Diet and lifestyle have a direct impact on cardiovascular health and may help improve the condition in many patients suffering from or at risk for cardiac diseases. Remote and in-person behavioral interventions were shown to prompt weight loss in obese individuals [Appel, L.J., Late-Breaking Clinical Trial presentation], thus helping reduce the cardiovascular risk. In that regard, and as an example, kiwifruit was noted to lower 24-hour blood pressure [Svendsen, M. et al., Abst 16175], whereas alcoholic beverages (at least red wine and vodka) were reported to improve the cardiovascular risk by increasing collateral perfusion and, in the case of red wine, to enhance antioxidant cardioprotection [Chu, L.M. et al., Abst 16380]. Drug therapy is required to treat a vast array of medical conditions affecting the heart and vessels, as well as many cardiovascular risk factors that are very common in the general population. These issues were widely discussed in the context of new findings with improved therapies tested in clinical or preclinical studies during the AHA's scientific sessions in Orlando, as summarized in the following report.
beta-Blockers have a well-established role in the treatment of heart failure. In fact, rapid use at optimized doses in patients with end-stage heart failure proved safe for improving ventricular remodeling and reducing mortality [Melo, D.S.B. et al., Abst 14985], where-as early use in patients with acute coronary syndromes was also reported beneficial for improving short-term outcomes and lowering mortality [Chatterjee, S. et al., Abst 11971]. However, use of such agents in patients with coronary artery disease but no myocardial infarction or heart failure undergoing percutaneous coronary intervention was associated with increased 3-year rates of cardiac death and a nonsignificant increase in the risk of myocardial infarction [Ozasa, N. et al., Abst 11031], while their use in patients with acute coronary syndromes but no heart failure reduced cardiovascular mortality and reinfarction, but not all-cause mortality [Singh, M. et al., Abst 15855]. However, in experimental animal models, carvedilol had a negative impact on survival after an endotoxin-induced shock [Sato, K. et al., Abst 138], although in models of atrial fibrillation it suppressed structural remodeling by suppressing periostin production [Kish-ihara, J. et al., Abst 8667]. In that context, bucindolol was shown to prevent atrial fibrillation in patients with chronic heart failure, the effect being maximized in patients carrying the 389 Arg/Arg genotype in the beta1-adrenoceptor gene (ADRB1) [Aleong, R. et al., Abst 10438]. On the other hand, compared to metoprolol, bisoprolol restored sympatholysis in hypertensive conditions independently of the reduction in blood pressure [Raheja, P. et al., Abst 14444].
Diuretics are also an important component of the pharmacological armamentarium for heart failure. In this regard, a newly designed chimeric natriuretic peptide, cenderitide, significantly improved natriuresis and reduced right atrial pressure and pulmonary vascular resistance in combination with furosemide boluses compared to the latter alone, without increasing the likelihood for hypotension [Costello, E.C. et al., Abst 14354]. In a similar way, M-atrial natriuretic peptide showed more sustained activity on blood pressure and left ventricular filling than nitroglycerin, while also enhancing renal function in experimental models of heart failure [McKie, P. et al., Abst 16030]. In addition, the vasopressin V2 receptor blocker lixivaptan, which possesses potent aquaretic effects, significantly reduced volume overload and body weight in patients with heart failure, regardless of preservation or reduction in ejection fraction, offering potential as a treatment for heart failure [Ghali, J.K. et al., Abst 15858] (Fig. 1).
Fig. 1. Change in body weight at day 1 in patients treated with lixivaptan or placebo [Ghali, J.K. et al., Abst 15858].
Aldosterone antagonists are also widely used in the management of heart failure, although analyses from the OPTIMIZE-HF study did not reveal any association between aldosterone antagonist prescription at discharge and subsequent mortality or hospitalization [Ahmed, A. et al., Abst 8493]. However, the results of the EMPHASIS-HF trial supported the use of add-on eplerenone, which reduced major event rates even in patients with mild systolic heart failure already receiving optimal therapy [Krum, H. et al., Abst 10483] (Fig. 2), and in patients with hypertension it significantly improved endothelial function while inhibiting hyperactivated rho-associated kinase activity [Fujimura, N. et al., Abst 12358].
Fig. 2. Cardiovascular death/heart failure-related hospitalization rates in patients adding eplerenone or placebo to beta-blockers and angiotensin-converting enzyme inhibitors used at over (high doses) or under (low doses) 50% of the target doses [Krum, H. et al., Abst 10483].
Calcium modulators such as levosimendan also have a role in the management of heart failure. However, no information was reported on such use of the agent, which in an experimental model of cardiopulmonary bypass was associated with preserved cardiac output and carotid artery flow, but a negative impact on cerebral white matter microstructure [Namachivayam, P. et al., Abst 16782].
Additional miscellaneous compounds suggested to be beneficial on cardiac function in specific situations included highly absorptive curcumin, which induced regression of left ventricular hypertrophy and improved left ventricular systolic and diastolic function independently of blood pressure in patients with hypertension [Morimoto, T. et al., Abst 14380]. In experimental animal models of LDL receptor deficiency, curcumin supplementation was also shown to reduce inflammation and improve glucose tolerance and atherosclerosis via a reduction on intestinal endotoxin release into the plasma through dysfunctional intestinal barrier [Bie, J. et al., Abst 10870].
In the experimental arena, chronic administration of tolvaptan prevented progression of left ventricular dysfunction and renal injury in models of hypertensive heart failure [Morooka, H. et al., Abst 8563], whereas chronic treatment with capadenoson improved left ventricular function and prevented progressive remodeling in models of chronic heart failure [Sabbah, H.N. et al., Abst 11280], and tranilast reduced postischemic fibrosis, improving cardiac function after a myocardial infarction [Watanabe, M. et al., Abst 12479]. Furthermore, while ciclosporin attenuated mitochondrial protein acetylation, resulting in cardioprotection [Nguyen, T.T. et al., Abst 10909], but intralipid proved superior to ciclosporin [Li, J. et al., Abst 272], treatment with angiotensin 1-7 suppressed inflammation and fibrogenic responses and improved remodeling after ischemia/reperfusion injuries [Zhao, W. et al., Abst 122], whereas the selective MAP kinase p38 inhibitor SB-203580 prevented fatal arrhythmias after ischemia/reperfusion only if administered during the ischemic but not the reperfusion phase [Surinkaew, S. et al., Abst 9418]. On the contrary, administration of sivelestat did not reduce superoxide production during reperfusion [Aune, S.E. et al., Abst 137], while additional compounds such as morphine [Huh, J. et al., Abst 15336], sildenafil [Yin, C. et al., Abst 16475], tadalafil [Koka, S. et al., Abst 17038], the dynamin-related protein-1 inhibitor dynasore [Gao, D.C. et al., Abst 26166], the free radical scavenger SS-31 [Kloner, R.A. et al., Abst 9581], the NAD-dependent deacetylase sirtuin-1 (SIRT1) activator SRT-1720 [Tong, C. et al., Abst 10153], the serine/threonine-protein kinase mTOR inhibitor sirolimus [Das, A. et al., Abst 14374] (the latter in diabetic conditions) and the caspase-independent necrotic cell death inhibitor NecroX [Kim, J.H. et al., Abst 15325] showed cardioprotective activity during ischemia/reperfusion. In addition, the addition of clenbuterol to metoprolol enhanced calcium handling and cardiac function without untoward effects on heart structure rate in models of heart failure, but did not prevent the negative consequences of mechanical unloading on cardiac myocyte size and function [Navaratnarajah, M. et al., Abst 9970]. In fact, clenbuterol's hypertrophic and inotropic effects were attributed partly to an effect on beta2-adrenoceptors, although receptor-independent effects could not be ruled out [Siedlecka, U. et al., Abst 10240]. However, racemic and d-clenbuterol, but not the levo-isomer, incremented sarcoplasmic reticulum calcium content and induced cardiac hypertrophy in normal and failing heart, again without preventing unloading-induced atrophy [Navaratnarajah, M. et al., Abst 10029; Navaratnarajah, M. et al., Abst 11931]. Similar effects were observed with ivabradine, which restored cardiomyocyte excitation-contraction coupling after mechanical unloading and reduced interstitial fibrosis in models of coronary artery ligation-induced car-diomyopathy [Navaratnarajah, M. et al., Abst 9342]. Ivabradine also inhibited mitochondrial permeability transition pore opening in the cardiomyocytes chronic heart failure animal models [Rastogi, S. et al., Abst 11819], whereas, at least in the in vitro laboratory, co-treatment with sildenafil (which was mechanistically related to improved cardiac energy and remodeling through enhanced cyclic GMP-protein kinase signaling [Zhu, G. et al., Abst 17460]) and brain natriuretic peptide improved diastolic function by correcting impaired titin phosphorylation through enhanced cyclic GMP availability [Hamdani, N. et al., Abst 12710]. With a different approach, the NADPH oxidase inhibitor apocynin prevented arrhythmogenicity and restored calcium handling and contractility in models of dystrophic cardiomyopathy [Gonzalez, D.R. et al., Abst 9161]. On the other hand, administration of dexmedetomidine (a drug that produced antiinflammatory effects in patients with severe sepsis [Taniguchi, T. et al., Abst 143]) during cardio-pulmonary resuscitation in other experimental animals improved early stroke volume and attenuated oxygen consumption [Badugu, S. et al., Abst 60; Badugu, S. et al., Abst 198], whereas the use of sodium nitroprusside prevented post-resuscitation left ventricular dysfunction and survival [Yannopoulos, D. et al., Abst 56], and post-resuscitation ciclosporin attenuated myocardial injury and preserved mitochondrial function [Gill, R.S. et al., Abst 136].
