Evolving Challenges in Promoting Cardiovascular Health

Journal Articles

David H. Adams

Adams DH, Anyanwu AC. Valve Disease: Asymptomatic mitral regurgitation: does surgery save lives? Nat. Rev. Cardiol. 2009;6(5):330-332.

Adams DH, Rosenhek R, Falk V. Degenerative mitral valve regurgitation: best practice revolution. Eur. Heart J. 2010;31(16):1958-1966.

Anyanwu AC, Adams DH. Ischemic mitral regurgitation: recent advances. Curr. Treat. Options Cardiovasc. Med. 2008;10(6):529-537.

Anyanwu AC, Bridgewater B, Adams DH. The lottery of mitral valve repair surgery. Heart 2010;96(24):1964-1967.

Castillo JG, Solís J, González-Pinto A, Adams DH. [Surgical echocardiography of the mitral valve]. Rev. Esp. Cardiol. 2011;64(12):1169-1181.

Lina Badimon

Badimon L, Storey RF, Vilahur G. Update on lipids, inflammation and atherothrombosis. Thromb. Haemost. 2011;105 Suppl 1:S34-42.

Cubedo J, Padró T, García-Moll X, et al. Proteomic signature of Apolipoprotein J in the early phase of new-onset myocardial infarction. J. Proteome Res. 2011;10(1):211-220.

García-Arguinzonis M, Padró T, Lugano R, Llorente-Cortes V, Badimon L. Low-density lipoproteins induce heat shock protein 27 dephosphorylation, oligomerization, and subcellular relocalization in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2010;30(6):1212-1219.

Ibanez B, Giannarelli C, Cimmino G, et al. Recombinant HDL(Milano) exerts greater anti-inflammatory and plaque stabilizing properties than HDL(wild-type). Atherosclerosis 2012;220(1):72-77.

Llorente-Cortes V, Casani L, Cal R, et al. Cholesterol-lowering strategies reduce vascular LRP1 overexpression induced by hypercholesterolaemia. Eur. J. Clin. Invest. 2011;41(10):1087-1097.

Josep Brugada Terradellas

Boussy T, Paparella G, de Asmundis C, et al. Genetic basis of ventricular arrhythmias. Heart Fail. Clin. 2010;6(2):249-266.

Capulzini L, Brugada P, Brugada J, Brugada R. Arrhythmia and right heart disease: from genetic basis to clinical practice. Rev. Esp. Cardiol. 2010;63(8):963-983.

Della Bella P, Brugada J, Zeppenfeld K, et al. Epicardial ablation for ventricular tachycardia: a European multicenter study. Circ. Arrhythm. Electrophysiol. 2011;4(5):653-659.

Guillem MS, Climent AM, Millet J, et al. Conduction abnormalities in the right ventricular outflow tract in Brugada syndrome detected body surface potential mapping. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010;2010:2537-2540.

Silva E, Sitges M, Doltra A, et al. Analysis of temporal delay in myocardial deformation throughout the cardiac cycle: utility for selecting candidates for cardiac resynchronization therapy. Heart Rhythm 2010;7(11):1580-1586.

Valentin Fuster

Corti R, Fuster V. Imaging of atherosclerosis: magnetic resonance imaging. European Heart Journal 2011;32(14):1709-1719.

Falk E, Sillesen H, Muntendam P, Fuster V. The high-risk plaque initiative: primary prevention of atherothrombotic events in the asymptomatic population. Curr. Atheroscler. Rep. 2011;13(5):359-366.

Fuster V, Kelly BB, Vedanthan R. Global cardiovascular health: urgent need for an intersectoral approach. J. Am. Coll. Cardiol. 2011;58(12):1208-1210.

Kovacic JC, Moreno P, Hachinski V, Nabel EG, Fuster V. Cellular senescence, vascular disease, and aging: part 1 of a 2-part review. Circulation 2011;123(15):1650-1660.

Sanz G, Fuster V, Guzmán L, et al. The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives. Am. Heart J. 2011;162(5):811-817.e1.

Michael A. Gimbrone, Jr.

Dai G, Vaughn S, Zhang Y, et al. Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ. Res. 2007;101(7):723-733.

García-Cardeña G, Gimbrone MA. Biomechanical modulation of endothelial phenotype: implications for health and disease. Handb. Exp. Pharmacol. 2006;(176 Pt 2):79-95.

Gimbrone MA. The Gordon Wilson lecture. Understanding vascular endothelium: a pilgrim's progress. Endothelial dysfunction, biomechanical forces and the pathobiology of atherosclerosis. Trans. Am. Clin. Climatol. Assoc. 2010;121:115-127; discussion 127.

Parmar KM, Nambudiri V, Dai G, et al. Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. J. Biol. Chem. 2005;280(29):26714-26719.

Parmar KM, Larman HB, Dai G, et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J. Clin. Invest. 2006;116(1):49-58.

Roger J. Hajjar

Hadri L, Hajjar RJ. Calcium cycling proteins and their association with heart failure. Clin. Pharmacol. Ther. 2011;90(4):620-624.

Ishikawa K, Tilemann L, Fish K, Hajjar RJ. Gene delivery methods in cardiac gene therapy. J. Gene Med. 2011;13(10):566-572.

Jessup M, Greenberg B, Mancini D, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+−ATPase in patients with advanced heart failure. Circulation 2011;124(3):304-313.

Kho C, Lee A, Jeong D, et al. SUMO1-dependent modulation of SERCA2a in heart failure. Nature 2011;477(7366):601-605.

Kratlian RG, Hajjar RJ. Cardiac gene therapy: from concept to reality. Curr. Heart Fail. Rep. 2012;9(1):33-39.

Jonathan L. Halperin

Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J. Am. Coll. Cardiol. 2007;50(7):e1-e157.

Broukhim M, Halperin JL. Stroke prevention in the high-risk atrial fibrillation patient: medical management. Curr. Cardiol. Rep. 2011;13(1):9-17.

Fraker TD, Fihn SD, Gibbons RJ, et al. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J. Am. Coll. Cardiol. 2007;50(23):2264-2274.

Lip GYH, Halperin JL. Improving stroke risk stratification in atrial fibrillation. Am. J. Med. 2010;123(6):484-488.

Viles-Gonzalez JF, Fuster V, Halperin JL. New anticoagulants for prevention of stroke in patients with atrial fibrillation. J. Cardiovasc. Electrophysiol. 2011;22(8):948-955.

Steen E. Husted

Husted SE, Nielsen HK. [Unfractionated heparin and low molecular weight heparin for acute coronary syndromes—assessment of a Cochrane review]. Ugeskr. Laeg. 2010;172(42):2888-2891.

Husted SE, Ziegler BK, Kher A. Long-term anticoagulant therapy in patients with coronary artery disease. Eur. Heart J. 2006;27(8):913-919.

Nielsen JD, Rasmussen HMS, Husted SE. [The antithrombotic-treated patient]. Ugeskr. Laeg. 2006;168(49):4296-4299.

