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Meeting Reports

European Society of Cardiology Congress 2011 (ESC)
August 27 - 31, 2011
Paris, France

INTRODUCTION

Paris is a world-famous major European city that everybody would like to visit at least once, and is known as the city of light or the illuminated city, after its nickname of la ville-lumière during the Age of Enlightenment. It is, thus, an appropriate site for a major international conference in which advances in research and new findings and observations are reported and discussed, as was the case during this year's ESC meeting. Indeed, new results from major clinical trials were presented during the meeting in the Paris room within the Parc des Expositions, a modern convention facility in the outskirts of Paris, where attendees crowded the entrances trying to get a seat from which to listen to speakers and see the presentation slides. Not only major clinical trials were presented; initial clinical and preclinical research results were also reported during the oral and poster sessions. In many cases, they represented major steps towards improved cardiovascular pharmacotherapy for many common diseases shortening the lives of people around the world. For those who could not attend the meeting, or who despite arriving in Paris could not gain access to conference rooms filled to capacity, and especially for those who were supposed to attend the meeting but could not because of flight interferences caused by hurricane Irene on the east coast of the U.S., DiabetesPro has wrapped up the major take-home messages from the meeting in the following report.

HEART FAILURE

beta-Blockers are one of the mainstays in the treatment of heart failure, and although no new clinical data - other than the superiority of carvedilol over metoprolol in reducing central blood pressure [Senthong, V. et al., Abst 5287] and the increasing likelihood for adverse outcomes in carvedilol-treated patients with polymorphisms associated with increased plasma renin activity and angiotensinogen levels [Petersen, M. et al., Abst 5291] - were presented during this year's ESC meeting, mechanistic insight revealed selective activity of carvedilol on atrial K2P3.1 potassium leak channels, suggesting class III antiarrhythmic activity [Thomas, D. et al., Abst P5090].

With clinical activity also in lowering systolic blood pressure in patients with refractory hypertension [Vaclavik, J. et al., Abst 3041; Vaclavic, J. et al., Abst 3733], reducing hypertension-related microalbuminuria (although not proteinuria) [Kocianova, E. et al., Abst P4934] and preventing recurrent atrial fibrillation, hemodynamic complications and systolic dysfunction after successful electrical cardioversion for atrial fibrillation [Marchetti, G. et al., Abst P3573], in the mechanistic arena, spironolactone attenuated fibrosis by inhibiting the transforming growth factor-beta1-Smad signaling pathway [Chen, R. et al., Abst P1727]. An alternative antialdosterone agent that proved effective for improving symptoms and outcomes compared to placebo in patients with systolic heart failure regardless of high-risk characteristics (Fig. 1) [Pitt, B., Abst 2177], eplerenone increased circulating endothelial progenitor cell counts [Jung, C. et al., Abst P4411] and showed antiatherosclerotic activity on lesion size and endothelial function independently of AT1 receptor activation [Pingel, S. et al., Abst P3151]. On the subject of aldosterone antagonists, the potassium binder RLY-5016 successfully maintained potassemia within the normal range in patients with heart failure and chronic kidney disease initiating spironolactone [Pitt, B. et al., Abst P4414].

Fig. 1. Cardiovascular death/heart failure hospitalization rates in patients treated with eplerenone or placebo in the EMPHASIS trial [Pitt, B., Abst 2177].

The calcium sensitizer levosimendan was corroborated effective for improving function in patients with acute heart failure in a retrospective chart review [Lazaro, M. et al., Abst P3519], resulting, according to an additional registry, in improved survival and a reduced likelihood of readmission [Bruno, N. et al., Abst P4369] and offering an option for inotrope weaning [Bresson, D. et al., Abst P4394]. Improvements in cardiac function in patients with decompensated heart failure were also demonstrated with milrinone added to low-dose beta-blockers [Kobayashi, S. et al., Abst P4400], while improved symptoms in similar patients were documented after treatment with recombinant human atrial natriuretic peptide [Wang, G., Abst P4399]. Biomarker studies suggested heart unloading benefits in patients with stable heart failure treated with the angiotensin receptor blocker LCZ-696 [Kobalava, Z. et al., Abst P4396]. The antihypertensive activity of the agent in patients with heart failure, resulting in decreased myocardial oxygen demand, was also confirmed [Kobalava, Z. et al., Abst P4409]. Benefits in chronic heart failure patients were likewise demonstrated with valsartan alone or combined with an anti-angiotensin AT1 receptor C-terminal fragment antibody [Zabolotneva, Y.U. et al., Abst P4407].

With activity compared to placebo in the prevention of recurrences of pericarditis in patients receiving conventional therapy for heart failure [Imazio, M. et al., Abst 415] and capable of preventing postoperative pericarditis and pleural effusion in patients undergoing cardiac surgery [Imazio, M. et al., Abst P3482], colchicine was shown to protect against experimental Chagas' disease in experimental animal models exposed to Trypanosoma cruzi [Fernandes, F. et al., Abst 2897].

In the preclinical arena, the soluble epoxide hydrolase inhibitor AUDA improved left ventricular systolic and diastolic function, increased myocardial perfusion and reduced oxidative stress in animal models of chronic heart failure [Merabet, N. et al., Abst P4001], whereas the ASK1 inhibitors G2261818A and G2358939A exerted antifibrotic and antiinflammatory activity in cardiac myocytes [Wang, B. et al., Abst P4392], the plasma membrane calcium-transporting ATPasd-4 inhibitor AP2 exerted in vitro and in vivo antihypertrophic activity [Abou Leisa, R., Abst 914] and the 3',4'-dihydroxyflavonol prodrug NP-202 and the active flavonol improved diabetes-associated systolic dysfunction and cardiomyocyte hypertrophy [Khong, F.L. et al., Abst P2343; Khong, F.L. et al., Abst P4404]. The dual vasopressin V1a/2 receptor blocker BR-5489 effectively blocked vasopressin's antidiuretic effect in experimental animals without compensatory activation of the renin-angiotensin-aldosterone system, suggesting potential therapeutic usefulness [Kolkhof, P. et al., Abst P4412]. In addition, inhibition of galectin-3 with N-acetyllactosamine prevented adverse myocardial remodeling and overt heart failure in heart failure-prone animal models through an antifibrogenic effect, suggesting potential as a treatment of fibrotic heart failure [Yu, L. et al., Abst P5801]. Prevention of cardiac hypertrophy in in vitro assays also resulted from blockade of the transient receptor potential subfamily C type 3 and 6 blocker BTP-2 [Kinoshita, H. et al., Abst P5788]. Regarding autoimmune cardiomyopathy, effective neutralization of anti-beta-receptor antibodies was demonstrated in animal models with the cyclic peptide COR-1 [Ungerer, M. et al., Abst P4402]. On the other hand, the addition of donepezil in chronic heart failure animal models treated with losartan synergistically prevented progression of left ventricular systolic dysfunction and improved the prognosis after extensive myocardial infarction [Li, M. et al., Abst 3721], in which regards cardiac unloading while maintaining renal function was demonstrated upon the addition of TRV-120027, a beta-arrestin ligand for the angiotensin receptor, to furosemide [Boerrigter, G. et al., Abst 5288]. In a similar way, adding CD-NP to furosemide significantly improved the diuretic and natriuretic effect of the latter [Costello, E.C. et al., Abst 5289].