Diet and dietary supplements have also been studied in the context of heart failure, and, at least in the experimental domain, levocarnitine supplementation was shown to prevent heart failure with preserved ejection fraction via enhanced prostacyclin production and prevention of left ventricular fibrosis and stiffness [Omori, Y. et al., Abst 8573]. In addition, low-sodium- and high-lycopene- and omega 3-polyunsaturated fatty acid-containing diet reduced symptoms and improved the quality of life in patients with established heart failure [Lennie, T.A. et al., Abst 10047], while omega 3-polyunsaturated fatty acids also attenuated postprandial hypertriglyceridemia, without affecting monocyte activation [Schirmer, S.H. et al., Abst 13791]. On the other hand, while activation of SIRT1 by the agent attenuated ventricular fibrosis and improved diastolic function in the left ventricle of dystrophin-deficient animals with cardiomyopathy [Kuno, A. et al., Abst 12266] by activating the cAMP-activated protein kinase pathway and suppressing the mTORC1 and p70S6 kinase pathways, resveratrol enhanced autophagy and prevented reverse myocardial remodeling after an experimental myocardial infarction [Kanamori, H. et al., Abst 8274]. Regarding negative experimental findings, the inhibitory effect of apelin on endothelin-1-induced vasoconstriction disappeared in patients with heart failure according to preclinical studies [Dalzell, J.R. et al., Abst 13342], although the agent enhanced myocardial glucose uptake through activation of AMP-dependent protein kinase and G-protein pathways [Xu, S. et al., Abst 14089].
Stem cell therapy has been increasingly studied as a treatment option for heart failure, and five-year results of the REPAIR-AMI trial corroborated the long-term benefit of intracoronary bone marrow-derived mononuclear cells on left ventricular function after an acute myocardial infarction [Traverse, J.H. et al., Clinical Science presentation; Leistner, D. et al., Clinical Science presentation]. Five-year and earlier-term observations from additional studies similarly concluded on the safety and benefits of intracoronary stem cell transplant on left ventricular remodeling, exercise tolerance and survival in patients with dilated cardiomyopathy [Vrtovec, B. et al., Abst 11986; Suarez de Lezo, J. et al., Abst 14838]; stem cell therapy was likewise reported to be effective for improving left ventricular function after an acute myocardial infarction in other studies [Terrovitis, J. et al., Abst 15127], while transendocardially injected allogeneic mesenchymal precursor cells proved safe for improving left ventricular ejection fraction, but not remodeling, in a phase II study [Perin, E.C., Clinical Science presentation]. In addition, a first-in-human trial documented the benefits of tissue-engineered skeletal muscle-derived cell sheet implantation on reverse remodeling and global and regional left ventricular function in patients with dilated cardiomyopathy already carrying a left ventricular assist device [Yoshikawa, Y. et al., Abst 12238], while another study documented greater myocardial retention rates in patients with dilated cardiomyopathy after transendocardial compared to intracoronary stem cell transplant [Vrtovec, B. et al., Abst 12881], and an additional study suggested greater benefits with intramyocardial injection of bone marrow-derived stem cells into the basal ventricular segments compared to other areas of the myocardium, although the benefits were significant regardless of the injection area in the majority of tested segments [Rodrigo, S. et al., Abst 14675]. In the experimental setting, transplant of mesenchymal stem cells after a myocardial infarction mitigated adverse electrophysiological remodeling of the heart by altering ion channel expression, particularly restoring inwardly rectifying potassium channels [Lai, P.F.H. et al., Abst 8096], whereas transplant of human embryonic stem cell-derived cardiomyocytes prevented postinfarction arrhythmias [Shiba, Y. et al., Abst 8897].
Gene therapy is another area of research for therapeutic value in heart failure. During AHA 2011 in Orlando, results were presented on the safety, feasibility and clinical activity of the nonviral plasmid-vectored stromal cell-derived factor 1 (SDF-1) gene therapy JVS-100, which improved walking distance, functional class and quality of life in patients with severe chronic heart failure [Penn, M.S. et al., Abst 10186].
Periprocedural use of amiodarone, which was mechanistically shown to block small-conductance calcium-activated potassium channels [Turker, I. et al., Abst 17232], during radiofrequency ablation for atrial fibrillation improved cardioversion and reduced radiofrequency requirements, but was associated with increased late recurrence rates [Di Biase, L. et al., Abst 14381]. However, analyses from the ATHENA trial results concluded on the cost-effectiveness of dronedarone for treating atrial fibrillation [Reynolds, M.R. et al., Abst 12552]. Furthermore, dronedarone, but not amiodarone, improved microcirculation during rapid pacing atrial tachyarrhythmia in experimental animals [Hammwöhner, M. et al., Abst 10164]. Another related compound, celivarone, showed no efficacy for preventing implantable cardioverter-defibrillator interventions or sudden cardiac death in patients with a history of ventricular fibrillation or flutter [Kowey, P.R. et al., Late-Breaking Clinical Trial presentation].
Among novel antiarrhythmic agents, the novel class III agent niferidile proved highly effective and safe for converting patients with persistent atrial fibrillation/flutter [Golitsyn, S. et al., Abst 10356]. On the other hand, and also in relation to atrial fibrillation, the use of digoxin was associated with an increased risk for stroke [Chang, S.S. et al., Abst 12709], while treatment with tranilast suppressed atrial fibrillation perpetuation and prevented rapid ventricular responses in animal models of atrial fibrillation by inhibiting atrial structural and electrical remodeling through a suppressive effect on transforming growth factor beta-1 [Nakatani, Y. et al., Abst 14702].
Concerning anticoagulation for preventing embolism and stroke in atrial fibrillation, while apixaban proved to be at least as effective as enoxaparin [Goldhaber, S.Z., Late-Breaking Clinical Trial presentation] and superior to aspirin, irrespective of baseline risk level [Lip, G.Y.H. et al., Abst 15542], rivaroxaban proved to be more effective in preventing stroke and systemic embolism, (Fig. X) but as safe as warfarin regarding major bleeding, although it was associated with lower intracranial and fatal bleeding rates [Mahaffey, K.W. et al., Abst 13482; Goodman, S.G. et al., Abst 16903] (Fig. 3). Dabigatran proved at least as effective as warfarin regardless of the presence of symptomatic heart failure [Ferreira, J. et al., Abst 10956] (Fig. 4), without increasing the risk for perioperative bleeding, even in patients submitted to emergency surgical procedures [Healey, J.S. et al., Abst 12041] or undergoing pulmonary vein isolation for catheter ablation [Bassiouny, M. et al., Abst 13128], although a small increase in periprocedural complications was documented in patients undergoing catheter ablation for atrial fibrillation without discontinuing dabigatran [Di Biase, L. et al., Abst 14277], and a meta-analysis suggested an increased risk for myocardial infarction or acute coronary syndrome in patients treated with the drug [Uchino, K. et al., Abst 15500]. Nevertheless, dabigatran was successfully used as a bridge antithrombotic for atrial fibrillation ablation in patients on warfarin anticoagulation [Bunch, T.J. et al., Abst 14708], and was also found to be as effective as acenocoumarol in patients carrying a ventricular assist device, although with a significantly lower risk for major bleeding [Terrovitis, J. et al., Abst 14809]. It should also be noted that, according to the results of a phase I trial, dabigatran is effectively cleared by hemodialysis [Wagner, F. et al., Abst 13303], whereas according to mechanistic studies in experimental models, dabigatran induced pleiotropic anti-atherosclerotic activity, inducing a more stable plaque phenotype by increasing collagen network condensation [Nagy, N. et al., Abst 15194]. On the other hand, the use of dabigatran in patients undergoing major orthopedic surgery was associated with a low rate of acute coronary syndromes, comparable to that observed with enoxaparin, both agents lacking clinically significant rebound phenomena [Barsness, G.W. et al., Abst 14413]. Dual antiplatelet therapy with clopidogrel and aspirin offered a more cost-effective option than aspirin monotherapy in patients unsuitable for warfarin therapy [Coleman, C.I. et al., Abst 8301]. In that context, heparin bolus loading before catheter ablation for atrial fibrillation was effective for preventing periprocedural silent ischemic stroke events [Di Biase, L. et al., Abst 10868].
Fig. 3. Stroke/systemic embolism in patients treated with rivaroxaban or warfarin [Mahaffey, K.W. et al., Abst 13482].
