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Meeting Reports

American Heart Association Scientific Sessions 2010 (AHA)
November 13 - 17, 2010
Chicago, Illinois, USA

INTRODUCTION

Temperatures were not very high in Chicago during this year's AHA Scientific Sessions, although as announced by the captain of the flight this reporter was on, "You'll be happy you're not landing in Minnesota!”, and indeed the river was free from any ice obstructing the flow of water. However, the weather is never an obstacle for sharing and exchanging scientific information at medical meetings, and important new information was indeed reported and discussed at the McCormick Plaza on relevant issues related to pharmacotherapy for cardiac and cardiovascular disorders. Like the Chicago river, running like an artery through the city and freely conducting water without the obstruction of thrombus-like ice blocks – but unlike the traffic jams blocking the main streets conducting people through downtown Chicago and to and from the huge convention center – the meeting conveyed a free and heavy flow of new information that is likely to impact how patients with heart failure, coronary artery disease, cardiac arrhythmia and other cardiac diseases will be treated in the future. Part of this new information is summarized briefly in the following report, with the hope opening a new artery, free of thrombi and stenosis, to conduct information to the relevant audience.

HEART FAILURE

beta-Blockers have become one of the major therapeutic approaches to the management of heart failure, and immediate oral beta-blockade also reduced in-hospital death rates after primary angioplasty for acute myocardial infarction [Jinnai, T. et al., Abst 15293]. Besides its known benefits in heart failure, which were confirmed in a study demonstrating reduced morality among patients prescribed carvedilol on discharge [Guichard, J. et al., Abst 20236], carvedilol also prevented cardiac events in patients with long QT syndrome type 2 [Kimura, H. et al., Abst 15060]. On the other hand, in experimental models of failing heart, extended-release metoprolol normalized epsilon, but not beta isoform left ventricular myocardial levels [Gupta, R.C. et al., Abst 11852].

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also have a well-established role in the overall management of heart failure. A first-in-human experience demonstrated the feasibility of switching from angiotensin-converting enzyme inhibitors to the dual angiotensin receptor blocker and neprilysin inhibitor LCZ-696 [Kobalava, Z. et al., Abst 19378].

Aldosterone blockade is a further approach to the treatment of heart failure, although a study with spironolactone demonstrated no benefit on exercise tolerance in elderly patients with preserved left ventricular ejection fraction despite improvements in echocardiographic indices of diastolic function [Kurrelmeyer, K. et al., Abst 20031]. However, presented as a late-breaking clinical trial during the meeting, the EMPHASIS-HF trial corroborated the benefits of eplerenone compared to placebo on cardiovascular mortality and heart failure-related hospitalization in patients with moderate chronic systolic heart failure [Zannad, F. et al., Abst 23221].

Recombinant natriuretic peptides have been developed with the aims of improving the management of acute heart failure, but the results of the ASCEND-HF trial did not demonstrate significant benefits of nesiritide over placebo in terms of mortality and/or heart failure hospitalization [Hernandez, A.F. et al., Abst 21828].

Gene therapies have also been developed as putative treatments for heart failure. Among these, AAV1/SERCA2a proved safe and well tolerated, while substantially improving one-year functional, clinical and biomarker outcomes, notably adverse cardiovascular events, compared to placebo [Mancini, D., Abst 19470].

Additional clinical studies and observations in the context of heart failure indicated improved myofilament calcium sensitivity resulting in improved diastolic dysfunction with ranolazine [Lardin, H.A. et al., Abst 20986], enhanced functional capacity and ventilator efficiency in chronic heart failure after treatment with sildenafil [Guazzi, M. et al., Abst 13384] (which also offered cardioprotective activity against ischemia/reperfusion through activation of SIRT1 [Shalwala, M. et al., Abst 14584]), and improvement of symptoms of chronic heart failure and renal function, regardless of the presence of anemia, in patients treated with ferric carboxymaltose [Ponikowski, P. et al., Abst 17341; Filippatos, G. et al., Abst 17546], although treatment of iron deficiency with intravenous ferric carboxymaltose also resulted in marked improvements in quality of life [Comin-Colet, J. et al., Abst 19027]. Moreover, according to the results of a randomized, placebo-controlled trial, allopurinol induced regression of left ventricular mass and improved endothelial dysfunction in patients with chronic kidney disease [Kao, M.P. et al., Abst 14498], while in patients with chronic angina the agent reduced brain-derived natriuretic peptide levels and exerted an overall antiischemic effect [Noman, A. et al., Abst 10324]. However, allopurinol did not increase the number of circulating endothelial precursor cells in patients with heart failure, an effect that was on the contrary demonstrated with rosuvastatin [Andreon, I. et al., Abst 20953]. In other news, a first-in-human study with a cyclic peptide, COR-1, that neutralizes anti-beta1-receptor antibodies in patients with heart failure demonstrated good tolerability and feasible pharmacokinetics and pharmacodynamics [Ungerer, M. et al., Abst 19730].

In addition to established therapies and selective experimental approaches to the treatment of heart failure, a retrospective study indicated improved outcomes in patients with congestive heart failure receiving selective serotonin reuptake inhibitors [Pizzi, C. et al., Abst 15372; Khullar, P. et al., Abst 20400], although the use of such drugs in patients receiving antiplatelet therapy resulted in an increased risk of major bleeding [Labos, C. et al., Abst 17475].

Omega 3 polyunsaturated fatty acid supplementation has also been reported beneficial in the managenement of heart failure, although only docosahexaenoic acid, not eicosapentaenoic acid, was shown to possess antiinflammatory activity resulting in prevention of overload-related left ventricular dysfunction [Duda, M.K. et al., Abst 20027]. On the other hand, prolonged myocyte repolarization and increased fibrillation inducibility by chronic supplementation in experimental animals suggested a risk for life-threatening arrhythmias in the setting of myocardial infarction [Li, C. et al., Abst 18299].

Moving to the preclinical laboratory, improvements in atrial electrophysiology in models of chronic heart failure resulted from treatment with sapropterin [Nishijima, Y. et al., Abst 17079]. Inhibition of caspase by Z-Asp-2,6-DCBMk showed protection against chronic pressure overload-induced cardiac dysfunction by preventing apoptosis of myocytes and apoptosis and fibrosis of other cell types [Park, M. et al., Abst 18497]. In addition, the dual antifibrotic, aldosterone-suppressing and renopreserving guanylate cyclase receptor activator CD-NP improved renal failure-induced diastolic dysfunction and fibrosis [Martin, F.L. et al., Abst 20240]. Experimental results were also reported with putative therapies, as exemplified by the attenuated adverse cardiac remodeling induced by angiotensin II after injection of adeno-associated virus serotype 9 expressing calsarcin-1 gene [Frank, D. et al., Abst 14707]. Finally, low-molecular-weight cardiomyocyte-proliferating chemicals that increased the proliferation of embryonic stem cells but also induced pluripotent stem cell-derived cardiomyocytes resulting in increased cardiomyocyte cell number were described, suggesting future advances in the treatment of heart failure [Uosaki, H. et al., Abst 14894], while a small-molecular-weight integrin alpha4beta1 agonist, THI-0019, was shown to enhance progenitor cell adhesion to key homing receptors [Vanderslice, P. et al., Abst 13214], adding putative strategies for regenerative therapy.

CORONARY ARTERY DISEASE

Antiplatelet therapy with aspirin remains the cornerstone in the management of coronary heart disease, although according to the JPAT study, benefits in the diabetic population were restricted to patients with milder forms of the disease on diet therapy only [Okada, S. et al., Abst 12166] or in patients with elevated blood pressure [Soejima, H. et al., Abst 12906]. In addition, primary prevention with aspirin was of dubious utility in patients without clinically established cardiovascular disease, according to a meta-analysis [Lala, A. et al., Abst 16394].