Overgaard K, Poulsen TS, Husted SE. [Antithrombotic therapy in ischemic stroke and transient ischemic attack]. Ugeskr. Laeg. 2007;169(40):3379-3382.

Sejersen HM, Nielsen HK, Thyssen JP, Husted SE. [Deep venous thrombosis—epidemiology, diagnosis and treatment]. Ugeskr. Laeg. 2007;169(2):109-111.

Borja Ibañez

Ibanez B, Badimon JJ. Cyclosporine in acute myocardial infarction. N. Engl. J. Med. 2008;359(21):2287; author reply 2288-2289.

Ibanez B, Fuster V. Ischaemic conditioning for myocardial salvage after AMI. Lancet 2010;375(9727):1691; author reply 1692.

Ibanez B, Cimmino G, Prat-González S, et al. The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion. Int. J. Cardiol. 2011;147(3):428-432.

Ibáñez B, Fuster V, Macaya C, et al. [Modulation of the beta-adrenergic system during acute myocardial infarction: rationale for a new clinical trial]. Rev. Esp. Cardiol. 2011;64 Suppl 2:28-33.

Suárez-Barrientos A, López-Romero P, Vivas D, et al. Circadian variations of infarct size in acute myocardial infarction. Heart 2011;97(12):970-976.

Carlos Macaya

Anguita M, Fernández-Ortiz A, Worner F, et al. [The Spanish Society of Cardiology and the ESC clinical practice guidelines: towards a new orientation]. Rev. Esp. Cardiol. 2011;64(9):795-796.

Escaned J, Macaya C, Serruys PW. Secondary coronary revascularisation. A comprehensive approach to coronary revascularisation in patients with previous surgical or percutaneous interventions. Foreword. EuroIntervention 2009;5 Suppl D:D5.

Franco E, Núñez-Gil IJ, Vivas D, et al. Heart failure and non-ST-segment elevation myocardial infarction: a review for a widespread situation. Eur. J. Intern. Med. 2011;22(6):533-540.

García E, Hernández-Antolín R, Dutary J, et al. [Rapidly evolving techniques for structural heart disease interventions]. Rev. Esp. Cardiol. 2011;64 Suppl 2:19-27.

Frederick A. Masoudi

Bonow RO, Douglas PS, Buxton AE, et al. ACCF/AHA methodology for the development of quality measures for cardiovascular technology: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures. J. Am. Coll. Cardiol. 2011;58(14):1517-1538.

Masoudi FA. Reflections on performance measurement in cardiovascular disease. Circ. Cardiovasc. Qual. Outcomes 2011;4(1):2-4.

Masoudi FA, Peterson ED, Anderson JL, Bonow RO, Jacobs AK. Clinical guidelines and performance measures; responsible guidance and accountability. J. Am. Coll. Cardiol. 2010;56(25):2081-2083.

Matlock DD, Kutner JS, Emsermann CB, et al. Regional variations in physicians' attitudes and recommendations surrounding implantable cardioverter-defibrillators. J. Card. Fail. 2011;17(4):318-324.

Peterson PN, Rumsfeld JS, Liang L, et al. Treatment and risk in heart failure: gaps in evidence or quality? Circ. Cardiovasc. Qual. Outcomes 2010;3(3):309-315.

Simón Mendéz-Ferrer

Ferraro F, Lymperi S, Méndez-Ferrer S, et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci. Transl. Med. 2011;3(104):104ra101.

Isern J, Méndez-Ferrer S. Stem cell interactions in a bone marrow niche. Curr. Osteoporos. Rep. 2011;9(4):210-218.

Méndez-Ferrer S, Chow A, Merad M, Frenette PS. Circadian rhythms influence hematopoietic stem cells. Curr. Opin. Hematol. 2009;16(4):235-242.

Méndez-Ferrer S, Battista M, Frenette PS. Cooperation of beta(2)- and beta(3)-adrenergic receptors in hematopoietic progenitor cell mobilization. Ann. N.Y. Acad. Sci. 2010;1192:139-144.

Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010;466(7308):829-834.

Pedro R. Moreno

Fernandez-Friera L, Garcia-Alvarez A, Romero A, et al. Lipid-rich obstructive coronary lesions is plaque characterization any important? JACC Cardiovasc. Imaging 2010;3(8):893-895.

Moreno PR. The high-risk thin-cap fibroatheroma: a new kid on the block. Circ. Cardiovasc. Interv. 2009;2(6):500-502.

Moreno PR, Astudillo L, Elmariah S, et al. Increased macrophage infiltration and neovascularization in congenital bicuspid aortic valve stenosis. J. Thorac. Cardiovasc. Surg. 2011;142(4):895-901.

Purushothaman K, Purushothaman M, Muntner P, et al. Inflammation, neovascularization and intra-plaque hemorrhage are associated with increased reparative collagen content: implication for plaque progression in diabetic atherosclerosis. Vasc. Med. 2011;16(2):103-108.

Sirol M, Moreno PR, Purushothaman K, et al. Increased neovascularization in advanced lipid-rich atherosclerotic lesions detected by gadofluorine-M-enhanced MRI: implications for plaque vulnerability. Circ. Cardiovasc. Imaging 2009;2(5):391-396.

Jagat Narula

Marwick TH, Narula J. Acquiring multiple parameters from multiple tests: the real principle of multimodality imaging. JACC Cardiovasc. Imaging 2011;4(6):688-689.

Marwick TH, Narula J. Imaging of pharmacologic intervention decoding therapeutic mechanism or defining effectiveness? JACC Cardiovasc. Imaging 2011;4(10):1146-1147.

Narula J, Strauss HW. Myo-Myo: Yes, papa. Eating sugar? No, papa! Modulating the myocardial menu for imaging coronary inflammation. Eur. J. Nucl. Med. Mol. Imaging 2011;38(11):2014-2017.

Sengupta PP, Marwick TH, Narula J. Adding dimensions to unimodal cardiac images. JACC Cardiovasc. Imaging 2011;4(7):816-818.

Verjans JWH, van de Borne SWM, Hofstra L, Narula J. Molecular imaging of myocardial remodeling after infarction. Methods Mol. Biol. 2011;680:227-235.

Robert A. Phillips

Davidson MH, Basile J, Garber AJ, Phillips RA. Reducing the risk of stroke through appropriate targets and treatments. Prev. Cardiol. 2007;10(4):215-221.

Gharavi A, Diamond JA, Phillips RA. Exercise capacity and left ventricular function. JAMA 2009;301(22):2326; author reply 2326-2327.

Phillips RA. Solving the paradox of self blood-pressure measurement. Nat. Clin. Pract. Cardiovasc. Med. 2008;5(6):306-307.

Pogue V, Rahman M, Lipkowitz M, et al. Disparate estimates of hypertension control from ambulatory and clinic blood pressure measurements in hypertensive kidney disease. Hypertension 2009;53(1):20-27.