Stem cell therapy is an area of intensive research in heart failure, and new trial results were presented during the meeting indicating the feasibility and safety of fetal stem cells as supportive therapy in patients awaiting cardiac transplantation [Klunnik, M. et al., Abst P2601] and of mesenchymal stem cells [Bartunek, J. et al., Abst P4652] and azacytidine-cultured bone marrow-derived stem cells [Belyavskaya, T.M. et al., Abst P4668], but apparently not uncultured bone marrow-derived stem cells [Popiel, M. et al., Abst P4667; Trzos, E. et al., Abst P4666], as a treatment for ischemic cardiomyopathy. Furthermore, while independent observations indicated safety for angiogenesis in no-option patients [Jimenez-Quevedo, P. et al., Abst P4654; Jimenez-Quevedo, P. et al., Abst P4654], the results of a further placebo-controlled trial suggested that CD133-positive stem cell therapy transiently improved myocardial viability in patients with ischemic, but not idiopathic dilated cardiomyopathy [Kakuchaya, T. et al., Abst P1758], whereas intramyocardial injection of concentrated bone marrow cells safely improved outcomes after an acute myocardial infarction in terms of ejection fraction, exercise capacity and remodeling in the case of larger infarcts [Bergmann, M.W. et al., Abst P2602].

Gene therapy has also been explored as a therapeutic option for heart failure, with clinical data supporting the safety and tolerability of JSV-100, a nonviral plasmid encoding for the human SFF-1 gene under control of the CMV promoter, and its dose-dependent favorable impact on the patients' functional ability and quality of life [Penn, M.S. et al., Abst 274].

A specific form of hereditary heart failure resulting from a lysosomal storage disease, long-term replacement therapy of Fabry's disease with agalsidase stabilized or improved function over at least 5 years if started in early disease states, but offered no meaningful benefits in patients with severe impairment at initiation [Niemann, M. et al., Abst P1700].

CARDIAC ARRHYTHMIA

Atrial fibrillation

While propafenone was confirmed effective for preventing episodes in patients with hypertension and chronic heart failure with preserved ejection fraction complicated with persistent atrial fibrillation [Miller, O. et al., Abst P5091], novel analyses from the ATHENA trial demonstrated comparable effectiveness of dronedarone on cardio- and cerebrovascular events in patients with permanent or other types of atrial fibrillation, an effect that will be further studied in the PALLAS trial, as announced at the meeting [Nieuwlaat, R. et al., Abst P3565]. Furthermore, pleiotropic activity was identified, dronedarone inhibiting thrombogenesis through regulation of plasminogen activator inhibitor-1 expression [Breitenstein, A. et al., Abst P5089]. However, real-world data with the drug indicated frequent adverse events resulting in early discontinuation and only moderate efficacy in preventing atrial arrhythmias [Salmas, J. et al., Abst P5092]. On the other hand, mechanistic experimental studies confirmed the selectivity of amiodarone for atrial versus ventricular myocyte sodium channels, which may contribute to the benefits of the agent on atrial fibrillation without impairing ventricular contractility [Suzuki, T. et al., Abst 1062]. However, a negative effect of amiodarone on respiratory failure after on-pump cardiac surgery was observed in a retrospective study [Hinna Danesi, T. et al., Abst 1061]. In the preclinical arena, in vitro studies in isolated heart models of atrial fibrillation could not demonstrate an antiarrhythmic effect of the sodium-calcium exchanger type 1 inhibitor SEA-0400 [Frommeyer, G. et al., Abst P5088].

Anticoagulation is essential for preventing cardioembolic complications in atrial fibrillation, in which regards warfarin offered therapeutic benefits translating into fewer strokes with no excessive bleeding [Lam, Y.Y. et al., Abst P3338]. However, use of warfarin in patients also receiving ibuprofen resulted in an increased risk of bleeding that should be considered [Raunsoe, J. et al., Abst P1653], and increased risk of bleeding was observed also in patients with international normalization ratio of anticoagulation above, as well as within and below the recommended therapeutic range [Azoulay, L. et al., Abst 3906]. Nevertheless, very advanced age per se was not identified as a predictor of bleeding during vitamin K antagonist therapy, and is not a contraindication, given the benefits on thromboprophylaxis [Poli, D. et al., Abst 3905]. On the contrary, concomitant use of warfarin and amiodarone was associated with increased risk of bleeding and death [Andersen, S.S. et al., Abst 3907].

Rivaroxaban proved effective for preventing stroke and systemic embolism in patients with atrial fibrillation, with reduced-dose treatment being equieffective compared to warfarin in patients with moderate renal dysfunction [Fox, K.A.A. et al., Abst 1159]. Rivaroxaban was also effectively used as bridge therapy in patients on chronic warfarin at high risk for venous thromboembolism who required invasive procedures [Majluf Cruz, A. et al., Abst P2429], and compared favorably with unfractionated heparin and enoxaparin in the prevention of thrombosis associated with mechanical cardiac valves [Kaeberich, A. et al., Abst P5624]. On that subject, effective reversal of rivaroxaban anticoagulation was demonstrated in preclinical studies with the engineered coagulation factor Xa analogue PRT-064445 [Lu, G. et al., Abst 3715].

Regarding novel anticoagulants, apixaban fared superior to aspirin in preventing stroke and systemic embolism without increasing the risk of bleeding in patients who had discontinued warfarin, irrespective of the cause for discontinuation, or who were otherwise not suitable for vitamin K antagonist therapy [Hart, R.G. et al., Abst 128; Eikelboom, J. et al., Abst P2631; Hohnloser, S. et al., Abst 3904]. Additional studies confirmed the superiority of apixaban over warfarin with better protection against stroke and systemic embolism at a lower risk for bleeding (Fig. 2), resulting in an 11% lower risk of all-cause death [Granger, C.B., Abst 413], as well as benefits of the agent on stroke and systemic embolism without excess risk of bleeding in atrial fibrillation patients with chronic kidney disease [Wallentin, L. et al., Abst 1157; Hart, R.G. et al., Abst 128]. On the other hand, while dabigatran was safely and effectively administered with antiplatelet drugs and was as effective as warfarin without excess risk of bleeding [Dans, A.M. et al., Abst 1161], mechanistic data with the agent indicated dose-dependent inhibition and delay of thrombin generation [Serebruany, V.L. et al., Abst P3335] with differences versus warfarin: both reduced fibrin formation but only the latter profoundly reduced coagulation factor VIIa [Siegbahn, A. et al., Abst P2636]. It should be added that a drug-drug interaction was demonstrated, with dronedarone, like other P-glycoprotein inhibitors such as warfarin and verapamil, increasing the absorption and bioavailability of dabigatran without affecting renal excretion [Brunet, A. et al., Abst P3566], although concomitant administration of P-glycoprotein inhibitors did not seem to alter the overall benefits of dabigatran for stroke prevention in the RE-LY trial [Reilly, P.A. et al., Abst 129]. Observations with a further novel anti-coagulation factor Xa agent, otamixaban, indicated lack of crossreactivity with heparin-induced thrombocytopenia antibodies and suggested potential use for anticoagulation in patients with heparin-induced thrombocytopenia or acquired or congenital antithrombin deficiency [Thethi, I. et al., Abst P4413].

Fig. 2. Stroke/systemic embolism and major bleeding rates during 30 months of treatment with apixaban or aspirin [Granger, C.B., Abst 413].

Ventricular arrhythmias

Compared to flecainide, ajmaline showed superiority as a diagnostic test for Brugada's syndrome in first-degree relatives of confirmed patients [Berne, P. et al., Abst 3881]. Regarding treatment, hydroquinidine reduced the likelihood of arrhythmia in patients with subclinical Brugada's syndrome, possibly avoiding the need for implantable cardioverters-defibrillators [Bouzeman, A. et al., Abst P5087].

In the preclinical arena, ranolazine seemed not to confer protection against torsades de pointes, lacking activity against sotalol- and low potassium-induced arrhythmia, although it did prevent early afterdepolarization [Zabel, M. et al., Abst P5093].

CORONARY ARTERY DISEASE

Fibrinolysis is one of the most immediate therapies for thrombotic coronary artery occlusion, in which regards accelerated streptokinase infusion (1.5 MU over 20 minutes) proved well tolerated but faster acting than conventional infusion, resulting in greater patency rates, better preservation of left ventricular systolic function and lower risk of ventricular and supraventricular arrhythmias and mortality in-hospital and at one year [Ghaffari, S. et al., Abst P4908].