Dual antiplatelet therapy has become the standard in patients undergoing percutaneous coronary interventions, and premature discontinuation of clopidogrel in patients with a drug-eluting stent also receiving aspirin has been related to an increased risk of death [Amin, A.P. et al., Abst 13139], although data discussed in Chicago during this year's meeting indicated limited value of aspirin in patients on high-level antiplatelet therapy with clopidogrel or ticagrelor, with aspirin in fact resulting in an increase in peripheral vascular resistance [Warner, T.D. et al., Abst 15019]. Pretreatment with clopidogrel in patients undergoing percutaneous coronary interventions for acute coronary syndrome was associated with reduced infarct size and degree of myonecrosis [Leonardi, S. et al., Abst 14813] and, in fact, clopidogrel was noted to improve endothelial function in patients with coronary artery disease independently of platelet aggregation [Willoughby, S.R. et al., Abst 16416], although preoperative administration in patients undergoing coronary artery bypass graft surgery was associated with increased operative mortality [Benedetto, U. et al., Abst 14394]. However, although pooled data from acute coronary syndrome trials did not demonstrate safety concerns with long-term clopidogrel plus aspirin therapy, the mortality benefit was higher in patients not receiving clopidogrel, rising concern over its use especially in patients undergoing primary percutaneous coronary interventions [Verheught, F.W.A. et al., Abst 19340]. On the other hand, the antiplatelet activity of the agent was not affected by concomitant administration of atorvastatin or rosuvastatin, regardless of CYP2C19 genotype [Dery, J.P. et al., Abst 16530], although CYP2C19 polymorphisms markedly affected the antiplatelet activity of clopidogrel, but not that of ticlopidine [Asai, T. et al., Abst 10265]. In addition, open-label observational studies have suggested an increased risk of cardiovascular events in patients taking clopidogrel with concomitant proton pump inhibitors, although a meta-analysis of individually underpowered randomized trials could not confirm such association [Shukla, A. et al., Abst 11290]. Additional data suggested a higher risk of community-acquired pneumonia in patients receiving the thienopyridine [Gross, A.K. et al., Abst 19964].

Resistance to aspirin and clopidogrel has been troublesome in a significant proportion of patients, resulting in an increased risk for recurrent atherothrombotic events [Breet, N.J. et al., Abst 16601], and was shown to depend, in addition to previously know factors, on polymorphic variations of the platelet alpha2a-adrenoceptor [Peace, A.J. et al., Abst 18363] and increased levels of fraktaline [Flierl, U. et al., Abst 12848]. Resistance to clopidogrel was predictable by the [14C]-pantoprazole breath test, which measures CYP2C19 function, according to some studies [Tazaki, J. et al., Abst 16319]. The use of higher doses has been advocated and, in the specific case of aspirin, twice-daily dosing improved platelet inhibition in patients with type 2 diabetes [Spectre, G. et al., Abst 15018]. Underresponsiveness to clopidogrel, but not to aspirin, was also related to the presence of end-stage renal disease [Fateh-Moghadam, S. et al., Abst 14540]. However, the results of the GRAVITAS study assessing the role of doubling the maintenance dose of clopidogrel after a percutaneous coronary intervention did not support such use, the incidence rate of cardiovascular death, myocardial infarction or stent thrombosis during 210 days of observation being identical in patients receiving 75 or 150 mg/day, despite enhanced platelet inhibition in the high-dose group [Price, M.J., Abst 21791]; additional studies also suggested the inability of increased-dose clopidogrel to overcome the increased risk of cardiovascular morbidity and mortality after drug-eluting stent implantation in patients with high platelet reactivity on standard-dose antiplatelet therapy [Trenk, D. et al., Abst 10457], although some form of resistance, namely polymorphic variability of the CYP2C19 metabolizing system, could be overcome by increasing maintenance doses of clopidogrel according to other evidence [Collet, J.P. et al., Abst 17991; Bonello, L. et al., Abst 18950]. The use of a 600-mg loading dose of clopidogrel was reported safe in patients undergoing primary percutaneous coronary interventions for ST segment-elevated myocardial infarction, resulting in a trend towards reduced clinical event rates [Zeymer, U. et al., Abst 20764].

An alternative for clopidogrel hyporesponsiveness could be the addition of a third drug such as cilostazol, as demonstrated in a study in patients undergoing percutaneous coronary interventions [Tanigawa, T. et al., Abst 14257]. A different alternative would be substituting other drugs for clopidogrel. As an example, ticagrelor offered superior platelet-inhibitory activity compared to clopidogrel regardless of the metabolizing phenotype and genotype of the patients [Gurbel, P.A. et al., Abst 20393], whereas substituting prasugrel was associated with lower death rates compared to clopidogrel in patients undergoing coronary artery bypass graft surgery, despite an increased likelihood of bleeding [Smith, P.K. et al., Abst 10881] (Fig. 1).

Fig. 1.

Fig. 1. Thirty-day all-cause death rates in patients receiving prasugrel or clopidogrel [Smith, P.K. et al., Abst 10881].

Also in the context of antiaggregatory therapies, intracoronary administration of abciximab during an ST segment-elevated myocardial infarction was associated with improved postischemic left ventricular function and a trend towards reduced major adverse cardiovascular events over the mid to long term [Fuernau, G. et al., Abst 20136] (Fig. 2). Eptifibatide also proved useful in patients with ST segment-elevated myocardial infarction undergoing emergency angiography and percutaneous coronary interventions, and in fact no differences were apparent comparing eptifibatide to abciximab in patients loaded with clopidogrel [Singh, H.S. et al., Abst 17531] (Fig. 3). On the other hand, early eptifibatide was associated with an increased risk of bleeding compared to delayed administration in patients undergoing early invasive therapy, the risk being further increased in elderly patients [Lopes, R.D. et al., Abst 12777]. A third drug within this group, tirofiban reduced thrombus burden and improved infarct-related artery patency and angiographic reperfusion when initiated early before a percutaneous coronary intervention [Hermanides, R. et al., Abst 17650], while tirofiban bridging was described as effective for preventing stent thrombosis in at-risk patients undergoing surgical procedures, without increasing the risk of perioperative bleeding [Wu, D. et al., Abst 18940].

Fig. 2. Change in the left ventricular ejection fraction at 6 months in patients receiving intracoronary or intravenous abciximab [Fuernau, G. et al., Abst 20136].

Fig. 3. Major adverse cardiovascular event rates at 30 days and 2 years in patients receiving eptifibatide or abciximab plus clopidogrel loading at doses of 300 or 600 mg [Singh, H.S. et al., Abst 17531].

As novelties regarding antiplatelet agents, the dimeric glycoprotein VI-Fc fusion protein PR-15 was shown effective for inhibiting platelet aggregation in a phase I trial that also demonstrated a lack of effect on bleeding time [Münch, G. et al., Abst 14971], whereas the anti-von Willebrand factor nanobody ALX-0081 effectively inhibited platelet reactivity without bleeding complications in patients with stable angina undergoing percutaneous coronary interventions [Bartunek, J. et al., Abst 15084]. In addition, experimental results with the novel protease-activated receptor PAR1 blocker F-16618 indicated inhibition of smooth muscle cell migration and proliferation in addition to its antiplatelet activity [Yane, P.C. et al., Abst 14339]. Also in the context of antiplatelet drugs, although unrelated to coronary artery disease, experimental studies confirmed the feasibility of blocking the interaction between glucoprotein Ib and von Willebrandt factor with ALX-0081 as a treatment for thromboembolic disorders, specifically ischemic stroke [Momi, S. et al., Abst 15828F].

