defects despite normal epicardial coronary arteries [Strandberg, T. et al., Abst P627; Cavusoglu, Y. et al., Abst P2068]. Results in 298 patients suggested that statin withdrawal during the perioperative period carried an increased risk for cardiac events after vascular surgery [Schouten, O. et al., Abst P366]. Furthermore, use of statins was associated with early recovery from renal dysfunction and improved long-term outcomes in patients undergoing major vascular surgery [Welten, G.M.J.M. et al., Abst 1632]. On the other hand, the use of statins in patients with coronary artery disease and metabolic syndrome was more beneficial than in patients without metabolic syndrome, an effect that was suggested to be mediated by benefits of statin therapy on estimated glomerular filtration rate and serum uric acid levels [Athyros, V. et al., Abst P540].

Regarding data on specific statins, the results of the MEGA study demonstrated benefits of pravastatin in reducing cardiovascular events and mortality in hypercholesterolemic subjects with or without additional cardiovascular risk factors [Nakaya, H.N. et al., Abst P4080]. Simvastatin was shown to attenuate cardiac hypertrophy but not myocardial fibrosis in experimental studies [Takayama, N. et al., Abst P1381], while suppressing inflammation and preserving myocardial function after coronary microemboli [Post, H. et al., Abst 3190]; combined with chronic insulin simvastatin improved cardiac mitochondrial function and increased ischemia tolerance [Monteiro, P.F. et al., Abst P2154]. While benefits on oxidative stress and acute inflammation were confirmed in new studies in hypercholesterolemic individuals [Dagre, A. et al., Abst P1385], intensive atorvastatin therapy was superior to standard pravastatin in lowering adverse cardiovascular outcome rates in the PROVE IT-TIMI 22 study [Giraldez, R. et al., Abst P1341]. Furthermore, intensive atorvastatin therapy also offered an effect in lowering triglyceride levels in subjects with metabolic syndrome, which have been related with the increased cardiovascular risk of these patients [Athyros, V. et al., Abst P2063], and reversed impaired placenta growth factor-induced monocyte chemotaxis in coronary artery disease patients with hypercholesterolemia [Czepluch, F.S. & Waltenberger, J., Abst 4262]. However, although atorvastatin was effective in lowering LDL-cholesterol in patients with type 2 diabetes on hemodialysis, N-terminal pro-B-type natriuretic peptide and C-reactive protein levels were markers of death not modified by the treatment, and clinical endpoints were not prevented in the 7D study with doses of 20 mg of the statin [Winkler, K. et al., Abst P1399]; additionally, results from a primary care database analysis suggested poorer results in patients on atorvastatin switching to simvastatin than in patients remaining on atorvastatin [Phillips, B. et al., Abst P4824]. In that respect, data from 24 patients undergoing coronary stent implantation demonstrated lowering of C-reactive protein levels with statin therapy, which translated into regression of necrotic core of fibrous fatty plaques [Noto, T. et al., Abst P4062]. Treatment with atorvastatin also prevented contrast-induced nephropathy in patients undergoing elective coronary angiography [Acikel, S. et al., Abst 921]. In experimental mechanistic studies, atorvastatin was shown to preserve endothelium-dependent vasomotion and nitric oxide bioavailability during vascular inflammation [Aznaouridis, K. et al., Abst P2875], while other studies confirmed the benefits of the statin on endothelial function [Antoniades, C. et al., Abst P2878]. Regarding rosuvastatin, with improvement in oxidative stress in the hypertensive retina [Sicard, P. et al., Abst P4848], inhibition of platelet-collagen interaction and prevention of platelet deposition were noted in experimental studies [Molins, B. et al., Abst P1258], while the notable apolipoprotein B-lowering effect of the statin correlated with reduced reverse cholesterol transport [Nestel, P. et al., Abst P2071]. Combined with folate, cyanocobalamin and pyridoxine, concomitant lowering of homocysteine and cholesterol by rosuvastatin improved endothelial function more than the respective therapies in patients with coronary or peripheral arterial disease [Wustmann, K. et al., Abst P4174]. Overall, a Finnish economic analysis suggested cost-effectiveness for rosuvastatin in reaching European lipid goals in patients with baseline LDL-cholesterol levels over 4.2-5.1 mmol/l, atorvastatin being more costly and less effective [Niskanen, L. et al., Abst P4811]. In that respect, the benefits of atorvastatin in patients with peripheral arterial disease and concomitant dyslipidemia were also demonstrated in an open-label study of 65 males [Buzin, A. et al., Abst 4378].