While aspirin exerted administration time-independent antihypertensive activity in patients with well-controlled hypertension [Lee, J.H. et al., Abst P4293], dual antiplatelet therapy with aspirin and clopidogrel effectively managed the increased cardiovascular risk after drug-eluting stent fracture [Katoh, H. et al., Abst P1529] and was associated with effective secondary prevention of cardiovascular events (myocardial infarction and coronary-related death) in patients with acute coronary syndromes or coronary artery stents in the primary care setting [Garcia Rodriguez, L.A. et al., Abst P1512]. Furthermore, administration of clopidogrel after coronary stent implantation for acute coronary syndrome exerted an antiinflammatory effect with reduced high-sensitivity C-reactive protein levels [Cekici, Y. et al., Abst P1630], suggesting the need for prolonged therapy that was confirmed by observations of an increased risk of recurrent myocardial infarction or death during the first 90 days after clopidogrel discontinuation [Charlot, M. et al., Abst P2455] or following discontinuation of low-dose aspirin also in the setting of secondary prevention [Cea-Soriano, L. et al., Abst 2847]. Results from the CREDO-KYOTO registry indicated no reduction of serious cardiovascular events but rather an increase in the likelihood of bleeding with prolonged dual antiplatelet therapy after drug-eluting stent implantation [Tada, T. et al., Abst 3128], and observations from a registry of patients with non-ST segment-elevated myocardial infarction did not find improved outcomes upon early preadmission initiation of high-dose clopidogrel, along with aspirin and heparin, in the ambulance [Postma, S. et al., Abst P4867]. On the other hand, pretreatment with the thienopyridine reduced in-hospital mortality in patients with acute ST segment-elevated myocardial infarction undergoing percutaneous interventions [Doerler, J. et al., Abst P2431], while a meta-analysis concluded that there is no compelling evidence of the need to discontinue clopidogrel five days prior to a coronary artery bypass graft intervention [Nijjer, S.S. et al., Abst P4224]. However, patients receiving triple therapy (i.e., adding warfarin to aspirin/clopidogrel) discontinued more frequently than patients on dual antiplatelet therapy, resulting in an increased likelihood for cardiovascular events [Sambola Ayala, A. et al., Abst P2372], although triple antiplatelet therapy with the addition of cilostazol to aspirin plus clopidogrel reduced restenosis after drug-eluting stent implantation without affecting the incidence of other major adverse cardiovascular events [Sakurai, R. et al., Abst P2944], particularly in patients with ST segment-elevated myocardial infarction and concomitant chronic kidney disease [Ha, S.J. et al., Abst P4893].

Resistance to the antiplatelet effects of aspirin and clopidogrel has been reported [Silvain, J. et al., Abst P2432; Lee, S. et al., Abst P2446], with high residual platelet reactivity being associated with worse clinical outcomes [Price, M. et al., Abst 3100], although neither drug's activity was affected by mutations or polymorphisms of a number of genes, including factor V, prothrombin, factor XIII, beta-fibrinogen and methyltetrahydrofolate reductase mutations and HPA-1, apolipoprotein-epsilon, plasminogen activator inhibitor, paraoxonase-1 and angiotensin-converting enzyme gene polymorphisms [Kaymaz, C. et al., Abst P1571; Hulot, J.S. et al., Abst 2099; Trenk, D. et al., Abst 3101], whereas polymorphisms of the CYP2C19, degradation by esterases and interaction with non-P-glycoprotein-inhibiting calcium channel blockers affected the activity of clopidogrel [Drouet, L. et al., Abst P1596; Jeong, Y.H. et al., Abst P1597; Zabalza Cerdeirina, M. et al., Abst P2210]. A direct comparison demonstrated effective equipotent inhibition of platelet activity by cilostazol in carriers of mutated CYP2C19 also receiving aspirin [Jeong, Y.H. et al., Abst P1592]. A particular observation indicated increased platelet reactivity by serotonin during dual therapy with aspirin and clopidogrel, and suggested the use of serotonin receptor blockers as add-on triple antiplatelet therapy [Duerschmied, D. et al., Abst P1598]. Increasing the doses was also advocated for overcoming resistances to antiplatelet therapy. However, while a 600-mg loading dose of clopidogrel followed by 12 months of treatment was associated with reduced major adverse cardiovascular event rates compared to standard loading and maintenance doses for 6 months [Jeger, R. et al., Abst P2441], the use of higher, 150-mg/day doses of clopidogrel improved major adverse cardiovascular and cerebrovascular outcomes in patients undergoing percutaneous coronary interventions, at the cost of also increasing minor bleeding rates [Pershukov, I. et al., Abst P1574]. However, higher doses of clopidogrel were not required in obese individuals [Rajamanickam, A. et al., Abst P4268]. Alternative novel P2Y12 inhibitors such as prasugrel, cangrelor, ticagrelor and elinogrel have been associated with improved antiplatelet activity and reduced mortality after percutaneous coronary interventions for ST segment-elevated myocardial infarction without an increased bleeding risk [Bellemain, A. et al., Abst P2454], although a meta-analysis of randomized controlled trials could not demonstrate additional benefit of the new-generation antiplatelet agents compared to clopidogrel, which was superior to placebo in the prevention of strokes in patients with ischemic heart disease [Aradi, D. et al., Abst P3314].

Compared to doubling the dose of clopidogrel, prasugrel was effective for overcoming clopidogrel resistance in patients with high platelet reactivity despite therapy with the latter [Xanthopoulou, I. et al., Abst P2438; Xanthopoulou, I. et al., Abst P2442]. However, suboptimal inhibition of platelet reactivity after percutaneous coronary interventions was also reported with prasugrel [Bonello, L. et al., Abst P1593], which, in an indirect treatment comparison using data from placebo-controlled trials was comparable to high-dose clopidogrel except for better prevention of stent thrombosis, although ticagrelor, which offered a similar overall profile and was not associated with higher risk of long-term kidney injury compared to clopidogrel [Akerblom, A. et al., Abst P2439], was the only drug to significantly lower all-cause death rates [Steiner, S. et al., Abst P1605]; this effect was associated in independent studies with a lower risk of stent thrombosis compared to clopidogrel in patients with acute coronary syndromes undergoing stent implantation (Fig. 3) [Steg, P.G. et al., Abst P2434]. Moreover, clopidogrel was associated with higher death rates after coronary artery bypass graft surgery, because of the increased risk of cardiac events, infections and bleeding compared to ticagrelor [Varenhorst, C. et al., Abst P2428]. A further related drug, elinogrel also proved superior to clopidogrel in terms of rapid and potent antiplatelet activity in patients undergoing non-urgent percutaneous coronary interventions [Angiolillo, D.J. et al., Abst P2437].

Fig. 3. Rates of definite, probable or possible stent thrombosis in patients receiving ticagrelor or clopidogrel [Steg, P.G. et al., Abst P2434].

Ex vivo studies in diabetic and nondiabetic patients with coronary artery disease and healthy volunteers evidenced no impaired thromboxane A2-dependent platelet responses to aspirin in diabetes, suggesting that there are other reasons for resistance to antiplatelet therapy in diabetic individuals [Femia, E.A. et al., Abst 1165]. On the other hand, maintained thromboxane B2 generation despite low-dose aspirin therapy was observed in patients undergoing percutaneous coronary interventions, although the addition of clopidogrel tended to lower plasma levels [Good, R.I.S. et al., Abst P1616].