Anticoagulants are also an essential part of the overall management of acute coronary syndromes, and the results of a randomized comparison indicated that fondaparinux was a suitable and equieffective alternative to unfractionated heparin for preventing graft failure after coronary artery bypass graft surgery [Sun , J.C.J. et al., Abst 9011]. In that context, while fondaparinux was also considered cost-effective compared to enoxaparin as a treatment for non-ST segment-elevated acute coronary syndromes [Lozano-Ortega, G. et al., Abst 17199], rivaroxaban was shown to inhibit arterial thrombosis in wild-type and hypercholesterolemic animal models [Heida, N.M. et al., Abst 14975], while inhibition of coagulation factor IX with RB-006, which potently and rapidly suppressed thrombin generation [Zelenkofske, S.L. et al., Abst 14661], was confirmed feasible pharmacokinetically and pharmacodynamically in patients with acute coronary syndromes undergoing catheterization or percutaneous coronary intervention [Povsic, T.J. et al., Abst 13255]. Real-world data from patients undergoing percutaneous coronary interventions demonstrated the favorable risk-benefit profile of a further anticoagulant, bivalirudin, which was associated with lower risk of bleeding compared to heparin, with or without glycoprotein IIbeta/IIIalpha inhibitors [Bangalore, S. et al., Abst 15708].

Antianginal agents are another chapter within the drug armamentarium for coronary artery disease, and effective improvements in microcirculatory resistance in patients with ST segment-elevated myocardial infarction was demonstrated with intracoronary nicorandil [Kurozumi, Y. et al., Abst 19111], while ranolazine improved angina and myocardial perfusion in women with nonobstructive ischemic coronary artery disease [Mehta, P.K. et al., Abst 16283] and induced transient coronary vasodilatory activity in experimental animals [Nieminen, T. et al., Abst 18539]. Among these agents, ivabradine was shown to reduce heart rate in octogenarians with stable angina, resulting in reduced attack frequency and nitrate consumption [Koester, R. et al., Abst 20934]; adding ivabradine on top of usual care for ST segment-elevated myocardial infarction not only reduced heart rate, but also tended to lower biomarker levels and electrocardiographic indices of ischemia and left ventricular volume [Steg, P.G. et al., Abst 14196]. While additional clinical studies attributed an endothelium-dependent coronary vasodilator activity to intracoronary delivered salbutamol [Puri, R. et al., Abst 14843], in the experimental setting, pentaerythrityl tetranitrate prevented left ventricular dysfunction and dilatation during chronic ischemic heart failure [Widder, J.D. et al., Abst 15407].

Regarding other treatment strategies, negative results were reported from the REVEAL trial, in which epoetin administration after percutaneous coronary intervention for ST segment-elevated myocardial infarction did not reduce infarct size, but increased adverse events [Rao, S.V. et al., Abst 21757], although epoetin showed cardioprotective activity in models of coronary artery occlusion [Yada, T. et al., Abst 13283]. Reductions in coronary artery calcium and adipose tissue were obtained with garlic extract, vitamin B, folate and l-arginine supplementation [Ahmadi, N. et al., Abst 20824] and improvements in arterial stiffness resulted from consumption of cranberry juice [Dohdwala, M.M. et al., Abst 16980].

In the experimental arena, observations related to treatment of coronary artery disease included the preventive effect of sildenafil on left ventricular function and adverse remodeling after myocardial infarction [Pokreisz, P. et al., Abst 21305]. Also as preclinical findings reported during the meeting, an undisclosed small-molecular-weight agonist of the integrin Cd11b/cd18 was shown to inhibit leukocyte migration into and infiltration of hyperplasic tissue after an ischemic injury, preventing neointimal hyperplasia [Maiguel, D. et al., Abst 16106]. Inhibition of neointimal proliferation after bare metal stent implantation in experimental animals was also demonstrated by the chemokine CCR2 receptor blocker CCX-140 [Teramoto, T. et al., Abst 17007], whereas the monocyte chemoattractant protein inhibitor bindarit reduced in-stent restenosis in additional studies [Guglielmotti, A. et al., Abst 11429]. On the other hand, both naproxen and celecoxib improved myocardial perfusion and function in models of hypercholesterolemic chronic myocardial ischemia, mainly by enhancing vasorelaxation [Chu, L.M. et al., Abst 20679], and celecoxib was reported safe in patients implanted with drug-eluting stents, while effective in reducing neointimal hyperplasia without increasing the likelihood of late incomplete stent apposition [Oh, I.Y. et al., Abst 19104].

As a different approach to the treatment of chronic angina, autologous CD34-positive cell therapy improved exercise tolerance and reduced the frequency of angina attacks over one year, with a trend towards reduced major adverse cardiovascular event rates over two years in patients with intractable angina [Losordo, D.W. et al., Abst 15621]. Enhanced cardioprotection by CD34-positive cells was noted after preconditioning with valproate in additional experimental studies [Burba, I. et al., Abst 14311].

Drug-eluting stents

New observations presented during the oral and poster sessions of AHA 2010 confirmed the benefits of sirolimus-, paclitaxel-, zotarolimus-, everolimus-, biolimus- and other drug-eluting stents in a broad range of patient typologies [Federspiel, J.J. et al., Abst 10200; Kamoi, D. et al., Abst 13516; Simsek, C. et al., Abst 14062; Kume, T. et al., Abst 14642; Park, D. et al., Abst 15162; Nakamura, S. et al., Abst 16791; Nakamura, S. et al., Abst 16836; Collet, C. et al., Abst 17960; Mrabet, K. et al., Abst 17662; Serruys, P.W. et al., Abst 17978; Vaquerizo, B. et al., Abst 18272; Hermiller, J. et al., Abst 18405; Chakravarty, T. et al., Abst 19031; Rha, S.W. et al., Abst 19070; Van den Branden, B.J. et al., Abst 20266; Sudhir, K. et al., Abst 20347; Krucoff, M.W. et al., Abst 40469; Sim, D.S. et al., Abst 20769; Vasaiwala, S. et al., Abst 20948; Vasaiwala, S. et al., Abst 20981; Kaul, S. et al., Abst 21035; Buszman, P.E. et al., Abst 21575], with initial studies in humans also demonstrating potential for novel bevacizumab-eluting stents [Toutouzas, K. et al., Abst 18198]. However, concerns remain regarding the risk of stent thrombosis associated with drug-eluting stents, and particularly sirolimus-eluting stents [Rha, S.W. et al., Abst 18947]. Comparisons between individual stents indicated similar outcomes with zotarolimus- and paclitaxel-eluting stents [Kim, W.J. et al., Abst 15245], but higher major adverse cardiovascular event rates with both compared to sirolimus-eluting stents in patients with diabetes [Park, D. et al., Abst 15221], whereas the latter showed no differences compared to everolimus-eluting stent in patients with bifurcation lesions [Pan, M. et al., Abst 16000] and no differences were apparent when comparing everolimus- to zotarolimus-eluting stents in de-novo coronary artery disease patients [Mahmoudi, M. et al., Abst 12754] or zotarolimus- to sirolimus-eluting stents on death, myocardial infarction and thrombosis despite the higher incidence of target lesion revascularization with the former [Zhang, F. et al., Abst 20754]. Direct comparisons of everolimus- and paclitaxel-eluting stents suggested lower risk for stent thrombosis and better protection against adverse outcomes with the former, especially in the nondiabetic population, without or with less difference when used in patients with diabetes [Stone, G.W. et al., Abst 17024; Kirtane, A. et al., Abst 17174; Kodumuri, V.K. et al., Abst 21257] but lower overall stent thrombosis rates and better overall safety and efficacy with everolimus-eluting stents [Kedhi, E. et al., Abst 14593; Zhang, F. et al., Abst 20653]. However, the superiority of sirolimus- over paclitaxel-eluting stents in patients with diabetes was attenuated in a comparative study between two and four years after implantation, with comparable long-term outcomes [Kim, H.S. et al., Abst 10234]. Regarding novel stents, a paclitaxel-eluting balloon catheter proved superior to conventional angioplasty in patients with sirolimus-eluting stent restenosis [Habara, S. et al., Abst 13689], while a bioabsorbable salicylate-based sirolimus-eluting stent was tested positive in experimental animal models [Matsumoto, D. et al., Abst 10891], although a meta-analysis of clinical trials could not identify differences in stent thrombosis rates comparing bioabsorbable versus persistent polymer-based drug-eluting stents [Salinas, P. et al., Abst 11322]. A novel polymer-free ciglitazone-eluting stent was also described that prevented neointimal proliferation more effectively than sirolimus-eluting stents in experimental studies [Poerner, T.C. et al., Abst 17076]; initial experience in humans failed to demonstrate the desired efficacy with a polymer-free paclitaxel-eluting stent [de Ribamar Costa, J. et al., Abst 17924]. In addition, novel chromium-cobalt drug-eluting stents were shown to reduce morbidity and mortality compared to older drug-eluting stents in a meta-analysis [Salinas, P. et al., Abst 18083]. As complementary information, it should be added that oral sirolimus therapy attenuated myocardial injuries in diabetes [Maalouf, R. et al., Abst 21398], and reduced myocardial infarction and inhibited cardiomyocyte apoptosis during experimental ischemia/reperfusion in experimental animal models [Das, A. et al., Abst 16207].