Vivek Reddy

Ahmed H, Reddy VY. Technical advances in the ablation of atrial fibrillation. Heart Rhythm 2009;6(8 Suppl):S39-44.

Dukkipati SR, Neuzil P, Skoda J, et al. Visual balloon-guided point-by-point ablation: reliable, reproducible, and persistent pulmonary vein isolation. Circ. Arrhythm. Electrophysiol. 2010;3(3):266-273.

Reddy VY. Atrial fibrillation: unanswered questions and future directions. Cardiol. Clin. 2009;27(1):201-216, x-xi.

Reddy VY, Morales G, Ahmed H, et al. Catheter ablation of atrial fibrillation without the use of fluoroscopy. Heart Rhythm 2010;7(11):1644-1653.

Viles-Gonzalez JF, Fuster V, Halperin J, Calkins H, Reddy VY. Rhythm control for management of patients with atrial fibrillation: balancing the use of antiarrhythmic drugs and catheter ablation. Clin. Cardiol. 2011;34(1):23-29.

Josep Rodés-Cabau

Bagur R, Rodés-Cabau J. Appropriate assessment of operative risk in patients with severe symptomatic aortic stenosis: importance for patient selection in the era of transcatheter aortic valve implantation. Ann. Thorac. Surg. 2011;92(3):1157-1158.

Bagur R, Rodés-Cabau J, Dumont E, et al. Performance-based functional assessment of patients undergoing transcatheter aortic valve implantation. Am. Heart J. 2011;161(4):726-734.

Clavel MA, Webb JG, Rodés-Cabau J, et al. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. Circulation 2010;122(19):1928-1936.

Kalavrouziotis D, Rodés-Cabau J, Bagur R, et al. Transcatheter aortic valve implantation in patients with severe aortic stenosis and small aortic annulus. J. Am. Coll. Cardiol. 2011;58(10):1016-1024.

Rodés-Cabau J. Transcatheter aortic valve implantation: current and future approaches. Nat. Rev. Cardiol. 2012;9(1):15-29.

James H.F. Rudd

Bucerius J, Duivenvoorden R, Mani V, et al. Prevalence and risk factors of carotid vessel wall inflammation in coronary artery disease patients: FDG-PET and CT imaging study. JACC Cardiovasc. Imaging 2011;4(11):1195-1205.

Dweck MR, Jones C, Joshi NV, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation 2012;125(1):76-86.

Fayad ZA, Mani V, Woodward M, et al. Rationale and design of dal-PLAQUE: a study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Am. Heart J. 2011;162(2):214-221.e2.

Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;378(9802):1547-1559.

Vucic E, Dickson SD, Calcagno C, et al. Pioglitazone modulates vascular inflammation in atherosclerotic rabbits noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging. JACC Cardiovasc. Imaging 2011;4(10):1100-1109.

Javier Sanz

Garcia-Alvarez A, Fernandez-Friera L, Lau JF, et al. Evaluation of right ventricular function and post-operative findings using cardiac computed tomography in patients with left ventricular assist devices. J. Heart Lung Transplant. 2011;30(8):896-903.

Ibanez B, Cimmino G, Bénézet-Mazuecos J, et al. Quantification of serial changes in plaque burden using multi-detector computed tomography in experimental atherosclerosis. Atherosclerosis 2009;202(1):185-191.

Prat-Gonzalez S, Sanz J, Garcia MJ. Cardiac CT: indications and limitations. J. Nucl. Med. Technol. 2008;36(1):18-24.

Sanz J, Kariisa M, Dellegrottaglie S, et al. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc. Imaging 2009;2(3):286-295.

Sanz J, Fernández-Friera L, Moral S. Imaging techniques and the evaluation of the right heart and the pulmonary circulation. Rev. Esp. Cardiol. 2010;63(2):209-223.

Laurence Sperling

Bhatt KN, Wells BJ, Sperling LS, Baer JT. High-density lipoprotein therapy: is there hope? Curr. Treat. Options Cardiovasc. Med. 2010;12(4):315-328.

Mehta PK, Baer J, Nell C, Sperling LS. Low-density lipoprotein apheresis as a treatment option for hyperlipidemia. Curr. Treat. Options Cardiovasc. Med. 2009;11(4):279-288.

Ramjee V, Sperling LS, Jacobson TA. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification: do the math. J. Am. Coll. Cardiol. 2011;58(5):457-463.

Ramsden CE, Faurot KR, Carrera-Bastos P, et al. Dietary fat quality and coronary heart disease prevention: a unified theory based on evolutionary, historical, global, and modern perspectives. Curr. Treat. Options Cardiovasc. Med. 2009;11(4):289-301.

Smiley III WH, Khan BV, Sperling LS. Management of the statin-intolerant patient. Curr. Treat. Options Cardiovasc. Med. 2009;11(4):263-271.

Andre Terzic

Banovic M, Ostojic MC, Bartunek J, et al. Brachial approach to NOGA-guided procedures: electromechanical mapping and transendocardial stem-cell injections. Tex. Heart Inst. J. 2011;38(2):179-182.

Martinez-Fernandez A, Nelson TJ, Terzic A. Nuclear reprogramming strategy modulates differentiation potential of induced pluripotent stem cells. J. Cardiovasc. Transl. Res. 2011;4(2):131-137.

Nelson TJ, Terzic A. Induced pluripotent stem cells: an emerging theranostics platform. Clin. Pharmacol. Ther. 2011;89(5):648-650.

Nelson TJ, Martinez-Fernandez A, Yamada S, et al. Induced pluripotent stem cells: advances to applications. Stem Cells Cloning 2010;3:29-37.

Terzic A, Folmes CD, Martinez-Fernandez A, Behfar A. Regenerative medicine: on the vanguard of health care. Mayo Clin. Proc. 2011;86(7):600-602.

Miguel Torres

Casanova JC, Uribe V, Badia-Careaga C, et al. Apical ectodermal ridge morphogenesis in limb development is controlled by Arid3b-mediated regulation of cell movements. Development 2011;138(6):1195-1205.

González-Rosa JM, Padrón-Barthe L, Torres M, Mercader N. [Lineage tracing of epicardial cells during development and regeneration]. Rev. Esp. Cardiol. 2010;63 Suppl 2:36-48.

González-Rosa JM, Martín V, Peralta M, Torres M, Mercader N. Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development 2011;138(9):1663-1674.

Roselló-Díez A, Torres M. Regulative patterning in limb bud transplants is induced by distalizing activity of apical ectodermal ridge signals on host limb cells. Dev. Dyn. 2011;240(5):1203-1211.

Roselló-Díez A, Ros MA, Torres M. Diffusible signals, not autonomous mechanisms, determine the main proximodistal limb subdivision. Science 2011;332(6033):1086-1088.

Clyde W. Yancy

Fonarow GC, Albert NM, Curtis AB, et al. Associations between outpatient heart failure process-of-care measures and mortality. Circulation 2011;123(15):1601-1610.