Regarding the use of aspirin alone or combined with clopidogrel, esomeprazole effectively managed the risk of peptic ulcer associated with daily low-dose aspirin across all levels of cardiovascular risk [Scheiman, J. et al., Abst 1909]. In relation to this, populational retrospective data confirmed the improved adherence to aspirin in people taking proton pump inhibitors [Singh, G. et al., Abst P2436], without the use of such agents increasing the risk of coronary events in patients receiving clopidogrel [Garcia Rodriguez, L.A. et al., Abst P2433], although esomeprazole did significantly attenuate clopidogrel's antiplatelet activity [Fernando, H. et al., Abst P2444] and in fact poorer outcomes were noted in patients receiving clopidogrel combined with a proton pump inhibitor compared to clopidogrel alone [Rajamanickam, A. et al., Abst P5608].

A further antiplatelet agent, cilostazol exerted antioxidant activity, preventing mitochondrial dysfunction and inhibiting mitochondrial depolarization, supporting an antiarrhythmic and cardioprotective activity [Chattipakorn, S. et al., Abst P2239]. In fact, increased adenosine and nitric oxide availability after treatment with the agent resulted in reduced experimental myocardial infarct size and inhibition of ATP-dependent potassium channel activity in animal models [Bay, Y.B. et al., Abst P3397].

Glycoprotein IIb/IIIa inhibitors are also used in the management of coronary events, with registry data confirming the mortality benefit of abciximab in patients with ST segment-elevated myocardial infarction or complex lesions undergoing percutaneous coronary interventions with or without thrombus aspiration [Iversen, A. et al., Abst P2445; Pyxaras, S. et al., Abst P4227] and observations from systematic reviews and meta-analyses confirmed the superior outcomes obtained with intracoronary compared to intravenous abciximab in patients with ST segment-elevated myocardial infarction undergoing percutaneous interventions [Sakurai, R. et al., Abst P2424; Piccolo, R. et al., Abst P2440]. However, independent retrospective data from similar patients indicated increases in blood flow and patency rates after abciximab administration only during the first hour after symptom onset [Bastos Fernandez, G. et al., Abst P2448], whereas preclinical data indicated no superiority of intracoronary abciximab added to peripheral bivalirudin as myocardial salvage after reperfusion injury [Buszman, P.P. et al., Abst P4897].

Before turning to other therapies, a subject that raises increasing interest and was also present during ESC 2011 is that of the usefulness of an aspirin-containing polypill for secondary cardiovascular prevention with the single daily pill theoretically increasing the likelihood of compliance. Theoretically, and based on epidemiological modeling using Markov approaches and Monte Carlo simulation, such a polypill would be cost-effective over the long term in patients with metabolic syndrome, halving the incidence of cardiovascular events and death compared to no intervention [Zomer, E. et al., Abst 5312]. In that regard, and as shown during the meeting, a combination of aspirin, an angiotensin-converting enzyme inhibitor and a statin effectively reduced one-year mortality after an acute myocardial infarction in patients already receiving beta-blockers [Zeymer, U. et al., Abst P2449].

Among the anticoagulants, the direct thrombin inhibitor bivalirudin improved survival after acute coronary syndrome or percutaneous coronary intervention, especially in subjects with moderate or severe left ventricular dysfunction [Dangas, G. et al., Abst P1526], whereas short-course dabigatran did not provide sufficient anticoagulation compared to unfractionated heparin during percutaneous coronary interventions [Vranckx, P. et al., Abst P2443]. Also in relation with anticoagulants, immediate reversal of heparin by protamine after coronary stent implantation was reported safe, without increasing the risk of acute or subacute stent thrombosis [Kremer Diniz Goncalves, B. et al., Abst P2369]. A novel coagulation factor Xa inhibitor, TAK-442, was tested positive for bleeding safety in the AXIOMA-ACS phase II trial that included patients with acute coronary syndrome also receiving aspirin and clopidogrel [Goldstein, S. et al., Abst P2430], whereas yet a further compound, edoxaban, exhibited favorable pharmacokinetics and pharmacodynamics at a dose of 90 mg o.d. regardless of age and gender in healthy volunteers [Mendell, J. et al., Abst P2614]. In addition, the dual coagulation factor Xa and thrombin inhibitor was as effective as unfractionated heparin and enoxaparin but superior to fondaparinux in vitro in anticoagulation tests [Kaeberich, A. et al., Abst P4226].

Add-on ivabradine improved left ventricular systolic structure and function (Fig. 4) [Tardif, J.C., Abst 2926], prevented early dilatation, decreased N-terminal-pro-atrial natriuretic factor levels more effectively and was safer than uptitration of metoprolol in patients with acute coronary syndromes [Amosova, E. et al., Abst 2093; Moiseev, V. et al., Abst P4192]; compared to bisoprolol, it reduced diastolic dysfunction and N-terminal pro-brain natriuretic peptide levels more effectively [Adamyan, K.G. et al., Abst P4403]. Alternative studies in patients also treated with beta-blockers further demonstrated the benefits of adding ivabradine, resulting in reduced heart rate, improved exercise tolerance and quality of life and reduced risk of adverse cardiovascular events (Fig. 5) [Macchi, A. et al., Abst 3720; Cay, S. et al., Abst P4861], whereas an additional study suggested superiority of ivabradine over atenolol for relieving effort symptoms in patients with mitral stenosis but normal sinus rhythm [Parakh, N. et al., Abst P5717]. Ivabradine also proved effective for reducing in-hospital events and infarct size in patients with acute heart failure complicating acute myocardial infarction [Rajagopal, J. et al., Abst 2094] and was used effectively for preventing paroxysmal atrial fibrillation attacks [Grigoryan, S. et al., Abst P3589]. In addition, ivabradine was found safe and well tolerated in patients with diastolic heart failure on hemodialysis, in whom it reduced heart rate while improving diastolic function [Cice, G. et al., Abst P5004]. Experimental animal studies confirmed that the heart rate-lowering activity of the drug improved aortic distensibility and left ventricular stiffness, resulting in benefits on contractility and diastolic function [Reil, J.C. et al., Abst P3557]. Overall, the results of the ADDITIONS trial indicated that ivabradine in combination with beta-blockers very effectively reduced heart rate, the number of angina attacks and nitrate consumption, while markedly improving the patients' quality of life [Werdan, K. et al., Abst 2095]. Improvements in cardiac structure, function and excitation/contraction coupling were also seen in models of ischemic cardiomyopathy [Navaratnarajah, M. et al., Abst P2019]. Without negatively affecting lung function, the drug also prevented salbutamol-induced tachycardia in patients with chronic obstructive pulmonary disease and coronary artery disease [Zagidullin, N. et al., Abst P697].

Fig. 4. Change in left ventricular end-systolic volume index after 8 months of treatment with ivabradine or placebo in the SHIFT trial [Tardif, J.C., Abst 2926].

Fig. 5. Thirty-day cardiovascular death/heart failure hospitalization/myocardial infarction rates in patients receiving ivabradine or placebo [Cay, S. et al., Abst P4861].

With superiority over nitrates for reducing angina frequency in patients with microvascular angina [Oraby, M.A. et al., Abst P3385], bolus administration of high-dose nicorandil resulted in improved microcirculatory resistance in patients with acute myocardial infarction undergoing percutaneous coronary interventions [Ito, N. et al., Abst 2000]. In patients with acute decompensated heart failure, nicorandil improved left ventricular diastolic function [Shigekiyo, M. et al., Abst 5270] as well as the cardiac index more effectively than carperitide, although the latter was superior in improving pulmonary capillary wedge pressure [Hattori, H. et al., Abst P4401]; it also prevented the thrombogenicity of sirolimus in experimental studies [Ishida, H. et al., Abst P4242]. Prevention of myocardial injury during such interventions was also demonstrated after pretreatment with ranolazine [Pelliccia, F. et al., Abst P2355], whereas trimetazidine, which in patients with angina improved intensity and frequency of attacks resulting in improvements in the quality of life [Na, J.O. et al., Abst P3383] and which was as effective as alternative non-heart rate-lowering antianginal drugs for improving exercise tolerance [Danchin, N. et al., Abst P3384], was associated with improved left ventricular systolic function and exercise tolerance in patients with coronary artery disease undergoing percutaneous interventions [Lopatin, Y.L. et al., Abst P3369]. In a similar way, intracoronary adenosine prevented microvascular reperfusion injury during percutaneous coronary interventions, decreasing the incidence of myonecrosis [Petrenko, I. et al., Abst P2359], whereas dipyridamole (an adenosine uptake inhibitor) prevented ischemia/reperfusion ischemia in the skeletal muscle in healthy volunteers, suggesting an activity to be further assessed [Wouters, C.W. et al., Abst P3410].