 

CARDIAC ARRHYTHMIA

Regarding treatment of supraventricular tachyarrhythmias, with good tolerability, ivabradine was able to correct inappropriate sinus tachycardia in a series of patients, offering an effective therapeutic alternative [Benezet-Mazuecos, J. et al., Abst 9361], being comparable to metoprolol on resting heart rate in such patients, although with a more favorable effect on heart rate during exercise or usual daily activity [Ptaszynski, P.A. et al., Abst 19221] (Fig. 4).

Fig. 4. Change in heart rate at rest or during exercise in patients with inappropriate sinus tachycardia treated with ivabradine or metoprolol [Ptaszynski, P.A., Abst 19221].

 

A comparative study specifically assessed the treatment of hydrops-related fetal atrial fibrillation/supraventricular arrhythmia, which was associated with low morbidity and mortality in spite of modest treatment success rates. However, transplacental flecainide was superior to sotalol for converting to sinus rate [Jaeggi, E.T. et al., Abst 20644], but high-dose sotalol remained effective in the treatment of refractory supraventricular tachyarrhythmia in neonates and infants [Knudson, J.D. et al., Abst 8868].

In the experimental domain, chloroquine was shown to terminate stretch-induced atrial fibrillation possibly through an effect on inward-rectifier potassium channels [Filgueiras-Rama, D. et al., Abst 10988]. In addition, trichostatin A, nicotinamide, tubacin and other histone deacetylase and sirtuin inhibitors protected against contractile dysfunction during rapid atrial pacing [Meijering, R. et al., Abst 12938], while SRT-1720, a selective sirtuin SIRT1 activator, improved age-related endothelial dysfunction in animals [Gano, L.B. et al., Abst 10813]. In addition, increased activity on atrial refractoriness prolongation by the I-Kur blocker BMS-394136 was shown during acute atrial ischemia [Xing, D. et al., Abst 12964].

In the context of atrial fibrillation prevention, prescription omega 3 polyunsaturated fatty acid ester supplementation had no benefit in the prevention of recurrent atrial fibrillation in patients free from structural cardiopathy, according to a placebo-controlled study [Kowey, P.R. et al., Abst 21811].

Anticoagulation to prevent stroke and embolism is an essential part of the management of atrial fibrillation, although exploratory naturalistic analysis suggested underuse of discharge warfarin [Lopes, R.D. et al., Abst 12640]. One of the major stories during this year's meeting was the presentation of the ROCKET AF trial as a late-breaking clinical trial. The study demonstrated the noninferiority of rivaroxaban versus warfarin, rather the superiority of the former in an on-treatment analysis, suggesting a valid alternative for moderate- to high-risk patients that was as safe and well tolerated as warfarin but associated with a lower rate of intracerebral hemorrhage and fatal bleeding [Patel, M.R., Abst 21839] (Fig. 5). Additional studies concluded on the cost-effectiveness of dabigatran for preventing stroke in patients with atrial fibrillation at high risk for either bleeding or stroke [Shah, S.V. et al., Abst 16179], the agent also showing an effect against atherothrombotic disease progression in experimental animal models [Borisoff, J.I. et al., Abst 19384]. As complementary information, anticoagulation with warfarin did not worsen outcomes during catheter ablation for atrial fibrillation in patients in cardiac tamponade [Latchamsetty, R. et al., Abst 12498].

Fig. 5. Stroke and non-central nervous system embolism rates in patients treated with rivaroxaban or warfarin (intention-to-treat and per-protocol analyses separately) [Patel, M.R., Abst 21839].

Ventricular tachyarrhythmias are a second important chapter in the context of cardiac arrhythmia discussed during this year's meeting. The b1-selective adrenoceptor blocker landiolol proved effective for treating tachyarrhythmia in patients with severe infections [Okajima, M. et al., Abst 14796]. On the other hand, a study in models of ischemia/reperfusion demonstrated the efficacy of ranolazine for treating ventricular arrhythmia as effectively as sotalol and lidocaine [Kloner, R.A. et al., Abst 12110]. Further experimental studies indicated potential for the gap junction modulator ZP-1210 for attenuating cardiac conduction slowing during metabolic stress [Ng, F.S. et al., Abst 13633].

 

HYPERCHOLESTEROLEMIA AND ATHEROSCLEROSIS

Although largely underused, at least in the diabetic population [Zhang, Q. et al., Abst 18546], statins are effective LDL-cholesterol-lowering drugs that have additional benefits on the cardiovascular risk profile. Among these agents, pravastatin was shown to reduce non-HDL-cholesterol levels regardless of the presence of diabetes, which translated into marked benefits on cardiovascular morbidity and mortality, even in diabetic subjects [Sone, H. et al., Abst 14143]. Furthermore, pravastatin synergistically enhanced cardiomyocyte differentiation in experimental ischemic conditions when combined with intracoronary allogeneic mesenchymal stem cell injection [Suzuki, G. et al., Abst 8791]. On the contrary, chronic use of statins, and specifically pravastatin, has been suggested to increase the risk of new-onset diabetes, although insight into the MEGA study indicated the effect to be dependent on poor adherence to dietary recommendations during statin therapy, and to be triggered by high body mass index, hypertriglyceridemia and male gender [Mizuno, K. et al., Abst 14146]. In that context, additional data also indicated the need for preventive management strategies beyond lipid control in patients receiving pravastatin if the objective is not lowering LDL-cholesterol, but maintaining heart health [Nakamura, H. et al., Abst 14898].