Fig. 4. Stroke/systemic embolism rates in patients with or without heart failure treated with dabigatran or warfarin [Ferreira, J. et al., Abst 10956].
As an alternative or complementary antiplatelet strategy, the novel cGMP-inhibited 3',5'-cyclic phosphodiesterase (PDE3) inhibitor and cilostazol analogue K-134 was shown to prevent thrombosis without affecting hemostasis in a pulmonary embolism model [Yoshida, H. et al., Abst 8694]. As a further putative antiplatelet therapy, the prostaglandin analogue ONO-1301 showed cardioprotective activity during an experimental myocardial infarction, resulting in survival benefits mediated at least in part by recruitment of bone marrow cells into ischemic tissue [Imanishi, Y. et al., Abst 9200]; the agent also improved cardiac function in models of dilated cardiomyopathy through reorganization of sarcoglycan and dystroglycan and reduced fibrosis [Ishimaru, K. et al., Abst 15201]. Moreover, the compound enhanced reverse ventricular remodeling in models of dilated cardiomyopathy when combined with skeletal myoblast cell transplant [Shirasaka, T. et al., Abst 11210].
Regarding ventricular fibrillation, while bepridil reduced ventricular fibrillation recurrence in patients with symptomatic Brugada syndrome by improving repolarization dynamics [Mizumaki, K. et al., Abst 12577], experimental observations in animal models indicated improvements in survival and hemodynamics upon return to spontaneous circulation after treatment with the TNF-alpha blocker infliximab [Youngquist, S. et al., Abst 10]. As a parallel comment, minocycline was shown to attenuate the rise in brain TNF-alpha levels during prolonged hypothermic cardiac arrest [Drabek, T. et al., Abst 15].
The results of a double-blind comparative trial indicated potential for vasopressin for improving survival in patients with prolonged cardiac arrest, although without differences in long-term survival versus epinephrine [Ong, M.E.H. et al., Abst 176] (Fig. 5). In this regard, experimental use of epinephrine during active compression-decompression cardiopulmonary resuscitation using an impedance threshold device exerted negative effects on carotid blood flow [Burnett, A.M. et al., Abst 189]. On the other hand, at least in experimental animal models, the use of levosimendan during cardiopulmonary resuscitation for cardiac arrest reduced cortical neuronal injuries and improved neurological function in survivors [Kelm, R.F. et al., Abst 197]. Also at the experimental level, the flavonoid baicalein was shown to improve myocardial function after resuscitation from a cardiac arrest by modulating the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/nitric oxide synthase, endothelial pathway [Chang, W.T. et al., Abst 9215]. In parallel, the novel artificial oxygen carrier liposome-encapsulated hemoglobin attenuated arrhythmogenicity during an experimental massive hemorrhagic shock [Takase, B. et al., Abst 283] and protected the myocardium against experimental ischemia/reperfusion lesions [Kawaguchi, A.T. et al., Abst 12215].
Fig. 5. Survival to admission and hospital discharge in patients with cardiac arrest receiving vasopressin 40 IU or epinephrine 1 mg in the emergency department [Ong, M.E.H. et al., Abst 176].
Pharmacotherapy does have a share in the management of valvular heart disease, as exemplified by the results of a randomized trial in which extended-release metoprolol preserved left ventricular systolic and diastolic function, although without attenuating left ventricular remodeling, in patients with chronic, degenerative mitral regurgitation [Ahmed, M.I. et al., Abst 14887].
Antiplatelet therapy remains the most popular cardioprotective approach in patients with or at risk for coronary artery disease, with aspirin being the most popular agent, especially in women with low or intermediate Framingham risk scores [Gupta, M. et al., Abst 9164], although according to data from other studies aspirin may not be sufficient for preventing cardiovascular morbidity and mortality in patients with additional risk factors besides older age and diabetes [Okada, S. et al., Abst 9426], although it remained active in preventing stroke in type 2 diabetes patients with higher C-reactive protein levels [Soejima, H. et al., Abst 9876]. In patients with type 2 diabetes with elevated inflammatory markers or active smoking, splitting the daily dose of aspirin into two improved the biological activity of the agent, markedly reducing antiplatelet resistance [Dillinger, J.G. et al., Abst 8537]. In this regard, serum lipids were noted to impair the antiplatelet effect of aspirin in diabetic conditions [Hohlfeld, T. et al., Abst 12704].
Clopidogrel is another antiplatelet agent commonly used in dual-drug strategies with aspirin, although a long-term follow-up did not demonstrate advantages for maintained dual therapy over five years over shorter exposure to two antiplatelet agents [Hara, H. et al., Abst 13206], albeit early discontinuation of dual antiplatelet therapy in other studies resulted in worse outcomes [Hasegawa, D. et al., Abst 14690], and treatment for over 12 months was associated with a lower risk of death and myocardial infarction in diabetic individuals submitted to drug-eluting stent implant [Kinlay, S. et al., Abst 18334]. In addition, although common, nuisance bleeding during dual secondary prevention with aspirin/clopidogrel was not associated with an increased risk for death, myocardial infarction or stroke [Baber, U. et al., Abst 13371]. On that subject, synchronous administration of enteric-coated aspirin, clopidogrel and enteric-coated omeprazole resulted in reduced platelet inhibition compared to separately dosed enteric-coated aspirin/immediate-release omeprazole and clopidogrel, which avoids the pharmacodynamic interaction between omeprazole and clopidogrel [Gurbel, P.A. et al., Abst 15852].
However, underresponsiveness to both agents is not uncommon, notably in the elderly [Silvain, J. et al., Abst 15857], and high residual platelet activity after aspirin was associated with an increased risk for acute coronary syndrome in healthy subjects [Qayyum, R. et al., Abst 16658], whereas high residual activity after clopidogrel loading correlated with larger intracoronary thrombi and worse outcomes [Vavuranakis, M. et al., Abst 14680], although increasing the dose of clopidogrel was able to overcome resistance mediated by poor cytochrome P450 2C19 metabolism [Horenstein, R.B. et al., Abst 10673; Tousek, P. et al., Abst 11369]. Notwithstanding, increasing the dose of clopidogrel reached optimal antiplatelet activity in CYP2C19*2 hetero- but not homozygotes [Mega, J.L. et al., Late-Breaking Clinical Trial presentation]. Nevertheless, metabolism did not completely explain resistance to clopidogrel, which was also related to ATP-binding cassette sub-family B member 1 (ABCB1) polymorphisms [Park, M.W. et al., Abst 14831], as well as inherent resistance in diabetic conditions during activation of protease-activated receptors [Cleator, J.H. et al., Abst 11336]. Increased paraoxonase 1 activity was also related to reduced responsiveness to clopidogrel [Tselepis, A.D. et al., Abst 12703].
Besides clopidogrel, prasugrel has also shown potential as an antiplatelet therapy with improved efficacy, as further demonstrated in the TRITON-TIMI 38 trial in which it was superior to clopidogrel in patients with ST segment-elevated myocardial infarction, regardless of the timing of percutaneous coronary interventions [Udell, J.A. et al., Abst 9309] (Fig. 6). Moreover, in patients suboptimally responding to standard-dose clopidogrel, prasugrel reduced platelet reactivity more effectively than clopidogrel dose uptitration, although with a parallel increase in major bleeding rates [Schmidtler, F. et al., Abst 10390], while pharmacoeconomic analysis suggested prasugrel to be dominant over clopidogrel in the setting of acute coronary syndromes submitted to early invasive procedures [Hillegass, W.B. et al., Abst 18228]. Cangrelor was also reported to be a potent, rapidly acting antiplatelet agent, switch to which after clopidogrel was not associated with pharmacodynamic interactions [Angiolillo, D.J. et al., Abst 13354], whereas the results of the PLATO trial documented similar preventive activity for ticagrelor and clopidogrel against vascular death, myocardial infarction or stroke in patients with acute coronary syndromes or peripheral artery disease, regardless of prior history of stroke or transient ischemic attack, without increasing the risk of bleeding [Patel, M.R. et al., Abst 14299; James, S.K. et al., Abst 15029].
Fig. 6. Cardiovascular death/myocardial infarction/stroke in patients undergoing primary or secondary percutaneous coronary interventions (PCI) treated with prasugrel or clopidogrel [Udell, J.A. et al., Abst 9309].
A possible alternative antiplatelet strategy, cilostazol combined with aspirin, reduced major adverse cardiovascular and cerebrovascular event rates over 2 years compared to aspirin alone after a coronary stent placement [Ueda, H. et al., Abst 14940] (Fig. 7). Furthermore, the addition of cilostazol to dual therapy with aspirin and clopidogrel further reduced the risk of restenosis and repeat revascularization after percutaneous coronary interventions, without impacting on the mortality or stent thrombosis rates [Jang, J.S. et al., Abst 12567]. Such triple antiplatelet therapy was also found to be safe and effective for secondary cardiovascular prevention after an ST segment-elevated myocardial infarction, even in older subjects with renal impairment [Kim, W. et al., Abst 14779].