Fonarow GC, Yancy CW, Hernandez AF, et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am. Heart J. 2011;161(6):1024-1030.e3.

Mehra MR, Albert NM, Curtis AB, et al. Factors associated with improvement in guideline-based use of ICDs in eligible heart failure patients. Pacing Clin. Electrophysiol. 2012;35(2):135-145.

Rao MV, Murray P, Yancy CW. Management of heart failure with renal artery ischemia. Cardiol. Clin. 2011;29(3):433-445.

Thomas KL, Hernandez AF, Dai D, et al. Association of race/ethnicity with clinical risk factors, quality of care, and acute outcomes in patients hospitalized with heart failure. Am. Heart J. 2011;161(4):746-754.

Sponsors

Presented by

Bronze Sponsors

Esteve

Ferrer

Fundación Ramón Areces

Academy Friends

Bayer HealthCare

Laboratorios Servier España

Siemens, S.A

This eBriefing is sponsored in part by

Grant Support

Supported by an independent education grant from Astellas Pharma Global Development and a strategic grant from The Edwards Lifesciences Fund.

This eBriefing is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation and The Mushett Family Foundation.

Cardiovascular disease affects millions of individuals worldwide and in Spain, where there has been a particular focus on this disease over the past few decades. Many advances in cardiology can be attributed, at least in part, to the leadership of Spanish cardiologist Valentin Fuster, who has made it his mission to attack cardiovascular disease on as many fronts as possible during the course of his distinguished career. Fuster, who trained in Spain, Canada, and the U.S., is currently associated with both the Mount Sinai Medical Center in New York and with the Centro Nacional de Investigaciones Cardiovasculares in Madrid.

In November 2011, Fuster organized a conference on cardiovascular disease that involved many distinguished speakers and covered most of the current hot topics in this disease area. This meeting was unusual among cardiology events in that it included speakers on the full range of cardiovascular research, from basic science to therapies involving genes and stem cells and to current challenges in the clinical management of these conditions.

Speakers on basic science topics included Michael A. Gimbrone, Jr., of Harvard Medical School, who spoke on new insights into vascular endothelial cell biology, Pedro R. Moreno of Mount Sinai Medical Center, who discussed the role of angiogenesis in atherosclerotic plaque formation, regression, and degeneration, and Lina Badimon of the Barcelona Cardiovascular Research Center, who described recent research on interactions between, and regulation and composition of, cholesterol-carrying lipoprotein particles in the blood.

Jagat Narula, also of Mount Sinai, and James H. F. Rudd of the University of Cambridge in the UK described emerging advances in noninvasive imaging techniques that are helping researchers gain new insights into the pathophysiology of plaque formation and its contribution to dangerous cardiovascular events such as acute myocardial infarction (MI). Discussions of cutting-edge research on gene- and cell-based therapies for cardiovascular disease complemented these talks. Simón Méndez-Ferrer and Miguel Torres, also of the Centro Nacional de Investigaciones Cardiovasculares, and Andre Terzic of the Mayo Clinic, spoke of their investigations into the regulation of stem cell activity and tissue regeneration processes, as part of efforts to regenerate heart tissue in individuals whose hearts have been damaged by acute MI or by chronic heart failure. Roger J. Hajjar of Mount Sinai described his efforts to correct molecular defects associated with chronic heart failure using gene therapy techniques.

The second day of the conference marked a turn to more clinical topics. Borja Ibáñez of the Centro Nacional de Investigaciones Cardiovasculares and Carlos Macaya of the Hospital Clínico San Carlos in Madrid described efforts to reduce the damage inflicted on the heart by acute MI, by using cardioprotective treatments and by shortening the time from symptom onset to revascularization. Steen E. Husted of Aarhus University Hospital in Aarhus, Denmark provided an extensive review of new and emerging oral anti-thrombotic agents, which are likely to improve outcomes in a wide range of cardiovascular conditions. Fuster described emerging evidence that cardiovascular disease and degenerative brain conditions, such as Alzheimer's disease, are closely related, providing increasing motivation for treating cardiovascular risk factors. Jonathan L. Halperin of Mount Sinai discussed the need for increasingly individualized treatment of cardiovascular disease in the elderly that goes beyond age to the consideration of other patient characteristics in the selection of therapies.

Later sessions focused on recent expert thinking on the treatment of cardiovascular risk factors and current evidence-based care for patients with cardiomyopathies and heart failure. Laurence Sperling of Emory University School of Medicine discussed current guidelines and recent research on optimal blood lipid targets for cardiovascular disease prevention, while Robert A. Phillips of the University of Massachusetts Medical School did the same for hypertension. Clyde W. Yancy of the Northwestern University Feinberg School of Medicine and Frederick A. Masoudi of the University of Colorado Denver discussed the latest quality of care guidelines for heart failure, while Javier Sanz of Mount Sinai covered recent advances in the imaging techniques that are improving diagnosis and prognostication for the cardiomyopathies.

The final sessions of the meeting focused on some of the most challenging conditions faced by cardiologists and patients today. Fuster described advances in the treatment of atrial fibrillation, as well as mounting evidence that this condition is also associated with degenerative brain disease. Josep Brugada Terradellas of the University of Barcelona and Vivek Reddy of Mount Sinai School discussed emerging approaches to risk determination and improved interventional treatments for conditions that involve abnormal electrical conduction in the heart, such as ventricular tachycardias and atrial fibrillation. Josep Rodés-Cabau, of Québec Heart and Lung Institute and David H. Adams of Mount Sinai reviewed current guidelines and recent advances in the treatment of structural heart disease such as aortic valve stenosis and mitral valve regurgitation. Fuster rounded out the final session with a discussion of thoracic aortic aneurysm, a dangerous and understudied condition that deserves more attention from clinicians and researchers.

Overall, the meeting provided a highly inclusive snapshot of the current state of cardiovascular research, acknowledging advances ranging from basic pathophysiology, to noninvasive imaging techniques and cutting edge therapies, and the latest clinical management strategies for acute MI, cardiomyopathies, chronic heart failure, atrial and ventricular arrhythmias, and structural heart disease. This soup-to-nuts approach is likely to make a lasting impression on the investigators who attended and to fertilize multiple new approaches to the ever-increasing health threat of cardiovascular disease.

Speakers:
Valentin Fuster, Mount Sinai Medical Center and Centro Nacional de Investigaciones Cardiovasculares
Michael A. Gimbrone, Jr., Harvard Medical School
Pedro R. Moreno, Mount Sinai Medical Center
Lina Badimon, Barcelona Cardiovascular Research Center

Highlights

• Basic, clinical, and population-wide research projects continue to improve prevention and management of cardiovascular diseases.
• Biomechanical forces experienced by endothelial cells in blood vessel walls alter their gene expression patterns, influencing the location of plaques in the vessel wall and suggesting new targets for pharmacologic intervention.
• Angiogenic processes play an important role in plaque pathophysiology, suggesting another potential therapeutic approach to atherosclerosis.
• New insights into the structure and contents of cholesterol-containing lipoprotein particles in the blood are also leading to new therapeutic approaches as well as to new approaches to risk determination.