Besides lowering LDL-cholesterol levels, statins, and at least atorvastatin, have been shown to lower C-reactive protein levels and to stabilize atherosclerotic plaques, with reduced uptake of [18F]-FDG [Ishii, H. et al., Abst 11090], although analyses from the ASCOT trial concluded that on-treatment or baseline levels of the marker did not correlate with reduction in cardiovascular risk beyond LDL-cholesterol reduction during treatment with atorvastatin [Sever, P.S. et al., Abst 21685]. Statins were also demonstrated to lower cardiac events after an acute myocardial infarction in patients with high lipoprotein(a) levels [Ikenaga, H. et al., Abst 13258]. Pleiotropic lipid-independent effects of statins were also discussed, including improvements in atherosclerotic plaque composition and histology with atorvastatin [Lee, S.W. et al., Abst 13301] and prevention of nitroglycerin-induced endothelial dysfunction [Liuni, A. et al., Abst 19498] and amelioration of endothelial function and inflammation [Brili, S. et al., Abst 14938] brought about by atorvastatin after successful reparation of aorta coarctation. Atorvastatin was furthermore noted to improve the myocardial redox state when administered for three days before coronary artery bypass graft surgery, which may explain the benefit demonstrated on postoperative complications [Demosthenous, M. et al., Abst 17030]. On the contrary, high-dose atorvastatin did not prevent atial fibrillation in patients with a history of stroke or transient ischemic attacks [Schwartz, G.G. et al., Abst 10897]. In addition, treatment with atorvasatin was associated with upregulation of intestinal Niemann-Pick C1-like-1 protein expression, a protein that plays an important role in cholesterol absorption [Tremblay, A. et al., Abst 14273].

A novel nitric oxide-donating derivative of atorvastatin, NCX-6560, proved as effective as atorvastatin in lowering LDL-cholesterol, even at lower total exposure of the active form of the drug or its active metabolites, suggesting a better safety profile [Djian, J.P. et al., Abst 14267]; the novel agent showed effective antiatherogenic activity in experimental animal models [Moni, S. et al., Abst 15758].

While modeling insight using Bayesian number needed to treat corroborated the potential of rosuvastatin to prevent venous thromboembolism in patients with raised C-reactive protein levels [Lang, C. et al., Abst 20862], additional pleiotropic activity was also described with the statin, which in an experimental study was shown to improve the effectiveness of transplanted mesenchymal stem cells in the infarcted myocardium by enhancing the activation of Janus kinase-2- and signal transduced and activator of transcription-3-dependent pathways [Xu, H. et al., Abst 11416]. However, while both pravastatin and rosuvastatin improved the lipoprotein profile and endothelium-dependent vasodilatation in patients with hypercholesterolemia, rosuvastatin significantly increased insulin and hemoglobin A1c levels and decreased adiponectin levels and insulin sensitivity, whereas pravastatin had the opposite effect [Koh, K.K. et al., Abst 15351]. In relation to rosuvastatin, it should also be mentioned that increased steady-state exposure was noted in patients carrying the breast cancer resistance protein (BRCP) gene c.421C>A single nucleotide polymorphic variant [Romaine, S.P. et al., Abst 18356].

Only experimental data were reported during the meeting related to pitavastatin, which suppressed apolipoprotein CIII-induced endothelial cell activation and monocyte adhesion [Zheng, C. et al., Abst 18070], stabilized atherosclerotic plaques by enhancing nitric oxide-dependent antiapoptotic mechanisms and, after nanoparticle-mediated selective monocyte delivery, prevented aortic aneurisms in experimental models of hypercholesterolemic atherogenesis [Katsuki, S. et al., 13315].

In addition to its lipid-improving effects, which were predicted by the presence of hypertriglyceridemia and low HDL-cholesterol levels, according to the ACCORD lipid trial [Elam, M.B. et al., Abst 19724], and resulted in a benefit on cardiovascular event rates even in the absence of an overall effect on lipids when added to a statin [Lovato, L.C. et al., Abst 20114], use of fenofibrate in patients with type 2 diabetes prevented and reversed established peripheral neuropathy over the long term [Rajamani, K. et al., Abst 18987]. On the other hand, analysis of predictors of cardiovascular morbidity and mortality in the FIELD trial demonstrated the benefit of fenofibrate on some, but not all indices of oxidative stress and inflammation, with significant decreases in oxidized LDL, myeloperoxidase, interleukin-6 and soluble E-selectin and increases in low-molecular-weight fluorophores, soluble intercellular and vascular cell adhesion molecules and leptin [Keech, A.C. et al., Abst 18865]. Besides fenofibrate, but without novel clinical and therapeutic information being reported, gemfibrozil was characterized as a soluble guanylate cyclase activator adding putative vasodilatory activity to the known lipid-lowering activity of this particular fibrate [Martin, E. et al., Abst 17467].

By blocking cholesterol absorption and fatty acid transport protein-4-mediated intracellular long-chain fatty acid trafficking [Masuda, D. et al., Abst 13867], ezetimibe has been studied extensively in combination with statins for magnifying the lipid-lowering effect of the latter, but in experimental animal models was also demonstrated to directly suppress dietary atherogenesis by oxidized cholesterol products [Sato, K. et al., Abst 14142]. In fact, while low-dose statin with ezetimibe resulted in lipidic benefits comparable to high-dose statin monotherapy, the combination with ezetimibe resulted in increased antiinflammatory activity and greater inhibition of platelet reactivity that deserve further analysis and attention [Pesaro, A.E. et al., Abst 11388]. Furthermore, through inhibition of Nieman-Pick protein NPC1L1, ezetimibe prevented oxidized cholesterol-related plaque destabilization and rupture [Sato, K. et al., Abst 14184].

Despite its benefits on HDL-cholesterol and triglycerides, comparable to those obtained with fenofibrate but complemented by significant decreases in apolipoprotein A3 albeit less effect on LDL-cholesterol and apolipopoprotein B [Franceschini, G. et al., Abst 16679] (Fig. 6), and its benefits on proinflammatory cytokine production by macrophages, as demonstrated in the experimental laboratory [Lipszyc, P.S. et al., Abst 15978], treatment of patients with normal glucose levels with niacin increased the risk of developing impaired fasting glucose, but not that of developing diabetes [Munoz, L. et al., Abst 20856].

Fig. 6. Change in lipoprotein and lipid levels after 6 weeks of treatment with extended-release niacin or fenofibrate [Franceschini, G. et al., Abst 16679].

Colesevelam is a further lipid-lowering pharmacological strategy which, in combination with metformin, improved the overall atherogenic profile, and especially LDL-cholesterol levels and LDL particle counts, in patients with early type 2 diabetes [Goldberg, R.B. et al., Abst 13046] (Fig. 7).

Fig. 7. Change in LDL, VLDL and HDL particle concentrations after 16 weeks of adding colesevelam or placebo to metformin [Goldberg, R.B. et al., Abst 13046].

Cholesteryl ester transfer protein inhibition has been tested as a pharmacological approach for increasing HDL- and decreasing LDL-cholesterol levels; the validity of this strategy was demonstrated with the novel agent DRL-17822 in healthy volunteers [Dasari, M. et al., Abst 13981] and with anacetrapib, which markedly improved HDL-, LDL- and non-HDL-cholesterol and lipoprotein(a) levels with an acceptable tolerability profile, in patients at risk for coronary heart disease [Cannon, C.P. et al., Abst 21824] (Fig. 8). Preclinical studies also corroborated the benefits of anacetrapib on HDL-cholesterol levels and sterol excretion [Johns, D.G. et al., Abst 18072], whereas ex vivo studies with dalcetrapib, a further cholesteryl ester transfer protein inhibitor that in experimental animals also increased macrophage reverse cholesterol transport [Okamoto, H. et al., Abst 23016], indicated no effect on pre-beta1-HDL formation by cholesteryl ester transfer protein, suggesting no detrimental effect on the atheroprotective effect of the latter [Niesor, E.J. et al., Abst 19187]. Acyl-cholesterol:cholesterol acyltransferase-2 inhibitors have also been tested as a pharmacological strategy for improving cholesterol levels and preventing atherosclerosis, and favorable experimental results were reported during the meeting with selective inhibitors such as pyripyropene A [Ohshiro, T. et al., Abst 19334].