The cholesterol absorption inhibitor ezetimibe has been used to enhance the lipid-lowering effects of statins, resulting in a cost-effective alternative to statin uptitration in most patients not at goal with statin monotherapy [Brady, A.J.B. et al., Abst P4798]. A fixed combination has been developed with simvastatin. Such combination or a combination of pravastatin plus ezetimibe effectively lowered LDL-cholesterol levels and induced a decrease in the carotid intima-media thickness in patients with coronary artery disease [Meaney, A.M.M. et al., Abst P1367] (Fig. 17), and the ezetimibe/simvastatin combination was safe and effective in the treatment of dyslipidemia in 19 heart transplant recipients who did not respond or could not tolerate higher doses of statins alone [Quarta, C. et al., Abst P2114]. Similarly, the combination of ezetimibe with atorvastatin improved HDL-cholesterol levels and the overall dyslipidemic profile in patients with established coronary artery disease [Deshpande, N.V. et al., Abst P4768]. Furthermore, while despite anticoagulant therapy high thrombin activity was also noted in elderly patients with atrial fibrillation, intensive atorvastatin/ezetimibe therapy prevented thrombus formation, while offering a positive impact on neurocognitive function, depression and white matter lesions [Van Kuilenburg, J.T. et al., Abst P602; Wezenberg, E. et al., Abst 836]. In that respect, a combination of fluvastatin and ezetimibe offered a feasible approach to lower LDL-cholesterol in patients with a history of statin-related adverse muscular events [Stein, E.A. et al., Abst P1350] (Fig. 18).

Fig. 17. Change in the carotid intima-media thickness after one year of treatment with simvastatin (80 mg), simvastatin/ezetimibe (40/10 mg) or pravastatin/ezetimibe (40/10 mg) [Meaney, A.M.M. et al., Abst P1367].

Fig. 18. Percent of patients attaining the ESC/NCEP goals after treatment with fluvastatin and/or ezetimibe [Stein, E.A. et al., Abst P1350].

Fibrates are a second large family of lipid-modifying drugs, but use of these drugs instead of statins resulted in increased total and cardiovascular death in 940 patients with coronary artery disease [Jankowski, P. et al., Abst P1347] (Fig. 19). Data from 300 patients completing a 12-month study suggested feasibility for alternate-day statin/fibrate combination therapy in subjects with combined hyperlipidemia [Ozdemir, K. et al., Abst P1353]. Because of stimulation of PPARα, some fibrates, including clofibrate, were reported to offer additional benefits in lowering blood pressure [Sanchez-Mendoza, A. et al., Abst P1487], but at least with fenofibrate triglyceride response to treatment was affected by polymorphisms of the organic anion transporting polypeptide 1B1 gene, with reduced triglyceride-lowering response in carriers of the ⁵²¹T→C variant [Straka, R.J. et al., Abst P2802].

Fig. 19. Total and cardiovascular death rates in patients with coronary artery disease receiving fibrates or alternative lipid-lowering therapies (control) [Jankowski, P. et al., Abst P1347].

A third alternative is nicotinic acid, the safety and tolerability of which was confirmed in a new observational study in 1,053 patients with high cardiovascular risk [Kastelein, J. et al., Abst P1395].

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is another proposed target for intervention in the treatment of dyslipidemia, but results with pactimibe in 408 patients with coronary artery disease revealed detrimental effect on plaque progression, though only in patients with higher elevations of LDL-cholesterol at baseline [Kalidindi, S.R. et al., Abst P1345].

With niacin having no effect on endothelial dysfunction in a randomized controlled study [Wild, P.S. et al., Abst 4310], a fixed combination of niacin and laropiprant exerted significant and durable lipid-modifying activity, with reductions in LDL-cholesterol, non-HDL-cholesterol, triglycerides and apolipoprotein B, and increases in HDL-cholesterol and apolipoprotein A1 levels in 1,613 dyslipidemic individuals [Maccubbin, D. et al., Abst P715] (Fig. 20).