Cardiovascular defense challenges at the basic, clinical, and population levels

Valentin Fuster, of the Mount Sinai Medical Center in New York City and the Centro Nacional de Investigaciones Cardiovasculares in Madrid, set the stage for the wide ranging topics to be covered at the conference by describing current basic, clinical, and population-wide research projects in his laboratory and others'. He noted that despite significant progress in the treatment of complex cardiovascular disease, much still needs to be done.

At the basic science level, Fuster described three important defense mechanisms that are used by the human body to work against atherosclerosis, the root cause of many cardiovascular conditions. These mechanisms, which work to promote cardiovascular homeostasis, include the production of new endothelial cells in blood vessel walls, microvascular changes within the walls of large vessels, and the transport of cholesterol away from the vessel wall by macrophages. Substantial basic research is needed to better understand these processes. Much of the work can be done in animals, but the development of new technologies, such as noninvasive imaging of human atherosclerotic lesions, will allow investigation of these important mechanisms in humans as well. These studies are needed to spur the design of new pharmacologic therapies and new interventions, and may lead to new gene- and cell-based therapies as well.

Moving from the basic to the clinical, Fuster discussed the status of cardiovascular risk management. Major risk factors such as obesity and insufficient physical activity continue to increase in prevalence, and on average, the population continues to age. Therapies exist to treat many modifiable cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes, but they are underused. Even among clinical trial participants, who receive extra medical attention, adherence to these medications is only around 20%. This situation represents an important challenge for the coming decades.

Meanwhile, advances in imaging technology are improving diagnosis and prognostication. Fuster's studies using advanced imaging techniques in humans show that conventional imaging technologies miss about one-third of atherosclerotic plaque. His work suggests that measuring overall plaque burden in the body may be more important than identifying specific vulnerable plaques that are likely to rupture and cause a cardiovascular event.

Moving to the global realm, Fuster described a number of population-wide projects intended to promote health through behavioral change in the developing world, where cardiovascular disease is increasing in prevalence. These projects include an educational program for children in Bogotá, Columbia; a support group program for adults in Grenada; and clinical trials of a polypill containing multiple risk-lowering agents that is intended to reduce cost and inconvenience, potentially improving adherence. Fuster called it "economically unsustainable" for the medical profession to continue treating the end results of cardiovascular disease instead of working to prevent it.

Vascular endothelium in health and disease: new insights into its pathobiology

Each of the next three speakers took it in turns to discuss one of the three basic mechanisms that the human vascular system uses to maintain homeostasis and to protect itself against atherosclerotic plaque. Michael A. Gimbrone, Jr., of Harvard Medical School, talked about his work on the endothelial cells that line blood vessel walls. Deleterious changes in these cells play key roles in some of the processes leading to cardiovascular disease, including chronic inflammation, hypertension, thrombosis, and atherosclerosis.

Gimbrone's group and others have done considerable work to characterize the contents and locations of atherosclerotic plaques. These plaques are lesions in the blood vessel wall where lipids, cells, and fibrotic materials collect. Their rupture can lead to the formation of a clot and subsequently to a cardiovascular event such as a myocardial infarction (MI). The plaques tend to occur near areas of curvature or branch points, suggesting that differences in biomechanical forces, such as shear stresses and hydrostatic pressures, might help drive plaque development, perhaps by modulating the behavior of the underlying endothelial cells.

Hemodynamic modeling of the forces experienced by different regions of the human carotid artery. (Image courtesy of Michael Gimbrone, Jr.)

Gimbrone and his group developed a cell culture system that replicates the biomechanical conditions experienced by cells in the blood vessel lining. Using genome-wide expression studies, they identified two small subsets of genes whose expression changed under atheroprone conditions, as in areas of curvature, and under atheroprotective conditions, as in straight areas where plaque is less likely to form. Their work shows that expression of the adhesion molecule VCAM1, an important determinant of plaque formation, is modulated by a transcription factor known as Koppel-like factor 2 (KLF2). KLF2 appears to be important in promoting atheroprotective conditions in blood vessel wall epithelial cells. This molecule and its associated signaling proteins represent a potential target for new anti-atherosclerotic agents.

The adventitia and the media vasa vasorum

Pedro R. Moreno of Mount Sinai Medical Center provided an overview of work on the second protective mechanism, which involves angiogenesis, or the growth of new blood vessels. Large blood vessels whose walls are many cell layers thick possess a system of smaller vessels, known as the vasa vasorum, that provides a pathway for nutrients in and waste products out of cells deep in the vessel wall. In areas of well established atherosclerotic plaque, microvessels derived from the vasa vasorum also infiltrate the plaque, in response to stimuli such as hypoxia (lack of oxygen), the presence of oxidized lipids, and, in some individuals, hyperglycemia. This natural defense mechanism helps prevent the formation of necrotic tissue inside the plaque, allows macrophages and other healing cells to pass in and out, and allows for removal of excess lipids and other waste materials associated with the plaque. These processes are essential for plaque regression as part of the healing process.

However, these newly created microvessels are weak, with walls only one cell thick, which can allow leakage of red blood cells into the plaque, a condition known as intraplaque hemorrhage. These red blood cells contribute to the cholesterol content of the plaque, and their lysis releases free hemoglobin, leading to the formation of reactive oxygen species and consequent tissue damage. Intraplaque hemorrhage is thought to play an important role in deleterious clinical events such as plaque rupture and clot formation. Clinical studies have shown that individuals with higher levels of intraplaque hemorrhage have a much higher risk of stroke, compared to individuals with the same level of blood vessel blockage but with less intraplaque hemorrhage.

Moreno described some of his own work in this area, which suggests that intraplaque hemorrhage is particularly important in diabetes. Plaques from individuals with diabetes show higher levels of vascularization, increased inflammation, and increased intraplaque hemorrhage compared to those of individuals without diabetes. Research in several model systems suggests that the increased blood glucose levels characteristic of diabetes may promote angiogenesis and increased vascularization.

These insights into the relationship between angiogenesis and plaque progression have potential clinical applications. For example, imaging the extent of new vessel formation may have prognostic value in patients with atherosclerosis. The results also suggest that antiangiogenic agents could be helpful in treating cardiovascular disease. Statins, which have been shown to prevent new microvessel formation in hypercholesterolemic pigs, might thus also treat atherosclerosis independently of their cholesterol-lowering effects. Further studies of plaque vascularization are likely to yield important new clinical avenues for treating cardiovascular disease.

Intimal LDL-C and HDL-C: inflammatory resolution vs. thrombotic chaos

Cholesterol is a major component of atherosclerotic plaque. In the bloodstream, cholesterol is carried by lipoprotein particles, including low density lipoprotein (LDL) particles and high density lipoprotein (HDL) particles. Over the years, considerable clinical study has established that increased levels of "bad" cholesterol, or LDL, and decreased levels of "good" cholesterol, or HDL, are important risk factors for the development of cardiovascular disease. Pharmacologic and behavioral interventions that reduce plasma levels of LDL can greatly reduce cardiovascular risk.