Fig. 7. Two-year major adverse cardio- and cerebrovascular event rates in patients receiving aspirin alone or combined with cilostazol [Ueda, H. et al., Abst 14940].
Glycoprotein IIb/IIIa inhibitors have also been extensively used in the context of acute coronary syndromes, and intracoronary administration during percutaneous coronary interventions was not only safe but also beneficial in improving flow rates and preventing target vessel revascularization, myocardial infarction and death [Brearley, W.D. et al., Abst 15236; Friedland, S. et al., Abst 16740]. However, abciximab combined with unfractionated heparin did not reduce major adverse cardiovascular event rates, but increased the risk for bleeding compared to bivalirudin in patients undergoing percutaneous coronary interventions for non-ST segment-elevated myocardial infarction [Kastrati, A. et al., Late-Breaking Clinical Trial presentation], while the use of intracoronary abciximab did not add benefit to intravenous treatment, but was associated with a lesser likelihood for congestive heart failure in another study [Thiele, H. et al., Late-Breaking Clinical Trial presentation]. In this regard, another antithrombotic agent, rivaroxaban, at low doses, effectively prevented cardiovascular events in patients with a recent acute coronary syndrome receiving optimal antiplatelet therapy [Gibson, C.M., Late-Breaking Clinical Trial presentation] (Fig. 8), whereas another platelet thrombin receptor blocker, vorapaxar, did not reduce major cardiovascular adverse event rates when added to standard of care in patients with non-ST segment-elevated acute coronary syndromes and significantly increased the risk for major bleeding and intracranial hemorrhage [Mahaffey, K.W., Late-Breaking Clinical Trial presentation].
Fig. 8. Cardiovascular death/myocardial infarction/stroke rates in patients receiving rivaroxaban or placebo [Gibson, C.M., Late-Breaking Clinical Trial presentation].
Among other available antiplatelet therapies, sarpogrelate improved not only vascular function but also glomerular filtration rate and long-term outcomes in patients with diabetes, stable angina and chronic kidney disease [Watanabe, H. et al., Abst 11204] (Fig. 9). The agent was also shown to induce angiogenesis and restore perfusion in ischemic limbs in experimental models of diabetes through stimulation of the endothelial nitric oxide synthase pathway [Iwabayashi, M. et al., Abst 11468].
Fig. 9. Eight-year major adverse cardiovascular event rates in patients receiving or not sarpogrelate [Watanabe, H. et al., Abst 11204].
As an alternative antiplatelet approach, the anti-activated factor IX aptamer pegnivacogin effectively lowered platelet activity in healthy volunteers, as well as residual platelet activity in patients with acute coronary syndrome undergoing percutaneous coronary interventions after clopidogrel and aspirin loading [Ahrens, I. et al., Abst 9771]. In addition, using pegnivacogin and the selective titratable antidote anivamersen, which within an hour fully restored the suppressed thrombin generation brought about by pegnivacogin without a rebound effect [Vavalle, J.P. et al., Abst 13826], effective anticoagulation with potential for early sheath removal after cardiac catheterization without delaying hemostasis or bleeding complications was considered a feasible option in patients with non-ST segment-elevated acute coronary syndromes [Vavalle, J.P. et al., Abst 13657]. Another innovative antiplatelet/antithrombotic strategy was the SCE5 (anti-glycoprotein IIb/IIIa antibody)-scuPA (urokinase) fusion protein, which selectively inhibited platelet activation targeting enriched fibrinolysis in in vivo studies [Eugen, C. et al., Abst 14119].
Besides antiplatelet therapies, anticoagulants such as enoxaparin afforded benefits on major ischemic events in patients undergoing primary percutaneous coronary interventions, with superiority comparing outcomes in patients receiving unfractionated heparin [Silvain, J. et al., Abst 15664]. In this regard, selective proapoptotic activity of quinacrine on smooth muscle cells in the absence of prothrombotic effects also suggested potential as an antirestenotic agent after coronary artery interventions [Perrino, C. et al., Abst 16451].
Regarding antianginal agents, pretreatment with ranolazine before elective percutaneous coronary interventions for stable angina reduced periprocedural ischemic injuries to the myocardium compared to placebo [Pelliccia, F. et al., Abst 8517] (Fig. 10); ranolazine use in patients with non-ST segment-elevated acute coronary syndromes also reduced the likelihood of atrial fibrillation attacks, although not that of most serious, symptomatic cases [Scirica, BM. et al., Abst 13798]. Mechanistically, ranolazine was shown to inhibit sodium currents more effectively in patients with long QT syndrome type 3 caused by sodium channel SCN5A gene mutations not interfering with binding of the agent to the channel [Hu, D. et al., Abst 15739]. Nicorandil proved nephroprotective against contrast-induced renal injury after percutaneous coronary interventions in patients with impaired renal function [Nawa, T. et al., Abst 12180], while perhexiline suppressed thioredoxin-interacting protein and increased AMP-dependent protein kinase and peroxisome proliferator-activated receptor delta coactivator-1alpha expression during myocardial ischemia, beneficially contributing to redox stress and energetic impairment [Ngo, D.T. et al., Abst 14461], although without protecting the myocardium during subsequent coronary artery bypass graft surgery [Druny, N.E. et al., Abst 15650]. In the experimental arena, a similarly acting agent, ivabradine, reduced post-myocardial infarction systolic heart failure and left ventricular remodeling [Smith, R.S. et al., Abst 11482].
Fig. 10. Percent of patients with levels of creatine kinase-MB (CK-MB), troponin I or myoglobin above the upper limit of normal after a 7-day pretreatment with ranolazine 500 mg b.i.d. or placebo [Pelliccia, F. et al., Abst 8517].
Miscellaneous additional pharmacotherapies discussed in the context of coronary artery disease included the cathepsin A inhibitor SAR-1, which markedly improved postinfarction left ventricular wall geometry in experimental animal models [Linz, W. et al., Abst 8779], the inhibitor of nuclear factor kappa-B kinase inhibitor IMD-1041, which also improved postinfarction remodeling through attenuated fibrosis [Matsumoto, R. et al., Abst 9400] (another inhibitor of nuclear factor kappa-B kinase inhibitor, IMD-0354, prevented neointima formation after arterial injuries [Hamaya, R. et al., Abst 10489], improved experimental autoimmune myocarditis [Watanabe, R. et al., Abst 9434] and inhibited pulmonary artery smooth muscle cell proliferation during pulmonary hypertension [Hosokawa, S., Abst 11420] by suppressing cytokine production and reducing inflammation) and the 5-lipoxygenase inhibitor zileuton, which improved endothelial function in patients with coronary artery disease harboring high-risk leukotriene haplotypes [Patel, R.S. et al., Abst 15501]. In addition, administration of granulocyte colony-stimulating factor in drug-eluting stent recipients attenuated endothelial dysfunction compared to placebo, widening the putative pharmacotherapies in that context [Iwata, Y. et al., Abst 14901], while, in the experimental arena, GLP-1-eluting mesenchymal stem cells proved feasible for improving post-myocardial infarction left ventricular function [de Jong, R. et al., Abst 15311].
In addition to pharmacotherapy, gene therapy was the subject of new studies presented in Orlando. A particular study with VEGF165 as the sole gene therapy demonstrated its safety and feasibility in patients with refractory angina, with only transient clinical improvements, but meaningful improvements in perfusion of ischemic areas [Rodrigues, C.B. et al., Abst 11855]. However, such treatment improved ejection fraction and symptoms and reduced myocardial ischemia for at least 6 months, and remained active on symptoms and ischemic burden at 24 months in another study in patients with chronic stable angina [Mendiz, O. et al., Abst 15235].
Dietary supplement therapies were also discussed during the meeting, as exemplified by the results of the JELIS study, indicating that the addition of high-purity eicosapentaenoic acid to statin therapy strongly induced coronary plaque regression in patients with angina [Wakita, Y. et al., Abst 8893], and the results of the MARINE trial concluding that highly purified icosapent ethyl reduced triglyceride, atherogenic lipoprotein, phospholipase A2 and highly-sensitive C-reactive protein levels, as well as large VLDL, total and small LDL and total HDL particle levels in patients with extremely high tri-glyceridemia [Bays, H. et al., Abst 14232; Ballantyne, C.M. et al., Abst 15071]. Furthermore, experimental studies corroborated a benefit for eicosapentaenoic acid in preserving dynamin-like 120 kDa protein, mitochondrial (OPA1) expression and oxidative phosphorylating activity after a myocardial infarction, attenuating postischemic remodeling [Kobara, M. et al., Abst 12493].