Clinical data from a randomized trial in patients undergoing coronary artery bypass graft surgery indicated significant reduction in the risk for myocardial infarction in patients receiving 4 g/day of curcuminoids on top of standard medical therapy (Fig. 6) [Wongcharoen, W. et al., Abst P618]. Additional clinical observations indicated reduction of the augmentation index by allopurinol in patients with coronary artery disease, explaining the reported antiischemic effect of the drug [Noman, A. et al., Abst P3390], and reduction of matrix metalloproteinase-9 levels (a biomarker of ST segment-elevated myocardial infarction) after treatment with acetylcysteine, supporting an effect against early remodeling [Talasaz, A.H. et al., Abst P4905]. In addition, the results of a phase I trial supported further development of the mitochondrial permeability transition pore inhibitor TRO-40303, which was pharmacologically active, safe and well tolerated in healthy volunteers [Schaller, S. et al., Abst P4216].

Fig. 6. In-hospital death/nonfatal myocardial infarction rates in patients receiving curcuminoids or placebo [Wongcharoen, W. et al., Abst P618].

Miscellaneous experimental information of putative therapeutic interest included the benefits of the chemokine CCR2 receptor blocker propagermanium on macrophage activation and postischemic remodeling [Troidl, C. et al., Abst P454], the prevention of neutrophil-mediated injuries during ischemia/reperfusion by the nicotinamide phosphoribosyltransferase inhibitor daporinad [Montecucco, F. et al., Abst P2010], the cardioprotective activity of adenosine A2A and A2B receptor agonists [Andreadou, I. et al., Abst P3419] and the protective activity against postischemic systolic impairment by the citrus flavonoid nobiletin [Morimoto, T. et al., Abst P5451].

Coronary stents

Although with a risk of late stent thrombosis related to superficial macrophage accumulation and plaque inflammation [Kawakami, H. et al., Abst P2394; Kitano, D. et al., Abst P4845], sirolimus- and paclitaxel-eluting stents continued to be reported effective in new trials, observations and registries discussed during this year's ESC meeting in Paris [Zahn, R. et al., Abst P641; Han, Y. et al., Abst P650; Umeda, H. et al., Abst P1537; Facchin, M. et al., Abst P2404; Jeong, J.O. et al., Abst P2412; Boden, H. et al., Abst 3809; Jimenez-Quevedo, P. et al., Abst 3810; Tanaka, H. et al., Abst P4269; Ahmed, K. et al., Abst P4286; Rathod, K.S. et al., Abst 5241; Barthelemy, O. et al., Abst P5578; Batyraliev, T. et al., Abst P5610]. New observations also confirmed previous findings pointing toward specific advantages of the former, which was associated with less luminal loss, adverse remodeling and plaque progression than paclitaxel-eluting stents [Kang, W.C. et al., Abst P651], although other findings indicated predisposition towards endothelial dysfunction by sirolimus-eluting compared to bare metal stents [Mischie, A.N. et al., Abst P4230]. Novel-generation stents, including everolimus- [Lee, K.H. et al., Abst P1560; Waksman, R. et al., Abst P2405; Baber, U. et al., Abst P2414; Patsa, C. et al., Abst P2409; De Waha, A. et al., Abst P2941; Byrne, R. et al., Abst P4241; Almalla, M. et al., Abst P4254; Kitano, D. et al., Abst P4846; Lansky, A.J. et al., Abst 5240; Ishii, H. et al., Abst P5577; Nogales, J.M. et al., Abst P5592], zotarolimus- [Mauri, L., Abst P636; Sakurai, R. et al., Abst P637; Gutierrez-Chico, J.L. et al., Abst P2399; Patsa, C. et al., Abst P2409; Nishinari, M. et al., Abst P4260; Kasim, S. et al., Abst P4273] and tacrolimus-eluting stents [Piscione, F. et al., Abst P663] and a bioresorbable polylactide polymer-coated biolimus-eluting stent [Gutierrez-Chico, J.L. et al., Abst P638] offered equivalent or superior results, with everolimus-, biolimus A9- and sirolimus-eluting stents being overall superior to paclitaxel-eluting stents and zotarolimus-eluting stents faring somehow in between [Nakamura, S. et al., Abst P4253; Yamaguchi, K. et al., Abst P4274; Nakamura, S. et al., Abst P5595; Nakamura, S. et al., Abst P5598].

Protection against arterial injury-induced neointima hyperplasia was demonstrated in experimental studies with the chemokine CXCR4 blocker POL-5551, which offered advantages over sirolimus regarding plaque phenotype and lack of negative effect on re-endothelization, suggesting advantages for preventing restenosis after stent implantation [Hamesch, K. et al., Abst P446].

CARDIOVASCULAR RISK FACTORS

Atherosclerosis

Reduced atherosclerosis by targeting activated macrophages was demonstrated experimentally with an anti-folate receptor-beta antibody conjugated to truncated Pseudomonas exotoxin A (PE38) [Furusho, Y. et al., Abst 2984]. Attenuated inflammation and atherogenesis in LDL receptor-deficient animal models was also demonstrated with the oral spleen tyrosine kinase inhibitor fostamatinib, probably by reducing inflammatory gene expression and inflammatory cell recruitment [Hilgendorf, I. et al., Abst P3144]. In addition, plaque stabilization in apolipoprotein E-deficient animal models resulted from treatment with the sphingosine phosphate SP1 receptor analogues/agonists fingolimod and AUY-954 [Larmann, J. et al., Abst P3169].

Dyslipidemia

Statins have a well-recognized role in the treatment of dyslipidemia, with pleiotropic effects resulting - as newly recognized in observations presented during the meeting - in reductions in mortality and target lesion revascularization rates in patients undergoing drug-eluting stent implantation or other subjects with coronary artery disease [Katoh, Y. et al., Abst P1530; Bouisset, F. et al., Abst 2846], prevention of new-onset and recurrent noninvasive procedure-related atrial fibrillation [Bang, C.N. et al., Abst P3583] or new-onset fibrillation after a first myocardial infarction [Bang, C.N. et al., Abst P3591] or, as demonstrated at least with fluvastatin, other surgical vascular procedures [Schouten, O. et al., Abst P2018]. In the mechanistic arena, cardioprotective activity was also confirmed with pravastatin, resulting in reduced experimental infarct size in hyperlipidemic animals [Andreadou, I. et al., Abst P2238]. However, pretreatment with high-dose atorvastatin in patients undergoing percutaneous coronary interventions did not reduce periprocedural infarction in patients already on chronic statin therapy [Veselka, J. et al., Abst P2362], although administration of atorvastatin in statin-naïve patients undergoing elective coronary artery bypass graft surgery was associated with reduced myocardial O2- and peroxynitrite formation and improved nitric oxide bioavailability, indicating protection against peri- and postprocedural oxidative complications [Antoniades, C. et al., Abst P611; Antoniades, C. et al., Abst 5376]; administration of the statin after drug-eluting stent implantation in experimental animals resulted in accelerated neointima formation, reducing the number of uncovered struts and the risk of thrombosis [Wang, T.J. et al., Abst P2380]. Atorvastatin at doses of 80 mg also protected against persistent atrial fibrillation after a non-ST segment-elevated myocardial infarction [Colivicchi, F. et al., Abst P3567]. Also regarding vascular benefits of the statin, improvements were demonstrated in tetrahydrobiopterin bioavailability and endothelial nitric oxide synthase coupling in arterial grafts, accompanied again by reduced O2- formation [Bakogiannis, C. et al., Abst 925]. These improvements in endothelial health were independent of metabolic and inflammatory status [Careri, G. et al., Abst P3331] and were maintained in patients with Behçet's disease, and were comparable to the benefits of lisinopril [Kaya, M.G. et al., Abst P3150].