However, cardiovascular events, such as MI, can still occur in individuals whose LDL levels are optimally controlled. This residual risk has been attributed to suboptimal levels of HDL. Several lines of clinical evidence support this idea, including studies which show that low HDL is an independent risk factor for premature coronary heart disease, and a predictor of coronary events in patients who are being treated with statins. Lina Badimon of the Barcelona Cardiovascular Research Center presented a review of ongoing work that is leading to a better understanding of LDL and HDL particles and their roles in plaque formation and regression.

Potential mechanisms for the beneficial effects of high HDL cholesterol. (Image courtesy of Lina Badimon)

Atherosclerotic plaques form between the epithelial lining of blood vessels and the underlying smooth muscle cells, a region known as the arterial intima. LDL promotes this process by aggregating within the intima and binding to proteoglycans associated with the extracellular matrix. The presence of aggregated LDL in the intima has multiple effects on the arterial wall that lead to vascular remodeling and plaque formation, including activation of endothelial and smooth muscle cells, and the promotion of innate immune responses. These responses can lead to plaque erosion and rupture.

Badimon described current thinking on the roles of HDL as well. HDL is important in reverse cholesterol transport, the main pathway for cholesterol excretion. HDL particles have other important physiologic effects that include antithrombotic, antioxidant, anti-inflammatory, and cytoprotective activities. There are two types of HDL particles, known as HDL2 and HDL3, and HDL3 particles are associated with more of the beneficial physiologic effects. Badimon and her lab group are using proteomic methods to study the composition of and differences between these particles in detail, and to investigate variant HDL patterns in individuals with hereditary lipid disorders.

Considerable clinical evidence supports the idea of raising HDL blood levels to reduce cardiovascular risk. Badimon described emerging strategies that include new therapeutic agents such as Apo A-1 Milano, niacin-laropiprant, and CETP inhibitors. Continuing study of HDL particles and their metabolism is likely to lead to further novel therapeutic approaches.

Speakers:
Jagat Narula, Mount Sinai School of Medicine
James H. F. Rudd, University of Cambridge
Simón Méndez-Ferrer, Centro Nacional de Investigaciones Cardiovasculares
Roger J. Hajjar, Mount Sinai School of Medicine
Miguel Torres, Centro Nacional de Investigaciones Cardiovasculares
Andre Terzic, Mayo Clinic

Highlights

• Advanced molecular imaging is helping investigators visualize important signaling molecules and structural proteins in vivo, illuminating the pathophysiology of conditions such as acute MI and chronic heart failure.
• PET/CT imaging of 18F-fluorodeoxyglucose (FDG) is a new technique for noninvasively visualizing inflammation in atherosclerotic plaque in living animals, including humans.
• New understanding of the mechanisms that regulate stem cell production, homing, and differentiation will inform the uses of these cells in the treatment of cardiovascular conditions.
• Gene therapy approaches enable the targeting of important molecules in heart dysfunction, such as the calcium transporter SERCA2a, that can be difficult to manipulate pharmacologically.
• Cell competition studies suggest that human adult hearts could be prompted to repair themselves with appropriate manipulation of signaling and apoptotic processes.
• Stem cells derived from bone marrow are currently in early clinical trials to repair heart muscle damaged by chronic heart failure.

An evolving role for imaging

Sessions II and III focused on two cutting-edge areas of cardiovascular research: novel imaging technologies, particularly in research, and studies of cell- and gene-based therapies that may one day help repair cardiovascular damage.

Jagat Narula of Mount Sinai School of Medicine is using advanced molecular imaging techniques to better understand the pathological changes that occur in cardiovascular conditions such as acute MI and end-stage chronic heart failure. His goal is to be able to follow subcellular events that occur in humans over time, and to use that information to improve diagnosis and prognosis.

In their work on MI, he and his group are using noninvasive methods to visualize changes in components of the angiotensin signaling pathway in the area of damaged tissue, known as the infarct, compared to unaffected tissue nearby. They observed changes in the levels of angiotensin 1 receptors and angiotensin converting enzyme (ACE) that reached maximum levels by three weeks post-MI. This result suggests that acute MI patients get the most benefit from ACE inhibitors early in treatment. The researchers have also monitored fibrotic changes in the infarct area with an imaging peptide, known as CRIP, that targets myofibroblasts and allows indirect monitoring of the extent of collagen deposition. Collagen helps stabilize the infarct after an MI has occurred.

Narula and his group have also visualized myocellular changes in heart failure. As heart failure progresses, the heart becomes more structurally abnormal and the remodeled areas are prone to apoptosis, or programmed cell death. The researchers are investigating the molecular events that lead to caspase-3 activation, cytoplasmic proteolysis, and DNA degradation, all of which are aspects of apoptosis. Their findings suggest that new therapies could either reduce pro-apoptotic signaling, or inhibit the apoptotic cascade, potentially reducing the loss of heart tissue. They have observed that some cells do not lose their nuclei, raising the possibility that these cells might be used to regenerate heart tissue, given appropriate knowledge of molecular events.

Another imaging technique uses meta-iodobenzylguanidine, or MIBG, to assess neuronal dysfunction in various cardiovascular disorders. Narula discussed the results of the ADMIRE-HF trial, which found that individuals with more severe heart failure had less MIBG uptake, indicating a loss of sympathetic innervation. These individuals have a significantly higher risk of life-threatening events or death, suggesting that this imaging technique could be used for prognosis and risk stratification in heart failure. In addition to acting as important research tools, these and other new imaging techniques are likely to improve care for severe cardiovascular conditions in the near future.

Detection of the high-risk atherosclerotic plaque: the role of PET/CT imaging

One of the goals of developing non-invasive imaging techniques is to detect plaques that are at high risk of rupturing and causing a life-threatening event. That information could be used to predict patients' risks of experiencing a cardiovascular event as well as to evaluate the efficacy of novel cardiovascular drugs and devices. James H. F. Rudd of the University of Cambridge discussed the role of PET/CT imaging in these efforts.

Much of our knowledge of high-risk plaques comes from autopsies, which have identified a number of high-risk characteristics, including a thin fibrous cap, significant infiltration of macrophages (a sign of inflammation), and a large necrotic core. These plaques often display expansive remodeling, increased angiogenesis, and the presence of small areas of calcification as well. Rudd said that most myocardial infarctions are caused by the rupture of plaques that appear relatively small when visualized by angiography.

Noninvasive imaging techniques, including ultrasound, CT, and MRI are all being used to investigate the size and composition of plaques in living individuals, to better understand the process of plaque formation and the progression of atherosclerosis. However, these methods do not detect inflammation well. For that, researchers have turned to PET/CT imaging techniques that visualize ¹⁸F-FDG, a glucose analog that is taken up in areas of high metabolic activity. It was hypothesized that this method would visualize macrophages when they are present in atherosclerotic plaque.