With overall superiority over bare metal stents regarding long-term outcomes [Wallace, E.L. et al., Abst 13080; Graham, A. et al., Abst 13959; Tsai, T.T. et al., Abst 17341], sirolimus- and paclitaxel-eluting stents continued to be reported as effective during this year's AHA scientific sessions in Orlando [Kato, M. et al., Abst 8886; Toyofuku, M. et al., Abst 11547; Zou, Y. et al., Abst 12401; Kume, T. et al., Abst 15492], although the results of meta-analyses of randomized, comparative trials concluded on the lower survival or higher repeat revascularization rates compared to patients undergoing coronary artery bypass graft surgery [Goto, S. et al., Abst 8562; Alam, M. et al., Abst 13250; Fuku, Y. et al., Abst 15681], despite another meta-analysis finding no differences between the two strategies [Jang, J.S. et al., Abst 12764]. Furthermore, at least in the case of sirolimus-eluting stents, a higher incidence of target lesion revascularization requirements was noted in patients with insulin-requiring diabetes [Hara, H. et al., Abst 14798]. Novel drug-eluting stents were also described as beneficial in patients with coronary artery disease undergoing percutaneous coronary interventions. These included an everolimus-eluting stent (which fared superior to sirolimus and paclitaxel stents and proved useful in patients with diabetes) [Nieman, K. et al., Abst 10570; Moynagh, A. et al., Abst 12502; Sakakibara, T. et al., Abst 12627; Moynagh, A. et al., Abst 12686; Habara, S. et al., Abst 14109; Baber, U. et al., Abst 15180; Lee, S.R. et al., Abst 17782; Park, K.W. et al., Abst 18068] and a zotarolimus-eluting stent [Hong, S.J. et al., Abst 15566; Lee, S.R. et al., Abst 17782; van Geuns, J.R., Clinical Science presentation]. An additional ectonucleoside triphosphate diphosphohydrolase gene-eluting stent was also reported to be effective for inhibiting excessive neointima growth and preventing in-stent restenosis in preclinical animal models [Sung, J.H. et al., Abst 15025]. However, differences were identified comparing specific drug-eluting stents, as novel drug-eluting stents, such as those releasing zotarolimus, biolimus A9 and everolimus, were associated with lower restenosis compared to first-generation stents [Nakamura, S. et al., Abst 15366; Nakamura, S. et al., Abst 15426]. For instance, a sirolimus-eluting stent increased but other drug-eluting stents decreased neointimal hyperplasia [Nakamura, D. et al., Abst 8634; Nakamura, D. et al., Abst 9316; Mori, N. et al., Abst 12546] (although in the case of zotarolimus, enhanced neointimal suppression was noted in female compared to male patients [Yamada, R. et al., Abst 12351], whereas both zotarolimus- and everolimus-eluting stents showed a lower incidence of uncovered struts and better vascular healing than first-generation drug-eluting stents [Otsuka, F. et al., Abst 14135; Mitsutake, Y. et al., Abst 14751; Yoshimura, T. et al., Abst 15375], although the zotarolimus-eluting stent was associated with better neointimal coverage and vessel healing compared to everolimus-eluting stents [Nishinari, M. et al., Abst 13235; Yoshimura, T. et al., Abst 14916]). In this respect, neointimal coverage, at least using sirolimus-eluting stents, prevented potential stent separation [Iwasaki, K. et al., Abst 13307]. In addition to drug-eluting stents, nitinol stents also improved outcomes compared to bare stainless steel stents [Kawamura, Y. et al., Abst 9689].
While registry data indicated an association between the use of warfarin and reduced mortality in patients with left ventricular systolic dysfunction and pulmonary hypertension [Goudie, A. et al., Abst 18290], studies in animal models of monocrotaline-induced pulmonary hypertension identified antiarrhythmogenic activity for sildenafil and beraprost, resulting in protection against sudden cardiac death [Takase, B. et al., Abst 273]. Using the same experimental model, PTGS1/COX1 gene therapy using transfected endothelium-like progenitor cells proved potentially useful for preventing pulmonary hypertension [Zhou, L. et al., Abst 9178], whereas genistein rescued depressed right ventricular output and reversed right ventricular and pulmonary arterial hypertrophy [Nadadur, R.D. et al., Abst 17006]. In models of left anterior descending coronary artery ligation-induced pulmonary hypertension, benefits on vascular remodeling were obtained with the phosphatase and tensin homolog (PTEN) gene expression promoter HO-3867 [Ravi, Y. et al., Abst 16618]. In addition, novel transient receptor potential channel TRPV4 blockers such as GSK-2193874, with potential for preventing high pulmonary capillary wedge pressure-induced pulmonary edema, were described as potential future therapies for pulmonary hypertension associated with heart failure [Thorneloe, K.S. et al., Abst 13510].
Through a combination of anti-edema, antiapoptotic, antiinflammatory, antioxidative and mitochondrial protective activity, a combination of ciclosporin and epoetin was superior to either monotherapy in preventing cerebral damage after an experimental ischemic stroke [Leu, S. et al., Abst 8534].
While cilostazol was reported to be useful for improving amputation-free survival and limb salvage after endovascular therapy for critical limb ischemia [Soga, Y. et al., Abst 10178] (Fig. 11), advances in the pharmacotherapy of intermittent claudication were foreseen, with results from a phase II trial revealing improvements in the treadmill walking performance in patients with peripheral arterial disease treated with K-134 comparable to those obtained with cilostazol [Hiatt, W.R. et al., Abst 9800] (Fig. 12), and the results of an additional study also demonstrating improvements in peak walking time, specifically in Japanese individuals [Shigematsu, H., Abst 14430].
Fig. 11. Five-year amputation-free survival in patients receiving or not cilostazol after endovascular therapy for critical limb ischemia [Soga, Y. et al., Abst 10178].
Fig. 12. Percent change in the peak walking time in patients treated with K-134, cilostazol or placebo [Hiatt, W.R. et al., Abst 9800].
Effective improvements in peak walking time and delays in claudication in patients with severe intermittent claudication were also demonstrated after single-dose auto-logous CD34-positive cell injection in a controlled trial [Losordo, D.W. et al., Abst 13688].
Repeated intramuscular injections of adipose tissue-derived mesenchymal stem cells safely improved angiogenesis in patients with critical limb ischemia refractory to standard therapy [Lee, H.C. et al., Abst 8381]. Safe improvements in time to failure in patients with no-option critical limb ischemia were similarly reported with ixmyelocel-T, a patient-specific cell-based therapy consisting of bone marrow-derived repair cells produced using a patented Using Tissue Repair cell technology [Marston, W. et al., Abst 8547] (Fig. 13), whereas enhanced angiogenesis in the experimental arena was demonstrated with a magnetized iPS vascular endothelial growth factor receptor 2-positive cell sheet created through a magnetite tissue engineering technology [Kito, T. et al., Abst 8572].
Fig. 13. Amputation/death/new gangrene/wound size doubling rates during 12 months in patients receiving or not ixmyelocel-T [Marston, W. et al., Abst 8547].
Regarding other forms of peripheral vascular disease, finding were reported on the benefits of vardenafil on digital blood flow and related symptoms in patients with primary or secondary Raynaud's phenomenon compared to placebo [Caglayan, E. et al., Abst 13048].
Observational results did not suggest a benefit for perioperative methylprednisolone in children undergoing cardiac surgery, while it showed a tendency to increase the risk for infections in patients at higher risk [Pasquali S.K. et al., Abst 8256]. On the contrary, postoperative colchicine prevented postoperative atrial fibrillation, pericardiotomy syndrome and effusion in patients undergoing cardiac procedures [Imazio, M., Late-Breaking Clinical Trial presentation] (Fig. 14).
Fig. 14. Postoperative atrial fibrillation rates in patients receiving colchicine or placebo [Imazio, M., Late-Breaking Clinical Trial presentation].
While among the diuretics indapamide was reported to improve endothelial and arterial function, as well as left ventricular function, more effectively than hydrochlorothiazide in mildly to moderately hypertensive individuals with diabetes [Ciobanu, A.O. et al., Abst 15043], no new clinical information was reported on calcium channel blockers during this year's AHA meeting other than novel analyses of the ASCOT trial that indicated comparable benefits on left ventricular mass index but better diastolic function after treatment with amlodipine compared to atenolol [Barron, A.J. et al., Abst 16804], an experimental study that indicated potential for N-type calcium channel blockade with cilnidipine for improving survival and reducing sudden death in models of dilated cardiomyopathy [Yamada, Y. et al., Abst 17054], and a mechanistic study according to which flecainide induced the appearance of larger arrhythmogenic calcium sparks in myocytes, possibly limiting its use in arrhythmic conditions [Sikkel, M.B. et al., Abst 11948]. Furthermore, the agent had no effect on larger calcium sparks observed in post-myocardial infarction hearts [Sikkel, M.B. et al., Abst 11969]. However, by blocking cytosolic sodium influx, flecainide was suggested to be potentially useful for alleviating arrhythmia burden during calcium overload [Poelzing, S. & Radwanski, P., Abst 13905], and in fact, flecainide, like (R)-propafenone, blocked calcium waves, preventing ventricular arrhythmia [Galimberti, E.S. et al., Abst 16593].