Fig. 20. Percent change in lipid parameters after treatment with niacin/laropiprant or placebo [Maccubbin, D. et al., Abst P715].

A novel cholesteryl ester transfer protein inhibitor, MK-0859 dose-dependently lowered LDL- and increased HDL-cholesterol levels in both healthy volunteers and patients with dyslipidemia [Krishna, R. et al., Abst 321] (Fig. 21) but had no rising effect on systolic or diastolic blood pressure in healthy volunteers [Krishna, R. et al., Abst 320].

Fig. 21. Change in LDL- and HDL-cholesterol levels after treatment with MK-0859 in dyslipidemic subjects [Krishna, R. et al., Abst 321].

Diet has a major impact on the risk for coronary events, and healthy eating brings about individual and societal benefits [Brunner, E. et al., Abst 1082], while regular, moderate consumption of red wine has been confirmed to decrease cardiovascular risk by favorably modifying tissue plasminogen activator antigen, total, LDL- and HDL-cholesterol, and fibrinogen levels [Bernardes-Correia, J. et al., Abst P4111]. In fact, experimental studies demonstrated vasodilatation without sympathetic activation after one drink of red wine or ethanol, but higher amounts of alcohol resulted in increases in heart rate, cardiac output and muscle sympathetic nerve activity [Spaak, J. et al., Abst P4830]; increases in blood pressure in heavy drinkers were confirmed in the Moli-sani project [Costanzo, S. et al., Abst P4849]. Benefits are also largely attributed to green tea, which in new studies brought about improvements in endothelial function independent of antioxidant effects [Alexopoulos, N. et al., Abst P4177]. Another dietary component with benefits in hypertension is dark chocolate, regular consumption of which was related with reduced aortic pulse pressure in healthy volunteers [Alexopoulos, N. et al., Abst P4851]. Examples of the benefits of other dietary components on the cardiovascular risk include reports on improvement in endothelial function by L-arginine in patients with recurrent chest pain but normal coronary arteries [Shechter, M. et al., Abst P4178], reductions in left ventricular hypertrophy also by L-arginine comparable to those attained with spironolactone in experimental animal models [Paulis, L. et al., Abst P4828], improved nitric oxide bioavailability and decreased oxidative stress by folate in patients with coronary artery disease [Antoniades, C. et al., Abst 4305], protection against insulin resistance and improvements in left ventricular contractile function through activation of estrogen receptors by resveratrol [Deng, J.Y. & Hung, L.M.,  Abst P1190]. Among dietary approaches to the management of dyslipidemia, new research disclosed this year in Vienna included data on the benefits of canola oil containing ω₃ polyunsaturated fatty acids by lowering LDL-cholesterol and improving endothelial function [Stricker, H. et al., Abst 330]; consumption of ω₃ polyunsaturated fatty acids also significantly reduced total mortality in patients with stable cardiovascular disease and prevent atrial fibrillation recurrence [De Waha, A. et al., Abst P1389; Mavrakis, H.E. et al., Abst P3911], and in experimental animals improved survival, systolic function and arrhythmogenic remodeling [Fischer, R. et al., Abst 4418]. Other reports focused on docosahexaenoic acid-depressed cyclooxygenase-2 induction through inhibition of NADP(H) oxidase and protein kinase C_ε [Massaro, M. et al., Abst P1831], while intake of 3’,4’-dihydroxyflanonol was described to reduce infarct size and preserve coronary endothelial function in experimental animals [Woodman, O. et al., Abst P2683]. In a similar way, the bioflavonoid quercetin improved vascular endothelial growth factor expression in patients with acute myocardial infarction [Kozhukhov, S. & Parkhomenko, A., Abst P3422], while reducing dendritic cell adhesion and oxidized LDL-induced dendritic cell differentiation in in vitro experiments [Nickel, T. et al., Abst P3640]. An interesting report was discussed pointing out benefits of beetroot juice on systolic and diastolic blood pressure and prevention of ischemia-induced endothelial dysfunction which were related with an increase in nitrite levels from the dietary nitrate contained in beetroot [Webb, A.J. et al., Abst P4834]. On the contrary, untoward effects were described for plant sterols which impaired endothelial function and aggravated ischemic brain injuries and atherogenesis in experimental animals [Weingartner, O. et al., Abst 4306].