Fig. 8. Change in LDL- and HDL-cholesterol levels after 76 weeks of treatment with anacetrapib or placebo [Cannon, C.P. et al., Abst 21824].

 

Lipidic benefits in patients with heterozygous familial hypercholesterolemia and coronary artery disease were obtained with mipomersen, which reduced total LDL levels while decreasing small and increasing large LDL particle numbers [Cromwell, W. et al., Abst 19931]. In addition, the soluble phospholipase A2 inhibitor varespladib improved inflammatory responses after acute coronary syndrome to a greater extent in diabetic compared to nondiabetic subjects [Rosenson, R.S. et al., Abst 11176].

Clinical trial data also supported the use of RVX-208, an apolipoprotein A1 synthesis inducer that improved apolipoprotein A1, HDL-cholesterol and C-reactive protein levels in patients with stable coronary artery disease [Nicholls, S.J. et al., Abst 21774] (Fig. 9), with effects of the agent on HDL and apolipoprotein A1 corroborated in experimental animal studies [Jahagirdar, R. et al., Abst 18435]. Meanwhile, gene therapy with alipogene tiparvovec was shown to normalize postprandial low-density chylomicron clearance and the triglyceride-rich lipoprotein profile in patients with lipoprotein lipase deficiency [Carpentier, A. et al., Abst 16900; Gaudet, D. et al., Abst 21355].

Fig. 9. Change in lipid levels after 12 weeks of treatment with RVX-208 or placebo [Nicholls, S.J. et al., Abst 21774].

In addition to clinical trials in patients with dyslipidemia, studies in healthy volunteers confirmed the pharmacodynamic activity of the proprotein convertase subtilisin kexin 9 monoclonal antibody SAR-236553 in healthy volunteers, resulting in decreases in LDL-cholesterol and apolipoprotein B without dose-limiting toxicity [Swergold, G. et al., Abst 23251].

In addition to pharmacotherapy, supplementation with eicosapentaenoic acid reduced small and very small HDL, dense LDL levels and pre-beta1 HDL particle levels without an impact on LDL- or HDL-cholesterol levels in patients on atorvastatin, offering additional antiatherosclerotic benefits [Nohara, A. et al., Abst 17785]. Eicosapentaenoic acid supplementation favorably modified the atherogenic lipid profile [Schaefer, E.J. et al., Abst 20007] and also induced plaque regression [Nakajima, K. et al., Abst 14983] and suppressed ischemia-induced ventricular fibrillation and improved myocardial function after ischemia/reperfusion [Tsuburaya, R. et al., Abst 13557; Gao, J.Y. et al., Abst 16377] in experimental animals, while supplementation with omega 3 polyunsaturated fatty acids also improved arterial wall function in healthy smokers [Zaromitidou, M. et al., Abst 17069].

Turning to preclinical findings, in experimental animal models of diabetes, the apolipoprotein A1 mimetic peptide D-4F prevented atherosclerosis while also reducing plaque inflammation [Morgantini, C. et al., Abst 16088], whereas the mimetic L-4F inhibited the inflammatory cascade in blood by blocking endotoxin binding to granulocytes, monocytes and lymphocytes [Sharifov, O.F. et al., Abst 16973]. Improved macrophage reverse cholesterol transport and increased pre-beta-HDL levels and cholesterol efflux from peripheral tissues in in vitro and in vivo studies were demonstrated with a further apolipoprotein A1 mimetic peptide coded FAMP [Uehara, Y. et al., Abst 12493; Tanigawa, H. et al., Abst 12500]. Benefits on total cholesterol levels through enhanced fecal excretion were demonstrated in additional animal models with the dual toll-like receptor-7/9 blocker IMO-3100 [Zhu, F.G. et al., Abst 11182]. On the other hand, the oral tyrosine kinase inhibitor fostamatinib reduced inflammation and atherogenesis in low density lipoprotein receptor-deficient experimental animal models [Hilgendorf, I. et al., Abst 12079], whereas inhibition of matrix metalloproteinase-13 by an undisclosed oral inhibitor increased collagen content of atherosclerosis plaques, suggesting potential for plaque stabilization and prevention of rupture [Quillard, T. et al., Abst 13288]. Direct antiatherosclerotic activity also resulted from the anti-interleukin-1beta monoclonal antibody XOMA-052 [Bhaskar, V. et al., Abst 12105], a recombinant truncated Pseudomonas aeruginosa exotoxin A acting against folate receptor beta in macrophages [Furusho, Y. et al., Abst 12787], the adenosine A2B agonist BAY-60-6583, which stabilized atherosclerotic plaques by increasing collagen content and protected against vascular injuries [Bot, I. et al., Abst 15247], and the A2A receptor agonist ATL-313, which also showed potent antiatherogenic effects through an effect on cholesterol transport [Voloshyna, I. et al., Abst 10260].

OBESITY

Obesity is a major driver of cardiovascular risk, and as intensive weight loss combined with exercise and diet has been associated with overall cardiovascular benefits [Ahmadi, N. et al., Abst 21230], therapies have been designed to improve body weight independently of the treatments for dyslipidemia and hyperglycemia. Among such pharmacological strategies, the use of a combination of phentermine and topiramate was noted to reduce the 10-year Reynolds' Risk Score in obese men and women, paralleling on-treatment body weight loss [Davidson, M.H. et al., Abst 13009] (Fig. 10).

Fig. 10. Change in the 10-year Reynolds' Risk Score after 56 weeks of treatment with phentermine/topiramate or placebo in obese men and women [Davidson, M.H. et al., Abst 13009].

DIABETES

Neither nateglinide nor voglibose had any further antiatherosclerotic benefits when added to lifestyle intervention in patients with early-stage diabetes [Kataoka, Y. et al., Abst 13499].

The favorable impact of pioglitazone on LDL particle size and composition translated into prevention of atherosclerosis progression and reduced plaque inflammation in patients with type 2 diabetes [Uno, K. et al., Abst 21403; Mizoguchi, M. et al., Abst 16505]; the thiazolidinedione also increased macrophage cholesterol efflux by increasing the expression of ATP-binding cassette transporters ABCA1 and ABCG1 [Ozasa, H. et al., Abst 15463] and, in an endothelial cell-selective nanoparticle formulation improved arteriogenesis and angiogenesis during peripheral arterial ischemia [Nagahama, R. et al., Abst 14130]. However, experimental studies comparing pioglitazone to glibenclamide indicated an adverse effect of the thiazolidinedione on conduction slowing in the ischemic myocardium, resulting in enhanced ischemic ventricular fibrillation and higher likelihood of death [Sarraf, M. et al., Abst 12678]. With a different but related approach, the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar decreased lipolysis and proinflammatory cytokine production in inflamed adipose tissue, contributing to prevention of insulin resistance and cardiovascular risk that were comparable to the effects obtained by pioglitazone and fenofibrate [Dzyakanchuk, A. et al., Abst 10854]. On the contrary, although currently withdrawn, results with rosiglitazone indicated suppression of vascular tissue factor expression, which may indicate the mechanism for the negative cardiovascular safety of the agent [Park, J.B. et al., Abst 14409]. In relation to that, both thiazolidinediones were shown to upregulate insulin-like growth factor-1 receptor expression by potentiating internal ribosomal entry site-dependent translation, an effect that may contribute to contractile protein expression and myocyte survival [Higashi, Y. et al., Abst 14600], whereas specific results with pioglitazone indicated attenuation of inflammatory atrial fibrosis and vulnerability to fibrillation in overload conditions [Takahashi, N. et al., Abst 10983].