Renin-angiotensin system-blocking antihypertensive drugs are highly popular in selected patient populations, including patients with left ventricular hypertrophy [Dechend, R. et al., Abst 16540] or a history of myocardial infarction, and in fact, both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were associated with reduced mortality in patients with coronary artery disease revascularized after a myocardial infarction, but not in patients without prior myocardial infarction [Nishino, T. et al., Abst 10587], while angiotensin receptor blockers were also associated with reduced progression of calcific aortic stenosis [Capoulade, R. et al., Abst 13786]. Furthermore, at least in the case of losartan, a direct antiplatelet activity was demonstrated in hypertensive individuals with atrial fibrillation [Sakamoto, T. et al., Abst 11301].
Among the angiotensin-converting enzyme inhibitors, direct comparison of zofenopril versus ramipril in the SMILE IV trial indicated better protection against major adverse cardiovascular events by the former in patients with post-myocardial infarction left ventricular dysfunction receiving aspirin [Borghi, C. & Ambrosioni, E., Abst 14717] (Fig. 15).
Fig. 15. One-year cardiovascular death/hospitalization rates in patients receiving zofenopril or ramipril [Borghi, C. & Ambrosioni, E., Abst 14717].
With comparable blood pressure-lowering activity, telmisartan prevented new episodes of atrial fibrillation more effectively than amlodipine in hypertensive individuals with paroxysmal atrial fibrillation, particularly in subjects with normal left atrial size [Fogari, R. et al., Abst 8236] (Fig. 16). Moreover, telmisartan exerted a plaque-stabilizing, antiinflammatory effect on the coronary arteries of hypertensive subjects [Yamaguchi, K. et al., Abst 9345]. Furthermore, as opposed to losartan and valsartan, telmisartan, as well as irbesartan (which possess peroxisome proliferator-activated receptor-gamma agonist activity in addition to angiotensin receptor blockade), improved insulin resistance and endothelial function in hypertensive individuals with chronic kidney disease and metabolic syndrome [Watanabe, H. et al., Abst 8787]; through dual angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activity, telmisartan induced sympathicolytic effects in models of metabolic syndrome [Kishi, T. et al., Abst 11564]. Irbesartan was mechanistically also shown to reduce inflammation and induce apoptosis in atherosclerotic plaques in apolipoprotein E-deficient animal models [Zhao, Y. et al., Abst 9624]. However, antiatherogenic effects in diabetic, apolipoprotein E-deficient animal models were also attained with a combination of olmesartan and azelnidipine, without the involvement of peroxisome proliferator-activated receptor-gamma [Noda, K. et al., Abst 9659], and olmesartan was further shown to restore the thrombolytic to fibrinolytic balance in models of atrial fibrillation [Aoyama, Y. et al., Abst 12866]. Nevertheless, candesartan, at least combined with amlodipine, also improved vascular insulin resistance in animal models of metabolic syndrome, the synergistic effect of the two agents being mediated by antiinflammatory activity and a reduction in adipocyte size [Sueta, D. et al., Abst 14148].
Fig. 16. One-year atrial fibrillation recurrence rates in patients receiving telmisartan 80160 mg or amlodipine 5-10 mg once daily according to left atrial (LA) size [Fogari, R. et al., Abst 8236].
While also improving insulin signaling in heart failure and hence relieving insulin resistance [Fukushima, A. et al., Abst 8812], by suppressing sympathetic activity, the addition of aliskiren to standard therapy for systolic heart failure lowered brain natriuretic peptide levels [Yoshihiro, I. et al., Abst 8406] and improved cardiac remodeling in animal models of dilated cardiomyopathy or nephropathic left ventricular dysfunction [Hongo, K. et al., Abst 10950; Ogawa, M. et al., Abst 11423]. Furthermore, aliskiren combined with amlodipine improved endothelial nitric oxide release by changes in blood pressure, suggesting a direct effect on the endothelium [Mason, R.P. et al., Abst 16093]. Direct blockade of renin by aliskiren, like treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, also prevented doxorubicin and trastuzumab cardiotoxicity in experimental animals [Bhullar, N. et al., Abst 8681], while beta-blockers and angiotensin-converting enzyme inhibitors exerted a cardioprotective effect in breast cancer patients receiving trastuzumab [Cook, T.B. et al., Abst 13988], and statins reduced the risk of heart failure and cardiac death in patients receiving anthracycline-based chemotherapy [Seicean, S. et al., Abst 14081]. However, direct renin inhibitors and angiotensin receptor blockers were associated with a significantly reduced risk for angioedema compared to angiotensin-converting enzyme inhibitors, especially in patients with heart failure [Makani, H. et al., Abst 13950], whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but not aldosterone inhibitors and direct renin inhibitors, were associated with a low but significant risk of hyperpotassemia [Romero, J. et al., Abst 14093]. At the preclinical level, another renin-angiotensin system-acting compound, the angiotensin-converting enzyme 2 activator diminazene decreased dysfunctional endothelial progenitor cell populations in models of pulmonary hypertension, putatively preventing monocrotaline-induced pulmonary hypertension [Shenoy, V. et al., Abst 13757].
Additional preclinical studies confirmed the long-acting blood pressure-lowering activity of another compound, the vasoactive intestinal polypeptide receptor 2-selective ligand PB-1046 (a fusion protein consisting of a conjugate of vasoactive intestinal peptide [VIP] and an elastin-like peptide [ELP] biopolymer produced in Escherichia coli), added to atenolol, amlodipine or ramipril [del Rio, C.L. et al., Abst 18208].
Although dietary measures can improve dyslipidemia and help prevent coronary artery and other cardiovascular diseases, with high fish intake, therapeutic lifestyle intervention reducing LDL and VLDL cholesterol and apolipoprotein B levels [Ooi, E.M. et al., Abst 10022], pharmacotherapy is usually required in a large proportion of patients with elevated LDL cholesterol or triglycerides or decreased HDL cholesterol to successfully prevent cardiovascular events.
While lowering LDL cholesterol levels, statins protect men and women against major coronary and vascular events [Fulcher, J. et al., Abst 17409], prevent stent thrombosis in patients undergoing percutaneous coronary interventions for acute myocardial infarction with high inflammatory marker levels [Jeong, H.C. et al., Abst 14440], and exert cardioprotective effects even in diabetic, normocholesterolemic individuals [Kojima, S. et al., Abst 14894], as further demonstrated, at least with hydrophilic statins, in patients with diabetes and a history of acute myocardial infarction [Shutta, R. et al., Abst 15131]. In addition, co-treatment with statins in patients with chronic kidney disease undergoing percutaneous coronary interventions with drug-eluting stent placement improved 1-year outcomes [Dasari, T.W. et al., Abst 8888], with higher doses further reducing atherosclerotic inflammation compared to lower doses [Takakol, A. et al., Abst 18242]. Furthermore, adherence to statins was identified as a predictor of better outcomes in patients with acute ischemic stroke or transient ischemic attack [Chen, P.S. et al., Abst 11997], whereas combined use of statins, beta-blockers and aspirin, but not angiotensin-converting enzyme inhibitors, was associated with more favorable 12-month outcomes after major vascular surgery in high-risk patients [Lau, W.C. et al., Abst 15238]. However, interim analyses of the CHART-2 study indicated that it is statin use, rather than low LDL cholesterol levels, which affords survival benefits to patients with ischemic heart failure [Nochioka, K. et al., Abst 14231], whereas a study comparing ethnic groups indicated lower plaque-stabilizing activity in South Asian people compared to other groups [Ahmadi, A. et al., Abst 15481]. Mechanistically, improvements in endothelial function brought about by statins were related to an effect on sphingosine-1-phosphate [Sugiura, T. et al., Abst 9660]. In this regard, observations from the LIPID trial identified reductions in lipoprotein-associated phospholipase A2 during the first year of treatment with pravastatin as a predictor of freedom from coronary events in patients with myocardial infarction or unstable angina, regardless of the effect on LDL cholesterol levels [White, H.D. et al., Abst 14857]. On the subject of pravastatin, reduced LDL cholesterol-lowering activity was observed in patients carrying the rs4149056 single-nucleotide polymorphic variant of the soluble carrier organic anion transporter (SLCO1B1) gene [Akao, H. et al., Abst 9782]. Regarding simvastatin, mechanistic preclinical studies indicated attenuation of myocardial dysfunction and angio-genic impairment in ischemic, diabetic conditions through an effect on hypoxia-inducible factor-1α/prolyl 4-hydroxylase subunit alpha-3 [Thirunavukkarasu, M. et al., Abst 16086] and induction of cardiac autophagy via activation of PTEN [Lee, P. et al., Abst 17420].