ATHEROSCLEROSIS AND VASCULAR INFLAMATION

Observations in 42 healthy males suggested that besides lowering lipid levels, plant sterols may also inhibit oxysterol, offering antiinflammatory and antiatherosclerotic effects that result in lowering of C-reactive protein levels [Kozlowska-Wojciechowska, M. & Naruszewicz, M., Abst 326], while a similar study comparing green and black tea suggested equiefficacy in improving endothelial function [Jochmann, N. et al., Abst 331].

DIABETES, INSULIN RESISTANCE AND IMPAIRED GLUCOSE TOLERANCE

Along with hypertension, diabetes is a potent risk factor for cardiovascular morbidity and mortality, with a population study on over three million people suggesting higher all-cause mortality among diabetic patients on hypoglycemic medication than nondiabetic subjects with a prior myocardial infarction [Schramm, T.K. et al., Abst 2479] and a registry of 610 patients suggesting an increased risk for very late stent thrombosis after drug-eluting stent implantation [Voudris, V. et al., Abst P3456]. However, analyses in 1,310 patients suggested lower 30-day mortality after acute myocardial infarction in subjects receiving β-cell-selective sulfonylureas (glimepiride or gliclazide) compared to glibenclamide or no sulfonylurea [Danchin, N. et al., Abst P2754]. Furthermore, experimental data suggested that chronic insulin therapy improves cardiac mitochondrial function towards reduced oxidative stress and higher ischemia tolerance [Monteiro, P.F. et al., Abst P2686]. On another issue, aspirin seemed less effective in preventing recurrent events after hospitalization for myocardial infarction in diabetic compared to nondiabetic subjects [Macchia, A. et al., Abst P2764], further emphasizing the need for properly addressing and managing the cardiovascular risk in diabetes.

Data from experimental studies confirmed the favorable role of pioglitazone on reverse cholesterol transport, eventually resulting in increased HDL-cholesterol levels [Carreon-Torres, J.E. et al., Abst P1340], while both pioglitazone and rosiglitazone attenuated doxorubicin-induced cardiomyocyte toxicity [Erkan, A.F. et al., Abst P2140], and the former also reduced myocardial infarct size during experimental ischemia [Yasuda, S. et al., Abst P2146]. Moreover, pioglitazone showed potential to stabilize coronary plaques and decrease the necrotic core, an effect related to increases in adiponectin levels [Ogasawara, D. et al., Abst 4381], and improved endothelial function in type 2 diabetes, an effect not demonstrated with glimepiride [Naka, K. et al., Abst P2799] (Fig. 22), while rosiglitazone, as opposed to glimepiride, improved myocardial diastolic function and reduced oxidative stress in patients with type 2 diabetes [Von Bibra, H. et al., Abst P2771] and induced gains in endothelial function in 31 insulin-dependent patients with type 2 diabetes [Naka, K. et al., Abst P2798]. Pioglitazone was also shown to improve myocardial blood flow and glucose utilization in 26 nondiabetic subjects with familial combined hyperlipidemia [Leccisotti, L. et al., Abst P4027]. Furthermore, despite concerns on safety and tolerability of thiazolidinediones, piglitazone was deemed safe with no deterioration of exercise capacity or systolic function in the treatment of type 2 diabetes patients with symptomatic heart failure [Giles, T. et al., Abst P2797], and use of thiazolidinediones after coronary stent implantation significantly reduced in-stent restenosis and target lesion revascularization rates over six months [Rosmarakis, E.S. et al., Abst P3467]. A mechanistic study with rosiglitazone demonstrated increases in apolipoprotein A1 synthesis and HDL surface electric charge, suggesting an impact on HDL kinetics and metabolism that may contribute to the antiatherosclerotic effects of the drug [Perez-Mendez, O. et al., Abst P4168]. Regarding thiazolidinedione-induced weight gain and cardiac hypertrophy, observations in experimental animals suggested a preventive role for high-dose thiamine supplementation [Soyama, A. et al., Abst P3373].