Compared to alternative therapies such as sulfonylureas, thiazolidinediones and insulin, treatment of type 2 diabetes with exenatide brought about a decrease in the risk of cardiovascular events, although no differences were apparent comparing exenatide to metformin or sitagliptin [Hoogwerf, B.J. et al., Abst 13242]. A related compound, liraglutide, showed a favorable cardiovascular safety profile in a pooled analysis of clinical trials [Marso, S.P. et al., Abst 16904] and improved inflammation and cardiac function in animal models of obesity [Noyan-Ashraf, M.H. et al., Abst 19477].

Sitagliptin effectively lowered postprandial triglyceride-rich lipoprotein levels in patients with diabetes, indicating a preventive on atherosclerotic cardiovascular disease [Tremblay, A.J. et al., Abst 14242]. Furthermore, sitagliptin also improved cardiorenal function in experimental models of heart failure [Mc Entee, K. et al., Abst 15196], while desfluorositagliptin improved endothelial function and reduced atherogenesis in atherosclerosis-prone experimental models [Matsubara, J. et al., Abst 14739]. Without hypoglycemia, vildagliptin also improved survival in experimental models of pressure overload-triggered heart failure [Takahashi, A. et al., Abst 19013], whereas alogliptin reduced atherosclerotic disease burden through effects on blood pressure and inflammatory monocyte activation [Shah, Z. et al., Abst 21648] and attenuated adipose tissue inflammation through inhibition of adenosine-mediated monocyte chemotaxis [Shah, Z. et al., Abst 21652].

On the whole, beyond improving glycemia, incretin-based therapies, including the glycogen-like peptide-1 analog liraglutide and the dipeptidylpeptidase-IV inhibitor PKF-275-055, reduced atherosclerosis by suppressing foam cell formation [Watanabe, T. et al., Abst 10278].

Studies in experimental animal models indicated benefits of sitagliptin on diabetic myocardial hypertrophy and fibrosis, resulting in improved diastolic function [Lorenzo, O. et al., Abst 10852].

Additional studies in experimental models of diabetes indicated prevention against diabetic diastolic dysfunction upon treatment with tadalafil [Koka, S. et al., Abst 16206], improved myocardial function and attenuated fibrosis after treatment with fasudil and vardenafil [Ameenuddin, S. et al., Abst 13153], prevention of diastolic dysfunction and cardiomyocyte hypertrophy by supplementation with ubidecarenone [Huynh, K. et al., Abst 14164], potentiation of the cardiovascular benefits of aspirin by treatment with minocycline [Bhatt, L.K. et al., Abst 12934] and improvements in nitric oxide function in the diabetic mesenteric artery by 3',4'-dihydroxyflavonol [Woodman, O.L. et al., Abst 12132].

HYPERTENSION

Besides lowering blood pressure, calcium channel blockers exert a number of additional benefits on the cardiovascular system. In that sense, mechanistic observations with diltiazem during diabetic ventricular and supraventricular tachycardia indicated decreased calcium spark frequency but increased sarcoplasmic reticulum calcium load and transient peak amplitude, suggesting attenuated arrhythmogenesis [Lacombe, V.A. et al., Abst 20958], whereas nifedipine suppressed coronary vasoconstriction and inflammation after paclitaxel-eluting stent implantation [Tsuburaya, R. et al., Abst 11317]. However, advanced-generation drugs may have advantages, and a meta-analysis comparing benipidine to nifedipine, amlodipine and diltiazem in patients with vasospastic angina indicated lower major adverse cardiovascular event rates with the former, while the frequency of angina attacks was lower with benidipine and nifedipine compared to the remaining two calcium channel blockers [Nishigaki, K. et al., Abst 14717]. Furthermore, additional data indicated that benidipine was able to reverse coronary vasomotor dysfunction during treatment with renin-angiotensin system-blocking drugs [Murakami, T. et al., Abst 13614].

Besides improving blood pressure and the overall cardiovascular risk profile, angiotensin-converting enzyme inhibitors were related to a decrease in overall mortality regardless of the presence or absence of obstructive coronary artery disease, although the benefit was greater in patients with nonobstructive disease [Manfrini, O. et al., Abst 20664]. Mechanistically, enalapril prevented monocyte release from the spleen during a myocardial infarction [Leuschner, F. et al., Abst 17181], while imidapril inhibited matrix metalloproteinase-9 activity more efficiently than losartan, resulting in benefits on left ventricular ejection fraction and brain-derived natriuretic peptide levels [Hoshiga, M. et al., Abst 12141].

In addition to lowering blood pressure, olmesartan improved long-term atherosclerosis outcomes over a three-year follow-up after percutaneous coronary intervention, with increased survival paralleling intravascular ultrasound imaging findings of plaque volume and stenosis [Hirohata, A. et al., Abst 8983] (Fig. 11) and, at an experimental level, inhibited atrial structural and electrical remodeling related to atrial fibrillation associated to chronic heart failure [Hirose, M. et al., Abst 10067]. Moreover, in preclinical animal models blockade of the angiotensin AT1 receptor with olmesartan in the prepubertal age exerted long-term benefits on hypertension and renal injury [Tamura, K. et al., Abst 14881], while also improving collateral coronary vasodilatation and diabetic microvascular endothelial dysfunction [Yada, T. et al., Abst 10218]. Furthermore, a beneficial effect of olmesartan on the myocardial intercalated discs was noted, which could explain the antiarrhythmogenic activity of the agent in heart failure [Yoshida, M. et al., Abst 10228]. In addition to other demonstrated benefits, angiotensin receptor blockers also reduced endothelial dysfunction and vasoconstriction after drug-eluting stent implantation compared to calcium channel blockers [Terashima, M. et al., Abst 15972] while, in the case of losartan, abrupt discontinuation increased transforming growth factor levels and accelerated aortic root growth in experimental models of Marfan's syndrome [Schoenhoff, F.S. et al., Abst 14479], the agent, like pravastatin, equipotently attenuating aortic root dilatation in further experimental models of the disease [McLoughlin, D. et al., Abst 21638]. Also in the experimental domain, candesartan prevented pressure overload-induced adverse cardiac electrical remodeling [Chang, G.J. et al., Abst 14304], while telmisartan protected endothelial cells against oxidative injury by enhancing mitochondrial biogenesis through an effect on AMP-activated protein kinase [Nozaki, T. et al., Abst 12547].

Fig. 11. Three-year major adverse cardio- and cerebrovascular event (MACCE) rates, including cardiovascular (CV) death, myocardial infarction (MI) and unstable angina (UA), in patients treated with olmesartan or alternative therapies [Hirohata, A. et al., Abst 8983].

A further strategy for the treatment of hypertension, the direct renin inhibitor aliskiren also offered additional benefits on postischemic adverse remodeling [Benedetto, U. et al., Abst 20766] that were magnified in patients with diabetes [Shah, A. et al., Abst 19414]. Furthermore, the agent magnified the benefits of angiotensin receptor blockade on cardiovascular injuries during hypertension, offering potential for a combination of aliskiren and valsartan [Yamamoto, E. et al., Abst 21085].

In the preclinical arena, central antihypertensive activity and prevention of cardiorenal injuries resulted from treatment with the chemokine CXCR4 receptor blocker AMD-3465 [Chu, P.Y. et al., Abst 15115].

Despite the effectiveness of single antihypertensive drugs, most patients require combination therapies to effectively control blood pressure. Comparing individual dual strategies, benazepril/amlodipine proved superior to benazepril/hydro­chloro­thiazide in preventing cardiovascular events, regardless of the presence of established coronary artery disease [Pitt, B. et al., Abst 20076]. In the context of fixed-drug combinations, a polypill containing atenolol, ramipril and hydrochlorothiazide plus the lipid-lowering agent simvastatin and the antiplatelet drug aspirin has been developed, which includes drugs already commonly used by patients with a broad range of cardiovascular risk conditions, including diabetes, established coronary artery disease, cerebrovascular disease and peripheral arterial disease [Lafeber, M. et al., Abst 14078].