With cardiovascular protective activity magnified at high doses even in patients with obesity or morbid obesity [Deedwania, P.C. et al., Abst 10651] (Fig. 17), in addition to the lipid-lowering and cardiovascular benefits of statins, atorvastatin improved endothelial function and preserved intercellular cadherin-catenin junctions independently of the metabolic and inflammatory status [Nerla, R. et al., Abst 13392; Haidari, M. et al., Abst 16242], reduced C-reactive protein levels largely by increasing its fractional catabolic rate [Thongtang, N. et al., Abst 10560], prevented progression of renal failure in patients with heart failure [Kawasaki, M. et al., Abst 15148] (Fig. 18), upmodulated NAD-dependent deacetylase sirtuin-1 expression, which may contribute to the improved endothelial function in patients with coronary artery disease [Tabuchi, T. et al., Abst 11510], and at high doses it also improved survival after a severe hemorrhagic shock [Kurita, A. et al., Abst 141], whereas low-dose treatment improved survival and inhibited inflammatory responses to endotoxin [Fujii, S. et al., Abst 140], at least in the experimental setting. Moreover, atorvastatin, especially at high doses, was shown to prevent new-onset atrial fibrillation in patients with myocardial infarction, in which regard it proved superior to pravastatin [Bang, C.N. et al., Abst 10443]. Furthermore, a direct and rapid effect of atorvastatin in increasing GTP cyclohydrolase expression in arteries, resulting in increased tetrahydrobiopterin bioavailability and endothelial nitric oxide synthase coupling, was observed ex vivo [Antoniades, C. et al., Abst 10311]. Such effects were corroborated in in vivo mechanistic studies in patients undergoing coronary artery bypass graft surgery, which demonstrated increases in tetrahydrobiopterin and nitric oxide bioavailability and parallel decreases in superoxide anion upon treatment with the statin [Antoniades, C. et al., Abst 10321]. On the other hand, the sympatholytic activity of a combination of atorvastatin and amlodipine was associated with improved cognitive-like function in experimental animal models [Kishi, T. et al., Abst 11557].
Fig. 17. Major adverse cardiovascular event rates in patients with a body mass index of > 28, > 30 or > 35 kg/m2 receiving atorvastatin 10 or 80 mg [Deedwania, P.C. et al., Abst 10651].
Fig. 18. Hemodialysis/heart failure hospitalization/cardiac death rates in patients with heart failure receiving or not atorvastatin [Kawasaki, M. et al., Abst 15148].
Rosuvastatin, a hydrophilic statin, was suggested to be more beneficial than atorvastatin, a lipophilic statin, based on observations on its activating effect on the ATP-binding cassette transporter 1 (ABCA1)-dependent cholesterol efflux and macrophagic reverse cholesterol transport in ex vivo studies [Shimizu, T. et al., Abst 11181]. In the clinical arena, rosuvastatin was also more beneficial than atorvastatin in salvaging myocardial tissue after an ST segment-elevated myocardial infarction at comparable LDL cholesterol-lowering activity, leading to better functional outcomes [Chitose, T. et al., Abst 11912] (Fig. 19). However, the results of the SATURN trial demonstrated moderately incremental benefits of rosuvastatin 40 mg over atorvastatin 80 mg on LDL and HDL cholesterol levels, without differences between the two agents in coronary atherosclerosis burden, as assessed by intravascular ultrasound [Nichols, S.J. et al., Late-Breaking Clinical Trial presentation].
Fig. 19. Change in left ventricular ejection fraction at 24 weeks in patients with ST segment-elevated myocardial infarction initiating therapy with rosuvastatin 5 mg/day or atorvastatin 10 mg/day [Chitose, T. et al., Abst 11912].
Like other statins, pitavastatin exerted pleiotropic activity, including improved left atrial structure and function and diastolic function in hypertensive patients with dys-lipidemia [Fujii, T. et al., Abst 8124] and reduced coronary hypercontraction after stenting [Matoba, T. et al., Abst 13004]. Furthermore, in experimental models of hypertension, coadministration of pitavastatin enhanced the beneficial effects of olmesartan in preventing renal injury through an attenuation of the angiotensin-mineralocorticoid receptor signaling interaction [Cheng, X.W. et al., Abst 8273], while the statin per se inhibited mast cell activation and atrial fibrosis, reducing atrial fibrillation inducibility during cardiac overload [Fujimoto, M. et al., Abst 9180].
Not all patients attain full lipid control with statins, but at least in the case of rosuvastatin and atorvastatin, the addition of ezetimibe improved LDL cholesterol levels more effectively than doubling the dose of the statin [Okada, K. et al., Abst 12204], while low-dose simvastatin combined with ezetimibe similarly improved fasting and postprandial lipid levels and endothelial function in patients with metabolic syndrome [Westerink, J. et al., Abst 15400]. Switch to ezetimibe/simvastatin was also more effective than doubling the dose of prior simvastatin or atorvastatin, and numerically superior to switch to rosuvastatin in patients with diabetes and coronary artery disease [Rosen, J.B. et al., Abst 15027] (Fig. 20).
Fig. 20. Proportion of patients attaining LDL cholesterol levels < 70 mg/dL after doubling the dose of prior simvastatin or atorvastatin to 40 and 20 mg, respectively, switching to rosuvastatin 10 mg or switching to ezetimibe/simvastatin 10/20 mg [Rosen, J.B. et al., Abst 15027].
Fibric acid derivatives also have potential therapeutic use in dyslipidemia, and a combination of fenofibrate with atorvastatin was shown to be powerfully effective for enhancing VLDL apolipoprotein E catabolism in subjects with metabolic syndrome [Ooi, E.M. et al., Abst 10106].
While exhibiting direct, lipid-independent antiinflammatory activity on monocytes [Digby, J.E. et al., Abst 14830], niacin has also been effectively used for improving lipid levels in patients with dyslipidemia, with the fixed-drug combination with laropiprant maintaining efficacy while reducing the incidence of flushing, whereas laropiprant discontinuation impaired tolerability [Chen, F. et al., Abst 8824]. Niacin/laropiprant combined with simvastatin was reported to be remarkably effective in decreasing the LDL:HDL cholesterol ratio, increasing HDL cholesterol levels and lowering triglycerides compared to atorvastatin even at high doses [Chen, F. et al., Abst 12811] (Fig. 21). However, despite increasing HDL cholesterol and lowering triglyceride levels, niacin added no benefit to statins in patients with stable coronary artery disease and LDL cholesterol levels already < 70 mg/dL [Boden, W.E. & Probstfield, J., Late-Breaking Clinical Trial presentation], but also brought about elevated expression of lipoprotein-associated phospholipase A2, suggesting a proinflammatory effect that may counteract the beneficial effects on lipid levels [Gundry, S.R. et al., Abst 16318]. Probucol also proved to be a useful alternative for the management of specific forms of dyslipidemia, namely low HDL cholesterol levels, while also enhancing antioxidative potential by increasing paraoxonase 1 activity [Inagaki, M. et al., Abst 12669].
Fig. 21. Percent change in the LDL:HDL cholesterol ratio after 12 weeks of treatment with simvastatin 20 or 40 mg plus niacin/laropiprant or increasing doses of atorvastatin monotherapy. Doses in the X axis refer to those of statins [Chen, F. et al., Abst 12811].
An emerging option for the management of dyslipidemia, mipomersen, significantly improved LDL cholesterol, lipoprotein(a) and apolipoprotein B levels compared to placebo with a favorable safety and tolerability profile in patients with familial hypercholesterolemia or at high risk for coronary artery disease not tolerating statins [Visser, M. et al., Abst 12999] (Fig. 22).
Fig. 22. Change in lipid levels after 26 weeks of treatment with mipomersen 200 mg/week or placebo [Visser, M. et al., Abst 12999].
Regarding other alternatives, while dalcetrapib uncoupled HDL remodeling, increasing pre-beta-HDL and ABCA1-specific cholesterol efflux [Maugeais, C. et al., Abst 15293], robust improvements in HDL cholesterol levels regardless of the baseline lipid profile were demonstrated in the DEFINE trial with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with diabetes or other high-risk characteristics on background statin therapy [Brinton, E. et al., Abst 9649]. Robust, dose-dependent increases in HDL cholesterol levels were also obtained with evacetrapib, which also lowered LDL cholesterol and offered incremental activity upon combination with statins [Nichols, S.J. et al., Late-Breaking Clinical Trial presentation] (Fig. 23). Mechanistically, a related agent, torcetrapib, induced a dispersion of LDL particle size distribution pattern not observed with other therapies [Leary, E.T. et al., Abst 13635].
Fig. 23. Change in HDL (HDL-C) and LDL cholesterol (LDL-C) levels after 12 weeks of treatment with evacetrapib or placebo [Nichols, S.J. et al., Late-Breaking Clinical Trial presentation].
Effective reduction of LDL cholesterol in patients with familial or nonfamilial hypercholesterolemia was demonstrated after monotherapy or combination therapy with the anti-proprotein convertase subtilisin/kexin type 9 monoclonal antibody REGN-727/SAR-236553 [Swergold, G. et al., Abst 16265]. In addition, favorable phase I clinical trial data with the anti-proprotein convertase subtilisin/kexin type 9 monoclonal antibody AMG-145 resulting in decreases in total and LDL cholesterol and apolipoprotein B levels in healthy adults indicated new potential pharmacological strategies for the management of dyslipidemia [Dias, C. et al., Abst 10701]. Furthermore, effective mobilization of cholesterol was demonstrated in dyslipidemic volunteers with the synthetic HDL mimetic CER-001, supporting benefits yet to be determined in clinical trials [Keyserling, C.H. et al., Abst 15525].