Fig. 22. Change in flow-mediated vasodilatation after treatment with pioglitazone or glimepiride [Naka, K. et al., Abst P2799].

Use of exenatide in experimental animals was associated with reduced reperfusion injury and improved cardiac function during experimental myocardial ischemia [Timmers, L. et al., Abst 3155]. Experimental studies indicated that tranilast inhibits transforming growth factor-β-induced mitogen-activated protein kinase activation, thus preventing structural and functional manifestations of diabetic cardiomyopathy [Connelly, K.A. et al., Abst P440].

OBESITY

An isolated presentation on sibutramine was discussed during the meeting, in which the results of the SCOUT trial were reported. In the trial, sibutramine exhibited opposing activity on central and peripheral α2 receptors, with blockade of the former and stimulation of the latter, resulting in increased heart rate. Hence, high-risk hypertensive patients were reported as benefiting from treatment, which brought about additional decreases in blood pressure [Torp-Pedersen, C. et al., Abst P4852].

MENOPAUSE

Hormone replacement therapy was reported as effective in increasing cardiovascular performance in menopausal women, especially through an effect on diastolic function [Duzenli, M.A. et al., Abst P655]. The vasodilatory effects of estradiol on human pulmonary circulation were demonstrated in experimental studies [Smith, A.M. et al., Abst P505]. In that respect, estradiol was also beneficial regarding sympathetic reinnervation and ventricular susceptibility after myocardial infarction through an effect on endothelin-1-dependent pathways [Lee, T.M. et al., Abst P546]

SMOKING

Hormone replacement therapy was reported as effective in increasing cardiovascular performance in menopausal women, especially through an effect on diastolic function [Duzenli, M.A. et al., Abst P655]. The vasodilatory effects of estradiol on human pulmonary circulation were demonstrated in experimental studies [Smith, A.M. et al., Abst P505]. In that respect, estradiol was also beneficial regarding sympathetic reinnervation and ventricular susceptibility after myocardial infarction through an effect on endothelin-1-dependent pathways [Lee, T.M. et al., Abst P546]

PERIPHERAL ARTERIAL DISEASE

Results from a double-blind, placebo-controlled trial did not support adding L-citrulline to statin therapy in the treatment of peripheral obstructive arterial disease [Leizorovicz, A. et al., Abst P577].

STROKE

The superiority of enoxaparin over unfractionated heparin, both combined with aspirin, in preventing neurological disability after an acute ischemic stroke was demonstrated by a comparative study in 100 patients [Saleh, A. et al., Abst P586].

Fig. 23. Change in the National Institutes of Healthy Stroke Scale scores after treatment with enoxaparin or heparin [Saleh, A. et al., Abst P586].

PULMONARY HYPERTENSION

Prostanoid analogs are among the oldest drugs developed for the treatment of pulmonary hypertension. A report on the use of continuous venous access ports for administration of epoprostenol suggested long-lasting benefits on complications and survival in 111 patients [Dickinson, M.G. et al., Abst P1941]. Furthermore, epoprostenol improved load-dependent right ventricular systolic function more effectively than sildenafil, resulting in greater decrease of pulmonary vascular resistance in 10 patients [Pavelescu, A. et al., Abst P2657] (Fig. 24).

Fig. 24. Change in cardiac output during hypoxia in patients treated with epoprostenol, sildenafil or placebo [Pavelescu, A. et al., Abst P2657].

While the EARLY study confirmed the benefits of bosentan in improving hemodynamics and delaying time to clinical worsening in 185 patients with mildly symptomatic pulmonary hypertension [Galie, N. et al., Abst 1011] (Fig. 25), the survival benefit of bosentan in patients with systemic sclerosis-associated pulmonary hypertension and pulmonary fibrosis was documented in a study of 305 patients that was honored with a young investigator’s award at the meeting [Kabunga, P. et al., Abst 785]. A new pediatric formulation of bosentan was tested in the FUTURE-1 study, demonstrating similar exposure to the standard adult formulation and nonlinear pharmacokinetics up to doses of 4 mg/kg [Beghetti, M. et al., Abst 1090]. In fact, severity of pulmonary hypertension associated with systemic to pulmonary shunt was reported as more severe in children than adults, both age groups responding to bosentan with short-term improvements in functional class and walking distance [Van Loon, R.L.E. et al., Abst P1939].