Although without an effect on inflammatory markers other than decreases in high sensitive C-reactive protein and interleukin-10 levels, treatment of metabolic syndrome with low HDL-cholesterol levels with rosuvastatin brought about decreases in small, dense LDL and increases in large HDL particle levels [Ural, D. et al., Abst P3259]. Furthermore, although in the preclinical setting, rosuvastatin prevented doxorubicin-induced cardiotoxicity through an antioxidant effect in the myocardium [Kim, Y.H. et al., Abst 5293].

While moderate cholesterol-lowering interventions exerted a preventive effect against progression, intensive lipid lowering with pitavastatin resulted in regression of carotid plaques after 1 year in adults with subclinical atherosclerosis (Fig. 7) [Ikeda, K. et al., Abst P1483].

Fig. 7. Change in the carotid intima-media thickness progression after 1 year of intensive or moderate cholesterol-lowering intervention with pitavastatin at median doses of 3.0 and 1.9 mg, respectively [Ikeda, K. et al., Abst P1483].

Ezetimibe, which according to novel studies improved visceral fat and insulin resistance in hyperlipidemic individuals with metabolic syndrome [Takase, H. et al., Abst P4008], has been effectively combined with statins to enhance their LDL-cholesterol-lowering activity, resulting, in combination with simvastatin and in patients with silent myocardial infarction, in reduction or resolution of ST segment depression [Kadro, W. et al., Abst P3381].

Niacin has been recognized effective in the management of certain forms of dyslipidemia, but an observational study presented in Paris during ESC 2011 indicated additional value for improving hemoglobin A1c levels used as add-on to ongoing statin therapy in patients with type 2 diabetes, with superiority over other augmentation therapies such as ezetimibe and fenofibrate (Fig. 8) [Toth, P. et al., Abst 1912]. In experimental models of diabetes, niacin was also related to increased endothelial progenitor cell counts, thus improving ischemic neovascularization [Lin, S.J. et al., Abst P2013]. However, 12-week data from a comparative study indicated similar benefits on HDL-cholesterol but better safety for inositol hexanicotinate compared to niacin (Fig. 9) [Kasetty, K.P. et al., Abst 2848], whereas data from the FIELD study also suggested long-term benefits of fenofibrate in patients with diabetes, with a significant decrease in the risk of cardiovascular events compared to placebo regardless of the presence of moderate renal impairment [Ting, R. et al., Abst 1910].

Fig. 8. Proportion of patients at hemoglobin A1c goal during treatment with statin monotherapy or niacin, ezetimibe or fenofibrate augmentation [Toth, P. et al., Abst 1912].

Fig. 9. Change in HDL-cholesterol levels after 12 weeks of treatment with inositol hexanicotinate or niacin [Kasetty, K.P. et al., Abst 2848].

Without the negative off-target effects of torcetrabib, dalcetrapib showed benefits by sustainedly and consistently increasing HDL-cholesterol levels in dyslipidemic individuals that were not accompanied by negative vascular effects or increases in blood pressure [Lüscher, T.F. et al., Abst 411]. Increases in HDL-cholesterol associated with reductions in inflammatory biomarker levels in patients with coronary artery disease on prior statin therapy resulted from administration of the apolipoprotein A1 inducer RVX-208 [Nicholls, S.J. et al., Abst P1514].

While icosapent ethyl ester markedly reduced triglyceride levels and improved the overall lipid profile in patients with severe hypertriglyceridemia [Bays, E. et al., Abst 2100] and induced benefits on the phospholipid composition of erythrocyte membranes indicative of reduced cardiovascular risk [Braeckman, R. et al., Abst P3138], and eicosapentaenoic acid protected cardiomyocytes against oxidative stress [Chiang, C.H. et al., Abst P5804] and prevented the adverse effects of C-reactive protein on cardiac remodeling in hypertensive conditions [Nagai, T. et al., Abst P4290], mechanistically, omega 3 polyunsaturated fatty acid supplementation lowered postprandial hypertriglyceridemia and prevented monocyte activation [Schirmer, S.H. et al., Abst P667]. The compounds also exerted antiplatelet activity mediated by increased negative platelet surface charge density [Rossi, J. et al., Abst P1595], and decreased thrombin formation and oxidative stress when added to dual antiplatelet therapy after a percutaneous coronary intervention [Gajos, G. et al., Abst P1614]. Through these or alternative mechanisms, supplementation with polyunsaturated fatty acids improved left ventricular systolic function and coronary blood flow in children with type 1 diabetes [Aburawi, E. et al., Abst P4830]. Overall, a meta-analysis of randomized clinical trials confirmed the value of fish oil in the secondary prevention of sudden cardiac death and myocardial infarction, with a protective effect against all-cause mortality [Zabat, G.M. et al., Abst P238]. These effects could be related to observations of gene expression modulation towards antiatherosclerotic, antiinflammatory and antiangiogenic activity [Massaro, M. et al., Abst 259]. Furthermore, observations indicated a possible preventive effect of omega 3 polyunsaturated fatty acids against ventricular fibrillation in patients with Brugada's syndrome [Tanaka, M. et al., Abst 3880]. However, studies in experimental animals indicated the possibility that dietary omega 3 polyunsaturated fatty acids increased the risk for ventricular tachyarrhythmia after a myocardial infarction by reducing calcium cycling stability in ventricular myocytes [Billman, G.E. et al., Abst P5103]. In a related manner, high levels of omega 3 polyunsaturated fatty acids in erythrocyte membranes were associated with increased likelihood for atrial fibrillation in patients undergoing coronary artery bypass graft surgery [Bjorgvinsdottir, L. et al., Abst P5094]. In fact, additional preclinical studies confirmed a proarrhythmic effect of omega 3 polyunsaturated fatty acids [Billman, G.E. et al., Abst P5086].

A comparative study in patients with polygenic primary hypercholesterolemia suggested superiority of a combination approach with berberine and red rice compared to ezetimibe as adjuvant to conventional therapy with statins (Fig. 10) [Pisciotta, L. et al., Abst P1484]. Independent studies confirmed the lipidemic benefits of a combination of nutraceuticals containing berberine, red rice and polycosanol in elderly hypercholesterolemic individuals [Marazzi, G. et al., Abst P4757].

Fig. 10. Change in total and LDL-cholesterol and triglyceride levels after 3 months of adding berberine/red rice or ezetimibe to statin therapy [Pisciotta, L. et al., Abst P1484].

Hypertension

Diuretics and beta-blockers remain a useful approach to the management of high blood pressure, with drugs such as chlorthalidone as initial stepped care and atenolol as second step resulting in survival benefits over the long term [Kostis, J.B. et al., Abst 5310]. However, a wide variety of newer drugs have been developed as a treatment for hypertension.

Calcium channel blockers are one such group of newer drugs. While antihypertensive effect of verapamil was accompanied by effective skeletal muscle precapillary vessel counterregulatory vasoconstriction, preventing vasodilatation of these vessels [Matisone D. et al., Abst P1668], that of benidipine was associated with cardioprotective activity related to suppression of inflammatory cytokines and reduced nitric oxide bioavailability [Kishimoto, C. et al., Abst P3474]. At least in the mechanistic arena, azelnidipine also exerted cardioprotective activity, inducing less negative inotropic effects on isolated cardiomyocytes compared to amlodipine [Iribe, G. et al., Abst P4935]. On the other hand, the fixed-drug combination of perindopril and amlodipine was safely used to control blood pressure in patients with coronary artery disease not responding to prior antihypertensive drugs [Nagy, V.L. et al., Abst P4922].