At an experimental level, the peroxisome proliferator-activated receptor-delta agonist RSC-451061 improved HDL cholesterol levels, improved inflammation and attenuated atherosclerosis progression in transgenic animal models [Fukao, K. et al., Abst 12358; Naya, N. et al., Abst 12388], whereas the bile salt-activated lipase inhibitor UC-1002 increased HDL cholesterol levels, lowered LDL and VLDL cholesterol levels, and increased reverse cholesterol transport in cholesteryl ester transfer protein transgenic animal models [Howles, P. et al., Abst 16934]. In addition, oral administration of neomycin and polymyxin B (nonabsorbable antibiotics) prevented diet-induced atherosclerosis in LDL receptor-deficient animal models, suggesting a role for gut decontamination and reduced endotoxin availability as an option for managing lipid-related disorders [Ghosh, S.S. et al., Abst 10861].
Benefits on lipid levels were also demonstrated with a nutraceutical containing red yeast rice, policosanol and berberine, which, added to ongoing statin therapy, significantly reduced cholesterol without metabolic adverse events [Pelliccia, F. et al., Abst 8523]. In the same context, a comparative study in subjects with visceral obesity indicated that substituting milk protein for soybean protein improved visceral and subcutaneous fat loss [Uehara, Y. et al., Abst 8570]. In addition, without a direct effect on the lipid profile or oxidative stress markers, consumption of cocoa was associated with increased epicatechin levels in dyslipidemic individuals [Engler, M.M. et al., Abst 10544].
Type 2 diabetes and hyperglycemia
Metformin remains one of the most popular therapies for type 2 diabetes, and data were presented during the meeting on its safety during coronary angiography or percutaneous intervention for acute myocardial infarction, which resulted in no increased hazard despite current recommendations of interrupting therapy prior to the procedure [Puymirat, E. et al., Abst 11554]. Furthermore, metformin was shown to protect the heart from overload-dependent heart failure through mechanisms not yet clarified but apparently independent from AMP-dependent protein kinase [Xu, X. et al., Abst 16017].
Among the thiazolidinediones, while pioglitazone improved left ventricular function in patients with type 2 diabetes [Hughes, A.D. et al., Abst 13277], prevented lipid deposition on and calcification of aortic valves [Chu, Y. et al., Abst 15805], improved atherosclerosis in apolipoprotein E-deficient animal models by acting on the effector and regulatory T-cell balance [Kishimoto, C. et al., Abst 9878], and exerted antiinflammatory activity comparable to that of simvastatin on epicardial adipose tissue in patients with coronary artery disease and metabolic syndrome [Grosso, A.F. et al., Abst 12038], pre-clinical findings suggested an anti-senescence effect on the endothelium mediated by inhibition of the endothelial mitochondrial death pathway [Werner, C. et al., Abst 16261]. However, pioglitazone also reduced hypoxia-inducible factor 1 activation and impaired angiogenesis in diabetic and nondiabetic animal models, suggesting a negative effect in patients with diabetes and established atherosclerosis [Dromparis, P. et al., Abst 16836]. Experimental mechanistic insight into the activity of rosiglitazone demonstrated acute cardioprotective activity during ischemia/reperfusion in nondiabetic conditions via modulation of AMP-dependent protein kinase, Akt and mitogen-activated protein kinase pathway [Morrison, A. et al., Abst 9827], and acute improvements in endothelial function in senescent animal models, the increases in flow-mediated dilation being independent of glycemic and lipid effects brought about by the agent [Sokolowski, S.A. et al., Abst 8926].
Mechanistic observations with sitagliptin in apolipoprotein E-deficient animal models indicated an effect in reducing plaque inflammation and increasing stability by reducing chemokine-induced monocyte migration and macrophage matrix metalloproteinase-9 expression [Burgmaier, M. et al., Abst 9436]. A related compound, des-fluoro-sitagliptin, also improved endothelial function in high-fat diet-fed apolipoprotein E-deficient animals [Matsubara, J. et al., Abst 11457].
A meta-analysis of 14 phase II/III trials comprising 6,228 patients corroborated the lack of increased risk for cardiovascular events during treatment with dapagliflozin, which was rather associated with a potential reduction in cardiovascular event rates [Langkilde, A.M. et al., Abst 8947]. This could be related to the also demonstrated ability of the agent for promoting urinary glucose excretion and reducing systolic blood pressure in patients with type 2 diabetes [Woo, V. et al., Abst 9520].
A single presentation on treatments for obesity identified vidarabine, an adenylate cyclase type 5 inhibitor, as a potential drug candidate for targeting obesity and preventing diabetes based on preclinical findings [Ho, D. et al., Abst 18237].
Direct antiatherosclerotic effects in experimental animal models were demonstrated with apolipoprotein E and apolipoprotein A-I mimetics, the latter without the favorable impact on cholesterol levels observed after treatment with the former [Nayyar, G. et al., Abst 13577; Lee, B.S. et al., Abst 14340], as well as a bile salt-sequestering pegylated quaternized polyamine nanogel [Matsumori, R. et al., Abst 26414]. Direct effects against atherosclerosis, as demonstrated by noninvasive imaging and histological analyses, were also seen after treatment with the liver X receptor agonist R-211945, which induced plaque regression not attained by treatment with atorvastatin [Vucic, E. et al., Abst 14911].
Additional risk factors
In-hospital initiation of bupropion in patients with cardiovascular disease was not associated with reduced long-term abstinence rates compared to placebo [Grandi, S. et al., Abst 13605]. Negative results were also reported from a study aimed at assessing whether vitamin D supplementation could improve endothelial function, vascular stiffness and inflammation in healthy postmenopausal women [Gepner, A.D. et al., Abst 8149].
Among miscellaneous news on heart transplants, a study in recipients indicated potential for early everolimus for preventing coronary allograft vasculopathy, but not for late treatment for improving the disorder once established [Potena, L. et al., Abst 10802]. Mechanistically, the agent dose-dependently induced human leukocyte antigen-G expression in coronary artery smooth muscle cells, which may partly explain its antirejection and graft vasculopathy-protective activity [Mociornita, A.G. et al., Abst 13205]. In the experimental preclinical arena, injection of adenosine prior to cardio-plegia significantly attenuated cold ischemia/reperfusion injury in the heart of old donors [Lim, S.H. et al., Abst 12101].
Fish and olive oil supplementation prevented the negative impact on the cardiovascular health of exposure to air pollution [Tong, H. et al., Abst 15654]. In that context, chronic coffee consumption blunted the effect of caffeine on aortic stiffness and wave reflections, indicating that substances other than caffeine may counterbalance the properties of the alkaloid [Ioakeimidis, N. et al., Abs 12112], whereas dark chocolate reduced arterial dysfunction-enhanced arterial dilation in smokers by lowering NADPH oxidase activity [Loffredo, L. et al., Abst 12436].
Dobutamine proved superior to milrinone for alleviating hemodynamic instability after focal cerebral ischemia secondary to vasospastic subarachnoid hemorrhage [Mutoh, T. et al., Abst 8110].
Dietary omega 3-polyunsaturated fatty acid supplementation in children with a history of impaired fetal growth prevented early increases in carotid artery wall thickness [Skilton, M. et al., Abst 8661].
In patients with severe Kawasaki disease, adding prednisolone to intravenous immunoglobulin better prevented coronary artery abnormalities [Kobayashi T. et al., Abst 9271].
The hyaluronidase inhibitor l-ascorbate-6-hexadecanoate prevented aortic aneurysms in CD44-deficient animal models by preventing hyaluronic acid fragmentation and the effect of fragments on CD44 [Miyoshi, T. et al., Abst 11614]. Edavarone also prevented aneurysm formation and prevented progression in experimental models of abdominal aortic aneurysm [Morimoto, K. et al., Abst 18192].
Co-treatment with nebivolol enhanced the activity of sildenafil, tadalafil and vardenafil on corpus cavernosum relaxation in diabetic patients with erectile dysfunction possibly by potentiating the nitric oxide/cyclic GMP signaling pathway [La Fuente, J.M. et al., Abst 12136].
Endothelial barrier-protective effects were described with imatinib, which were related to inhibition of ABL-related gene rather to direct inhibition of c-Abl [Aman, J. et al., Abst 13436].
A new perfusion agent with improved cardiac and hepatic kinetics, [99mTc]-N-MPO, improved imaging of the inferior left ventricular wall by single-photon emission computed tomography compared to alternative tracers, including [99mTc]-sestamibi [Liu, Z. et al., Abst 13531]. Improved myocardial scintigraphy for predicting impaired myocardial function reserve during a dobutamine stress test was similarly reported with [125I]-MIBG in patients with dilated cardiomyopathy [Ohshima, S. et al., Abst 14907].
Rapid waning of responses to influenza vaccination was demonstrated even after double-dose immunization in patients with heart failure [Vardeny, O. et al., Abst 16608].
Add-on methotrexate improved the clinical and metabolic status and reduced corticosteroid requirements in patients with cardiac sarcoidosis [Yazaki, Y. et al., Abst 17849].