PULMONARY HYPERTENSION

Although clinical activity was not discussed during the meeting, an improved injectable formulation of epoprostenol showed pharmacokinetic feasibility in healthy subjects [Galitz, L. et al., Abst 21458], whereas use of infusional epoprostenol in patients with hereditary pulmonary hypertension carried a risk of hyperthyroidism [Funasako, M. et al., Abst 19627].

In vitro observations in airway smooth muscle cells isolated from patients with chronic thromboembolic pulmonary hypertension demonstrated an antiproliferative effect for bosentan [Ogawa, A. et al., Abst 16380]. In addition, imatinib was also noted to inhibit proliferation and induce apoptosis of pulmonary artery smooth muscle cells from patients with idiopathic pulmonary hypertension [Nakamura, K. et al., Abst 13830].

In the preclinical setting, effects in models of monocrotaline-induced pulmonary hypertension suggestive of clinical usefulness were reported with the endothelin-1 downmodulating 4-aminobenzoic acid derivative aminaftone [Fumagalli, F. et al., Abst 15583], the Janus kinase inhibitor CYT-387 [Zisman, L.S. et al., Abst 8785] and prasterone [Meloche, J. et al., Abst 17741]. In addition, genistein rescued severely impaired right ventricular function in experimental animals with severe pulmonary hypertension, resulting in decreases in intraventricular pressure and lung weight and reversal of right ventricular hypertrophy [Matori, H. et al., Abst 18581].

PERIPHERAL ARTERIAL DISEASE

Treatment with beta-blockers was well tolerated and improved walking distance in patients with peripheral arterial disease resulting in intermittent claudication, although compared to metoprolol, only nebivolol also significantly improved the pain-free walking distance [Espinola-Klein, C. et al., Abst 14441] (Fig. 12).

Fig. 12. Change in the absolute and initial (pain-free) claudication distance in patients treated with nebivolol or metoprolol [Espinola-Klein, C. et al., Abst 14441].

On the other hand, despite prior findings from previous studies, a late-breaking clinical trial presented during this year's AHA's scientific sessions demonstrated no improvement in amputation-free survival in patients with critical limb ischemia receiving gene therapy with NV1FGF compared to placebo, regardless of the presence of diabetes or other risk characteristics [Hiatt, W.R. et al., Abst 21790].

Regarding adjuvant therapies, cilostazol proved effective for reducing the likelihood of restenosis after stenting for femoropopliteal arterial disease [Soga, Y. et al., Abst 13541].

CARDIAC SURGERY

Miscellaneous information on adjuvant pharmacotherapy in patients undergoing cardiac surgery including a report on the effect of dexmedetomidine in reducing the incidence of supraventricular and ventricular tachyarrhythmia [Chrysostomou, C. et al., Abst 10442]. In addition, colchicine was found safe and effective for preventing postpericardiotomy syndrome and its complications following cardiac surgery [Imazio, M. et al., Abst 18395]. On the other hand, use of statins was associated with a decreased risk of acute kidney injury during cardiac surgery [Mithani, S. et al., Abst 9039].

A specific issue related to cardiac surgery is anticoagulation after valve replacement, in which context general underuse of warfarin was reported, despite the demonstrated benefit of adding warfarin to aspirin in terms of improving survival and reducing ischemic events [Brennan, J.M. et al., Abst 16782].

HEART TRANSPLANTATION

Scarce information on supportive pharmacotherapy in the setting of heart transplantation included a study that demonstrated prevention of myocardial remodeling, scarring and fibrosis in patients receiving everolimus [Hiemann, N.E. et al., Abst 13653].

CONGENITAL CARDIAC DISEASE

Concomitant use of atenolol or propranolol and losartan attenuated or prevented aortic root dilatation in patients with Marfan's syndrome more effectively than beta-blockade alone [Chiu, H.H. et al., Abst 21342]. On the other hand, adding clopidogrel to aspirin in young infants undergoing systemic to pulmonary artery shunt to relieve cyanogic congenital heart disease did not further reduce mortality or morbidity [Wessel, D.L. et al., Abst 19459].

MISCELLANEOUS

Treatment of HIV infection in patients with cardiovascular disease with abacavir resulted in an increased risk of of cardiovascular events over the long term [Aziz, E.F. et al., Abst 21178].

The cardiotoxicity of trastuzumab was mediated, at least in part, by impairment of resident cardiac stem cells [Barth, A.S. et al., Abst 18574].

Use of nonsteroidal antiinflammatory agents in patients with coronary artery disease resulted in an increased risk of major adverse cardiovascular events [Bavry, A.A. et al., Abst 12424].

The fatty acid oxidase inhibitor CVT-4325 abrogated the benefit of intralipid for rescuing bupivacaine cardiotoxicity in experimental animals [Partownavid, P. et al., Abst 20545].

Although reliable and as useful as dipyridamole for stress imaging [Harrison, E. et al., Abst 17832], regadenoson for vasodilatation during symptom-limited exercise stress was well tolerated, but resulted in changes in systolic blood pressure not noted at rest [Thompson, R.C. et al., Abst 20926]. The agent was reported safe in patients with chronic hepatic failure [Aljaroudi, W. et al., Abst 13151], and was found useful for detecting relevant coronary artery disease in intermediate-risk patients [Porter, T.R. et al., Abst 10419].

Acetylcysteine did not reduce the risk of contrast-induced nephropathy compared to placebo in a trial including at-risk patients undergoing intravascular angiography [Berwanger, O., Abst 21843], but a combination of acetylcysteine and ascorbate did offer protection against contrast-induced nephropathy in high-risk patients with acute coronary syndrome undergoing coronary interventions [Grygier, M. et al., Abst 12743], and ascorbate prevented the rise in soluble CD40 ligand during percutaneous coronary interventions [Pignatelli, P. et al., Abst 15021].

Endothelial dysfunction caused by ciclosporin was related to inhibition of translocation of the nuclear factor Nrf2 in endothelial cells [Ghashghai, A. et al., Abst 13883].

Administration of atomoxetine to patients with postural tachycardia syndrome increased standing heart rate and worsened symptoms without an impact on systolic blood pressure [Raj, S.R. et al., Abst 16180].

By inhibiting pyruvate dehydrogenase kinase, dichloroacetate reverted impaired ventricular function and glucose oxidation in the hypertrophic right ventricle [Sidhu, V.K. et al., Abst 20289].

In experimental animal models, dehydroascorbate was shown to attenuate septic cardiomyopathy, improving contractile dysfunction and the chemokine expression pattern during exposure to endotoxin [Fisher, B.J. et al., Abst 13053].

Administration of recombinant activated coagulation factor VII was able to counteract life-threatening bleeding during fondaparinux therapy, with clinical cessation of bleeding in most patients [Schiele, F. et al., Abst 15195]. Along with that, the heparin antagonist PMX-60056 rapidly and completely reverted the anticoagulant effect of heparin in healthy volunteers [McAllister, R.E. et al., Abst 17322], and also reverted the effects of tinzaparin [McAllister, R.E. et al., Abst 17226].

Intrapericardial cisplatin effectively prevented recurrences of malignant pericardial effusion, with greater effectiveness in lung compared to breast cancer patients [Maisch, B. et al., Abst 20072].

Fluoxetine was noted to revert psychological stress-related loss of neovascularization after experimental peripheral ischemia [Maingrette, F. et al., Abst 16089].