Fig. 25. Worsening rates during 24 weeks of follow-up in patients treated with bosentan or placebo [Galie, N. et al., Abst 1011].

New results from clinical trials confirmed the benefits of sildenafil in patients with advanced heart failure and pulmonary hypertension, with acute reduction of pulmonary arterial hypertension in 20 heart transplant candidates [Freitas, A. et al., Abst P460] and improvements in exercise capacity and hemodynamics in patients with congenital cardiac shunt or chronic heart failure [Palazzini, M. et al., Abst P1938; Clausell, N. et al., Abst 2439], with chronic thromboembolic pulmonary hypertension [Romanazzi, S. et al., Abst P3866], or awaiting heart transplantation [Maruszsewski, M. et al., Abst P3355], and the COMPASS-1 study suggested significant reductions in pulmonary vascular resistance and total pulmonary resistance after addition of sildenafil to bosentan in 45 patients treated for 12 weeks [Gruenig, E. et al., Abst 1012]. Sildenafil was considered an effective, well tolerated therapy for cor pulmonale, improving the clinical condition and exercise capacity while lowering pulmonary artery pressure [Jain, V.K. & Gupta, K., Abst P3867]. Furthermore, sildenafil significantly decreased pulse wave velocity in normotensive individuals, although the effect was greater in hypertensive patients, suggesting an effect on arterial distensibility [Assad, M. et al., Abst P4829]. In the experimental arena, sildenafil improved right ventricular systolic function during pressure overload in models of pulmonary hypertension [Andersen, A. et al., Abst P495]. Further experimental insights suggested attenuation of hypoxic pulmonary vasoconstriction without negative effects on gas exchange with intravenous vardenafil and tezosentan, while only vardenafil increased the cardiac index [Geiger, R. et al., Abst P499].

Further poster presentations revealed the favorable safety profile and lack of impact on gas exchange of BAY-63-2521, a new oral soluble guanylate cyclase activator currently on phase II research [Ghofrani, H.A. et al., Abst 1013], the benefits of low-dose rosuvastatin on pulmonary hypertension  [Barreto, A.C. et al., Abst P3868], and the efficacy of cilostazol [Yip, H.K., Abst P494] and mesenchymal stem cell-based prostacyclin synthase gene therapy [Takemiya, K. et al., Abst 1014] in preventing monocrotaline-induced pulmonary hypertension in experimental animals.

ANGIOGRAPHY AND CONTRAST-INDUCED NEPHROPATHY

Use of iodixanol was associated with a low incidence of contrast-induced nephropathy when sufficient hydration with sodium chloride was administered [Adolph, E. et al., Abst P1397]; the contrast agent scored better than ioversol regarding prevention of contrast-induced nephropathy in 250 diabetic subjects undergoing coronary angiography or interventions [Hernandez, F. et al., Abst P2749]. However, no differences were noted between iodixanol and iopamidol in the diabetic high-risk patients included in the CARE study [Sharma, S.K. et al., Abst P3502], and iodixanol was associated with higher thrombogenicity compared to ioxaglate [Collet, J.P. et al., Abst P4001]. Additionally, increase in serum creatinine was significantly higher after administration of iodixanol than iomeprol, though no differences in other contrast-induced nephropathy endpoints were apparent [Thomsen, H.K. et al., Abst P3669] (Fig. 26). Use of hypotonic solution hydration with ascorbate was noted to reduce the risk for contrast-induced nephropathy in diabetic patients, with a low associated cost [Macchi, A. et al., Abst P3504]. On the other hand, observations in 414 patients with moderate to severe chronic renal insufficiency in the CARE study suggested no impact for acetylcysteine on the risk of contrast-induced nephropathy during angiography [Staniloae, C. et al., Abst P1973].

Fig. 26. Percent of patients with ≥0.5 mg/dl increase in serum creatinine after administration of iomeprol or iodixanol [Thomsen, H.K. et al., Abst P3669].

MISCELLANEOUS

At the usual doses, methadone maintenance for opiate addiction was associated with QTc interval prolongation [Pathak, A. et al., Abst P393].