A double-blind trial, the SMILE IV study, was reported in which zofenopril was compared to ramipril in patients with left ventricular dysfunction also receiving aspirin. At similar blood pressure-lowering activity, the former was superior in preventing cardiovascular events, mainly hospitalization and a further decline in ejection fraction [Borghi, C. et al., Abst 5292].

Among the angiotensin receptor blockers, losartan combined with hydrochlorothiazide brought about improvements in left ventricular hypertrophy and diastolic function in hypertensive patients suboptimally controlled with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker alone [Ishii, K. et al., Abst P5012]. Blood pressure-lowering intervention with valsartan prevented cardio- and cerebrovascular events more effectively than non-angiotensin receptor-blocker drugs (Fig. 11) regardless of age, gender and the presence of coronary artery disease or chronic kidney disease in high-risk hypertensive individuals, although in patients with established coronary artery disease the antianginal activity of the agent was accompanied by enhanced stroke prevention [Sawada, T., Abst 1153; Shiraishi, J. et al., Abst P1509; Koide, M. et al., Abst 2079; Sawada, T. et al., Abst P5256]; stroke prevention by valsartan was greater in patients not receiving concomitant calcium channel blockers [Yamada, H. et al., Abst P4933]. Clinical benefits were likewise demonstrated with irbesartan, which prevented death and cardiovascular hospitalization, although only in heart failure patients with low N-terminal pro-brain natriuretic peptide levels, suggesting an effect in earlier but not later, higher-risk disease [Anand, I.S. et al., Abst 3003]. Besides lowering blood pressure, a further angiotensin receptor blocker, olmesartan, also improved coronary atherosclerosis and major adverse cardiovascular event rates, as demonstrated in the OLIVUS trial (Fig. 12) [Hirohata, A. et al., Abst 2844]. Mechanistically, olmesartan and amlodipine reduced endothelial cell activation in atherogenic conditions, and inhibited monocyte chemotaxis and adherence to the endothelium, explaining the antiatherogenic activity of the drugs [Cicha, I. et al., Abst P3152]; in the clinical setting amlodipine was as effective as valsartan in lowering blood pressure and preventing cardiovascular events, although only the angiotensin receptor blocker reverted left ventricular hypertrophy and microalbuminuria [Hasegawa, H. et al., Abst 3731]. Mechanistic observations were also reported on losartan, which inhibited LDL-induced dendritic cell maturation and function, suggesting potential antiatherogenic activity [Huang, D. et al., Abst P3139], and on telmisartan, which improved endothelial dysfunction after drug-eluting stent implantation more effectively than amlodipine [Terashima, M. et al., Abst P4229]. On the other hand, use of candesartan as a treatment for hypertension was not associated with an increased risk of cancer or cancer-related death compared to non-angiotensin receptor-blocker therapies [Ogawa, H. et al., Abst 2102].

Fig. 11. Major adverse cardio-/cerebrovascular event rates in patients treated with valsartan or non-renin-angiotensin system-inhibiting antihypertensive drugs in the Kyoto-Heart study [Sawada, T., Abst 1153].

Fig. 12. Major adverse cardio-/cerebrovascular event rates during 4 years of adding or not olmesartan to standard therapy in hypertensive patients undergoing percutaneous coronary interventions for stable angina [Hirohata, A. et al., Abst 2844].

Besides lowering blood pressure, aliskiren decreased left ventricular end-diastolic volume and mass index in patients with dilated cardiomyopathy [Sakai, H. et al., Abst P4405] and decreased QT interval duration variability in hypertensive individuals with diabetes [Fogari, R. et al., Abst P1672] and protected experimental animals from doxorubicin-induced cardiomyopathy [Najmi, A.K. et al., Abst 1309].

Diabetes

Diabetes is an independent cardiovascular risk factor for developing coronary artery disease, while hyperglycemia, rather than diabetes per se, is an indicator of poor prognosis in patients with established disease [Monteiro, S. et al., Abst P665], thus justifying intensive therapies for preventing diabetes and controlling glycemia.

Improved mitochondrial integrity by metformin resulting in improved cardiac contractility was demonstrated in animal models of heart failure [Mgandela, P. et al., P2228]. On the other hand, compared to metformin, use of sulfonylureas in the treatment of diabetes was associated with worse clinical outcomes in patients with a stroke [Lund-Andersen, C. et al., Abst P3340].

Among the thiazolidinediones, pioglitazone did not differ from metformin on improvements in flow-mediated vasodilatation in type 2 diabetes patients also receiving sulfonylureas, but offered more consistent improvements in insulin levels and sensitivity [Naka, K.K. et al., Abst P571]. Furthermore, besides improving indices of insulin resistance, pioglitazone administration in patients undergoing percutaneous coronary interventions also reduced microvascular damage [Okawa, K. et al., Abst P1627]. On the other hand, a meta-analysis of available clinical data found no compelling evidence of untoward effects of rosiglitazone compared to standard antidiabetic therapy on cardiovascular outcomes, especially under vigilance and with prompt medical treatment of fluid retention during therapy [Colquhoun, D. et al., Abst P572]. However, studies in experimental animals indicated enhanced propensity for ventricular fibrillation by the thiazolidinedione [Palee, S. et al., Abst P3405].

In the experimental arena, exenatide inhibited smooth muscle proliferation thus preventing neointimal hyperplasia after vascular injury, suggesting potential antiatherosclerotic activity [Hirata, Y. et al., Abst P443]. The agent posttranslationally inhibited inducible nitric oxide synthase expression in endotoxin-challenged macrophages [Chang, S.Y. et al., Abst P459].

While in patients with diabetes-associated heart failure sitagliptin increased bioactive brain natriuretic peptide levels, decreased aldosterone levels and improved the left ventricular mass index [Tsutamoto, T. et al., Abst P5023], at least in experimental animal models, the drug attenuated myocardial hypertrophy and fibrosis by reducing peroxisome proliferator-activated receptor-delta activation and downregulating transforming growth factor-beta, connective tissue growth factor, fibronectin and cardiotrophin-1 expression [Picatoste, B. et al., Abst P1745; Lenski, M. et al., Abst P4011].

Further preclinical studies indicated benefits of undisclosed protein tyrosine phosphatase 1B inhibitors on cardiac and vascular complications of insulin-resistant diabetes [Gomez, E. et al., Abst P4418] and those of the rho kinase inhibitor fasudil on focal coronary stenosis associated to diabetes [Jenkins, M.J. et al., Abst 5112].

Smoking

While a real-world comparative study confirmed the superiority of varenicline over nicotine replacement therapy in terms of four-week smoking cessation rates in patients also receiving motivational interviewing with phone-based counseling [Shand, J. et al., Abst P2293], mechanistic differences between the two drugs indicated dose-dependent upregulation of cortical alpha4 and hippocampal beta2 nicotinic receptor subunit by varenicline, whereas nicotine induced region-independent upregulation of the beta2 subunit [Both, C. et al., Abst P2303]. Promising smoking cessation outcomes were reported from a public intervention program named "Board the Bus and Quit”, with 60% of subjects included completing the scheduled intervention and being identified as successful quitters at 3 months [Casalino, L. et al., Abst P1487].