¹⁸F-FDG PET/CT labeling reveals areas of inflammation in coronary arteries in acute coronary syndrome (ACS). (Image courtesy of James Rudd)

Several lines of evidence support the idea that ¹⁸F-FDG uptake is a marker for inflammation and increased cardiovascular risk. Work from Rudd's laboratory, for example, has shown that ¹⁸F-FDG uptake correlates with macrophage infiltration, as measured histologically, in plaques from human carotid arteries. Other studies show that individuals with cardiovascular disease risk factors, such as high plasma levels of C-reactive protein and LDL, show higher ¹⁸F-FDG uptake in their carotid arteries. Studies of the coronary arteries in recent MI patients show higher ¹⁸F-FDG uptake in the ruptured lesion.

This method can also measure changes in inflammation resulting from treatment. Rudd and others have looked at ¹⁸F-FDG uptake as a measure of inflammation in patients treated with anti-dyslipidemia agents, including statins, the CETP inhibitor dalceptrapib, the novel agent losmapimod, and the antiglycemic agent pioglitazone. PET/CT has been used alone and in combination with other methods such as MRI to simultaneously measure plaque morphology and inflammation and to assess changes in atherosclerotic burden occurring with treatment.

Rudd's group is developing newer PET markers for macrophages that show continued promise for imaging areas of inflammation. Others are studying the prognostic value of measuring ¹⁸F-FDG uptake. A recent study in cancer patients showed that those with the highest levels of ¹⁸F-FDG uptake were most likely to have a cardiovascular event within six months of the study. The High-Risk Plaque BioImage Study will continue to investigate the role of this novel imaging technique in the evaluation of patients at risk for cardiovascular disease.

Tissue regeneration: bone marrow cell-cell interaction & release

The theme of the conference next turned from novel imaging techniques to investigational methods for repairing heart damage, whether from an acute coronary event or as a result of chronic heart disease. Stem cells offer one potential method of repairing damaged hearts, but first researchers will need to learn how to mobilize them, how to get them to go to the right tissues, and how to prompt them to differentiate appropriately once in place. Simón Méndez-Ferrer of the Centro Nacional de Investigaciones Cardiovasculares in Madrid described his work on the mobilization and homing of hematopoietic stem cells, a highly studied cell type used in bone marrow transplants.

All stem cells are maintained and regulated by a niche, comprised of their physical location in a given tissue and the cellular and molecular signals that determine their functional characteristics. In bone marrow, the niche occupied by hematopoietic (blood forming) stem cells allows them to preserve their ability to self-renew and at the same time renew the population of blood cells when needed.

Méndez-Ferrer and his group are studying the mechanisms that regulate these cells and their functions. Their work has shown that hematopoietic stem cells are released according to circadian rhythm, with release peaking during the low activity resting phase. For humans, this is night time, but for rodents and other nocturnal animals, it happens during the daylight hours. The sympathetic nervous system regulates this process by connecting the bone marrow with the suprachiasmatic nucleus, a small group of cells in the brain that is responsible for regulating circadian rhythms. A better understanding of circadian regulation of stem cell activity could lead to new ways of manipulating stem cells pharmacologically, or to improved timing of stem cell procedures in human patients that take advantage of peak stem cell release and homing times.

Bone marrow also contains mesenchymal stem cells, which are the precursors of multiple other cell types, including bone, fat, and cartilage cells. Méndez-Ferrer and his group have identified a subset of these cells, positive for a protein called nestin, that also regulate the traffic of hematopoietic stem cells. The mesenchymal stem cells perform niche functions that help hematopoietic stem cells find their homes in bone marrow. The researchers are investigating the signaling pathways that are used in this process, a highly important one for patients, since hematopoietic stem cell homing and engraftment in the bone marrow are critical for the success of bone marrow transplants. Eventually, improved understanding of these processes will assist with the use of stem cells in other applications, including heart muscle repair.

Gene therapy for the treatment of heart failure

Congestive heart failure is a progressive disease that leads to increasing weakness and structural changes, known as remodeling, in the heart muscle. Innovative new therapies are greatly needed to repair the damage caused by this condition. Roger J. Hajjar of the Mount Sinai School of Medicine is investigating the use of gene-based therapies in heart failure patients. The possibility of gene therapy in this area has come about relatively recently, as a result of the identification of targetable cardiomyocyte functions that are otherwise difficult to manipulate, and as a result of the availability of improved techniques that can move genes specifically into these cells.

One such target is SERCA2a, a calcium-dependent ATPase. SERCA2a is crucial for the functions of the sarcoplasmic reticulum, the intracellular organelle that regulates the contractility of muscle cells by taking up and releasing calcium. In human heart failure patients, loss of SERCA2a activity leads to reduced calcium uptake during heart muscle relaxation, subsequently reducing contractility. This important transmembrane protein has thus far resisted attempts to modulate its activity with drugs.

Hajjar and his coworkers prepared a SERCA2a-carrying genetic construct based on adeno-associated virus (AAV), a small, non-pathogenic virus, as a vector. This construct is safely, efficiently, and specifically incorporated into cardiomyocytes, causing long term expression of SERCA2a. The gene-based therapy has already passed through phase 1 and 2 clinical trials, where it was administered to patients with moderate to severe heart failure by infusion into cardiac blood vessels. Patients who received gene therapy in these trials showed clinically meaningful improvements in functional status, symptoms, and cardiac structure, with an acceptable safety profile. Phase 3 trials are now underway.

One potential drawback of this approach is that about half of heart failure patients have pre-existing antibodies to AAV that prevent the virus from reaching its target. The investigators are working on ways to circumvent this issue, including the use of plasmapheresis to reduce the number of anti-AAV antibodies in the blood. They are also working on modified vectors that will be resistant to pre-existing antibodies. Hajjar described a number of other potential approaches to the modulation of SERCA2a activity, including targeting proteins that associate closely with the transporter and regulate its expression, localization, and post-translational modification. These approaches may allow gene therapy for heart failure to be fine-tuned in the future.

From understanding cardiac development and homeostasis to designing heart repair strategies

The adult mammalian heart does not have the capacity to repair itself after major damage. However, researchers including Miguel Torres of the Centro Nacional de Investigaciones Cardiovasculares are working on methods to promote heart self-repair. Torres's work is based on the principles of cell competition, a mechanism for maintaining tissue homeostasis that was first described in Drosophila. Cell competition promotes the expansion of the fittest cells through the apoptotic elimination of viable but suboptimal cells residing in the same tissue. This process is thought to maintain tissue quality and plays a role in metazoan development and in tissue regeneration in some animals. Several clues suggest that this process may already take place naturally in the adult mammalian heart, although at very low levels. For example, adult cardiomyocytes undergo low but consistent rates of cell death and proliferation, and this process is stimulated in regions of heart injury, such as the borders of a myocardial infarct.