A combination of deferoxamine and deferiprone proved superior to deferoxamine alone in preventing major adverse cardiovascular outcomes in 101 patients with thalassemia major and iron-induced cardiomyopathy [Pepe, A. et al., Abst P481].

Treatment with ramipril significantly improved endothelial function and decreased interleukin-6 levels in normotensive subjects after successfully repaired coarctation of the aorta, suggesting direct benefits of the compound on vascular function and inflammation [Brili, S. et al., Abst P669].

Fluvastatin and pravastatin exhibited significant antiinflammatory effects in experimental models of Kawasaki’s disease [Ozawa, S.I. et al., Abst P688].

Losartan was suggested effective in preventing aortic aneurysm in Marfan’s syndrome, based on observations in 31 patients [Pini, A. et al., Abst P697].

Clozapine-induced myocarditis was reported as dependent on β-adrenergic system and cytokine interactions [Wang, J.F. et al., Abst P1373].

Acetylcysteine significantly attenuated oxidative stress after percutaneous coronary interventions for ST segment-elevated acute myocardial infarction [Iltumur, K. & Gulsum, S., Abst P1391].

Preliminary results from a randomized study suggested benefits of warfarin anticoagulation in patients with permanent transvenous lead implantation for pacemaker [Costa, R. et al., Abst 1539], while the compound proved effective in preventing systemic embolism in patients with nonvalvular atrial fibrillation [Andersen, L.V. et al., Abst P3301]. Heparin and acenocoumarol were also effective oral anticoagulants in patients undergoing pacemaker implantation or replacement [Tolosana, J.M. et al., Abst 1542]. With respect to antibiotic prophylaxis for pacemaker-related infections, postoperative antibiotic therapy for 3-4 days significantly reduced the risk [Jayasuriya, A. et al., Abst 1543].

The cardiotoxic effect of doxorubicin was associated with the regulation of insulin-like growth factor receptor-1 (antiapoptotic) and insulin-like growth factor-binding protein-3 (proapoptotic) expression through redox-sensitive and p53-dependent pathways [Fabbi, P. et al., Abst P2629].

Agalsidase beta replacement therapy stabilized left ventricular structure and function in patients with Fabry’s disease [Lubanda, J.C. et al., Abst P2840].

Early selenium supplementation improved neurological outcomes after cardiac arrest  in a series of 191 patients [Reisinger, J. et al., Abst 3247].

A report on 76 patient with nonrheumatic persistent atrial fibrillation suggested efficacy of nimesulide in preventing recurrence through modulation of inflammatory pathways [Grigoryan, S. et al., Abst P3308].

A novel angiotensin receptor blocker, CV-11974 suppressed mobilization of bone marrow-derived smooth muscle cell-like progenitor cells in experimental animals, and prevented neointimal hyperplasia after vascular injury, suggesting a role for angiotensin AT₁ receptors in the process of neointima formation [Yamada, T. et al., Abst P3624].

Atazanavir had no effect on vascular function in HIV-positive patients, despite significantly improving the lipid profile compared to alternative protease inhibitor-containing antiretroviral therapies [Flammer, A. et al., Abst P4189].

Treatment with tiotropium improved cardiorespiratory symptoms and exercise capacity and ameliorated the severity of chronic heart failure in 40 patients with chronic obstructive pulmonary disease (COPD) [Kato, M. et al., Abst P487]. Regadenoson proved safer than but as effective as adenosine for radionuclide myocardial perfusion imaging in women and in patients with COPD [Senior, R. et al., Abst P4230; Reyes, E. et al., Abst 4231].

Experimental data on imaging and positron-emission tomography suggested promise for [¹⁸F]-BMS-747158-02 as a specific myocardial uptake flow tracer [Nekolla, S. Et al., Abst 4534].

Finally, the small molecule CXCR4 receptor blocker AMD-3465 reduced neointimal formation, neointimal smooth muscle cell content and stromal cell-derived factor-1α-mediated smooth muscle progenitor cell mobilization after arterial injuries [Zagorac, D. et al., Abst P4556].

Report prepared by: X. Rabasseda, Prous Science Medical Information Department