DIET AND CARDIOVASCULAR HEALTH

That diet has a very direct impact on cardiovascular health has long been recognized, and further expanded by an observation of improved blood pressure control in patients with coronary artery disease and higher fruit and vegetable intake [Heazlewood, V. et al., Abst P738], and in fact adherence to what is usually considered the Mediterranean diet [Kastorini, C.M. et al., Abst P4159], as well as a gap between dinner and sleep of at least one hour [Kastorini, C.M. et al., Abst P4158] were associated with a reduced likelihood for acute coronary syndromes and strokes, whereas an increased proportion of saturated fatty acids in the diet positively correlated with coronary heart disease-related mortality [Nakamura, Y. et al., Abst P4157]. Improved blood pressure profiles and prevention of arrhythmia in experimental models of hypertension were reported after red palm oil supplementation [Tribulova, N. et al., Abst P1661], whereas cranberry juice decreased osteocalcin-positive endothelial progenitor cell counts in early stages of atherosclerosis [Flammer, A. et al., Abst P4140]. Daily tomato paste intake [Xaplanteris, P. et al., Abst P4141], red grape extract supplementation [Felice, F. et al., Abst P4139] and Greek (boiled) coffee consumption [Oikonomou, E. et al., Abst P4143] were associated with improved endothelial function over the long term, although dark coffee in other studies was associated with increased LDL-cholesterol levels without an impact on the LDL:HDL ratio [Mioto, B.M. et al., Abst P4142]. In addition, increased chocolate consumption was related to reduced risk of cardiometabolic disorders [Franco Duran, O.H. et al., Abst P4137]. Cardioprotection in experimental animals was also demonstrated with regular moderate red wine consumption, the effect depending on signal transduction and activator of transcription-3 (STAT3) activation [Lamont, K.T. et al., Abst P2016], although improved levels of aging biomarkers during chronic red wine consumption in animals was not associated with prolonged lifespan [Tanaka, L.Y. et al., Abst P4138]. Regular administration of beer improved the coronary function protecting against ischemia [Vilahur, G. et al., Abst P2015].

PERIPHERAL ARTERIAL DISEASE

While randomized, controlled clinical trial data demonstrated significant improvements in peripheral blood flow and symptoms in patients with Raynaud's phenomenon [Caglayan, E. et al., Abst 3812], experimental studies in models of hind limb ischemia indicated beneficial effects of cilostazol on endothelial progenitor cell differentiation through activation of the Akt kinase/endothelial nitric oxide synthase pathway [Chao, T.H. et al., Abst P431]. Benefits on proinflammatory mediator expression and tissue perfusion in models of atherosclerotic peripheral arterial disease were likewise described with sildenafil [Valatsou, A. et al., Abst P1384].

PULMONARY HYPERTENSION

Novel studies presented during ESC 2011 corroborated the effectiveness of bosentan in connective tissue disease-related pulmonary hypertension and Eisenmenger's syndrome in adults, with benefits on clinical status, exercise tolerance and hemodynamics [D'alto, M. et al., Abst P758]. The agent also improved pulmonary endothelial function, at least in patients with Eisenmenger's physiology resulting from congenital heart disease [Mebus, S. et al., Abst P772], while improving peripheral endothelial function in subjects with type 2 diabetic microangiopathy [Rafnsson, A. et al., Abst P3153]. A study with a further endothelin receptor blocker, atrasentan, indicated potential for preventing coronary plaque progression in patients with early atherosclerosis and endothelial dysfunction [Reriani, M. et al., Abst P1619].

With clinical improvements demonstrated in patients with idiopathic pulmonary hypertension or disease associated to connective tissue disease, porto-pulmonary disease or HIV infection [Badesch, D. et al., Abst 1179; Rizzo, N. et al., Abst P1180], the benefits of sildenafil on functional capacity, exercise tolerance, oxygen saturation and right ventricular performance in patients with pulmonary hypertension and right ventricular dysfunction secondary to congenital systemic-to-pulmonary shunt were magnified by surgical correction of shunts [Palii, I. et al., Abst P759].

Hemodynamic gains in patients with idiopathic or chronic thromboembolic pulmonary hypertension were documented upon adding subcutaneous treprostinil to dual endothelin receptor blocker/phosphodiesterase inhibitor therapy [Conficoni, E. et al., Abst P1178]. Registry data confirmed the frequent use of a further prostaglandin analogue, epoprostenol, even as first-line therapy for severe pulmonary hypertension [Bergot, E. et al., Abst P1177].

While in vitro data indicated antiproliferative and proapoptotic activity of imatinib on pulmonary artery smooth muscle cells from patients with idiopathic pulmonary hypertension [Nakamura, K. et al., Abst P2507], additional clinical observations supported the use of the agent in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis [Ogawa, A. et al., Abst P777].

Benefits in experimental models of monocrotaline-induced pulmonary hypertension were shown with endothelin-converting enzyme-1-targeted small hairpin RNA molecules [Son, J.S. et al., Abst P439].

MISCELLANEOUS

Prevention of aortic aneurysms by the hyaluronidase inhibitor l-ascorbate-6-hexadecanoate suggested potential therapeutic usefulness [Miyoshi, T. et al., Abst P441].

Nitrosopine, a nitroso-derivative of nifedipine, prevented the adverse vascular remodeling induced by angiotensin II in experimental animals [Ishizawa, K. et al., Abst P448].

Ciclosporin administration after experimental heart transplantation prevented upregulated factor VII-activating protease expression in monocytes and macrophages, resulting in prevention of acute allograft rejection [Worsch, M. et al., Abst P1643].

Neither acetylcysteine nor ascorbate significantly prevented contrast-induced nephropathy compared to placebo in patients with preexisting renal dysfunction undergoing coronary angiography or percutaneous coronary interventions [Brueck, M. et al., Abst P1640], although the combination of acetylcysteine and ascorbate exhibited protection in high-risk patients with acute coronary syndromes undergoing coronary interventions [Grygier, M. et al., Abst 5232]. Prevention of contrast-induced nephropathy in the latter patient population was also demonstrated with short-term high-dose atorvastatin [Ricottini, E. et al., Abst 5231; Ha, S.J. et al., Abst P5584], nicorandil [Nawa, T. et al., abst P5583] and carperitide [Mizuno, T. et al., Abst P5582].

No benefit was apparent of terbutaline for early cardiovascular resuscitation after endotoxemia in experimental animals [Roul, D. et al., Abst P2610].

Similarly to angiotensin1-7 but through different mechanisms, enalapril and irbesartan prevented atrial tachycardia-induced sodium channel and electrical remodeling in experimental animals [Liu, E. et al., Abst P2644; Wang, X.W. et al., Abst P2668]. Prevention or slowing of electrical atrial remodeling was likewise demonstrated with the NADPH oxidase inhibitor apocynin [Zhang, D.X. et al., Abst P2642].

Efficacy was demonstrated against neoplastic and radiation-induced pericardial effusion recurrences with intrapericardial cisplatin and triamcinolone acetonide, respectively [Maisch, B. et al., Abst P3493].

Regardless of the presence or absence of coronary artery disease, treatment of rheumatoid arthritis with the interleukin-1 receptor blocker anakinra reduced apoptotic myocardial remodeling [Ikonomidis, I. et al., Abst P3495].

Deferiprone proved superior to deferasirox for improving myocardial siderosis and maintaining left ventricular systolic function in patients with thalassemia major [Pepe, A. et al., Abst 5284].

At least in experimental animals, simultaneous administration of furosemide with clarithromycin resulted in QT interval prolongation with a risk for torsades de pointes [Klimas, J. et al., Abst 5305].

Acetazolamide counteracted the rise in blood pressure and augmentation index caused by exposure to high altitude [Revera, M. et al., Abst P5713].

Paracalcitol reverted left ventricular hypertrophy in patients on hemodialysis with secondary hyperparathyroidism [Culebras, C. et al., Abst P5702].

Retrospective data from a single center suggested benefits of preoperative enoximone on renal function after cardiac surgery [Angeloni, E. et al., Abst 163].