Some animals, including fish, amphibians, and newborn mammals, are able repair their hearts after major damage. In order to find out whether cell competition is active during heart formation in developing mice, Torres and his group produced mice with genetically mosaic heart tissues. Some cardiomyocytes in the developing mice overexpressed the oncogene c-Myc, which has been shown to promote cell survival in competitive situations, and others did not. During gestation, the c-Myc-overexpressing cardiomyocytes outcompeted and displaced wild-type cardiomyocytes. Inhibiting apoptosis prevented this displacement, indicating that the c-Myc-overexpressing cells displaced the wild-type cells by actively inducing their death. Torres's studies show that cell competition is responsible for replacing cardiomyocytes throughout fetal life. He and his group are currently exploring ways of manipulating cell competition to promote the death of less active cardiomyocytes in adult mouse hearts as well.

These studies suggest three potential strategies for heart repair: introduce new cells that can contribute to regeneration, find ways to stimulate the proliferation and renewal of cardiomyocytes that are already there, perhaps by cell competition, or stimulate the growth and differentiation of endogenous stem cells that are also already present in the heart tissue.

Regenerating heart tissue

Andre Terzic of the Mayo Clinic is working on an approach for chronic heart failure that involves the first of these three possibilities, using stem cells harvested from bone marrow to repair damaged heart tissue. Current options for the treatment of heart failure include drug therapy, mechanical devices that support or stimulate heart function, or receiving a new heart through a transplant. Each of these strategies has advantages and disadvantages, and none results in repair of existing heart tissue. There is a need to add to the armamentarium of heart failure approaches by developing therapies that can repair the heart.

Terzic and his group have developed methods to harvest cells from bone marrow and then to isolate and expand a specific population known as mesenchymal stem cells. These cells can be induced to differentiate into potential cardiac cells with the addition of a growth factor cocktail, whose content is based on an understanding of cell signaling events that occur during human heart development. The cells are then delivered to the heart and monitored to determine their fates.

Conversion of bone marrow stem cells to cardiac-lineage specified cells for injection into and repair of human heart muscle. (Image courtesy of Andre Terzic)

Terzic and his colleagues are conducting a phase 2 clinical trial, known as C-Cure, to test this process in humans. The trial is using autologous cardiopoietic stem cells to treat patients with chronic ischemic cardiomyopathy. Stem cells that have been started on the path to cardiac differentiation by exposure to growth factors are injected into dysfunctional but otherwise viable myocardial tissue. The trial, which involves 45 patients, is randomized to compare current standard of care for these patients with the standard of care plus stem cell injection. Although the study is designed mainly to test safety rather than efficacy, Terzic said that there are signs of improved cardiac function and clinical performance in the patients who received the stem cells. Thus far, these studies demonstrate the feasibility and safety of this approach in patients with chronic ischemic cardiomyopathy.

Terzic and others are also working on alternate versions of these techniques. In diseases such as diabetes, for example, the heart loses its regenerative capacity and may not be able to support the growth of cells that have initiated cardiac specialization but that are not completely differentiated. They are investigating other sources of cells that might be reprogrammed and induced to form cardiac tissues. Skin fibroblasts, for example, can be reprogrammed to form induced pluripotent stem cells (iPSCs) that can then be used to generate new heart cells. Such cells have been shown to engraft successfully in a mouse model of cardiomyopathy. Terzic's group and others are investigating alternate methods of nuclear reprogramming in these cells as well. These methods may provide new ways to repair hearts damaged by cardiomyopathy and other cardiovascular disorders.

Speakers:
Borja Ibáñez, Centro Nacional de Investigaciones Cardiovasculares, Madrid
Carlos Macaya, Hospital Clínico San Carlos, Madrid
Steen E. Husted, Aarhus University Hospital, Aarhus
Valentin Fuster, Mount Sinai Medical Center and Centro Nacional de Investigaciones Cardiovasculares
Jonathan L. Halperin, Mount Sinai Medical Center

Highlights

• Several simple, low-cost methods, including peri-conditioning and medical therapies, can help reduce infarct size and preserve heart function in acute MI patients.
• Reducing the length of time between symptom onset and first medical contact and diagnosis is the next important target in the quest to reduce the time to treatment in acute MI.
• Alternatives to warfarin will soon be available for a wide range of cardiovascular conditions where anticoagulation therapy is important.
• Cardiovascular disease and degenerative brain conditions, such as Alzheimer's disease, may be closely related, and therapeutic approaches that promote heart health may also protect the brain.
• Clinical data on effective treatment choices in elderly individuals with cardiovascular disease is expanding, but more data are needed to ensure that this population receives appropriately individualized care.

Myocardial protection therapy

The next session of the meeting dealt with one of the most common manifestations of cardiovascular disease, acute MI. This and related conditions such as angina are caused by the buildup and rupture of atherosclerotic plaque in the coronary arteries, the vessels that supply the heart muscle itself with oxygen and nutrients and that remove wastes.

An acute MI occurs when blood can no longer reach part of the heart due to the occlusion of a coronary artery, usually as a result of plaque rupture and subsequent blood clot formation. All of the heart tissue served by the occluded artery is at risk of dying, but often some tissue survives. Borja Ibáñez of the Centro Nacional de Investigaciones Cardiovasculares described ongoing efforts to find ways to protect heart tissue from dying during an acute MI.

In the early 1980s, many studies showed that the main determinant of the extent of myocardial necrosis is the length of time that the heart muscle is deprived of blood. Quickly opening the occluded artery by medical or interventional reperfusion treatments limits the extent of cell death. Since then, many institutions and professional bodies have instituted policies and procedures to shorten the time between the onset of MI symptoms and the restoration of blood flow. These new procedures have substantially reduced the morbidity and mortality associated with acute MI. However, even with shortened times to perfusion, the infarct size is still quite large in many acute MI patients, suggesting a need for further improvements in care. In addition, in many cases reperfusion itself creates further myocardial injury that also contributes to the final necrotic size, representing a further target of efforts to reduce cell death.

Ibáñez described a number of relatively simple, low cost methods that have been found to help limit the size of myocardial infarcts. One such method is post-conditioning, which involves brief episodes of coronary artery occlusion and opening after an MI. This technique has been found to reduce the extent of myocardial injury by preventing reperfusion injury. Another technique, peri-conditioning, involves intermittently stopping the blood supply to a remote organ during ongoing ischemia in the heart. This can be done very simply, for example, by inflating and deflating a blood pressure cuff on the patient's arm. The mechanism by which this technique prevents heart damage is unclear.

Other methods rely on drugs such as cyclosporine, a non-selective inhibitor of the mitochondrial permeability transition pore, whose inappropriate opening is associated with ischemia and reperfusion injury in cardiac tissue. Ibáñez and his collaborators are testing the effects of the beta-adrenergic receptor blocker metoprolol, which has been shown to stop apoptosis of cardiomyocytes. Metoprolol is the subject of a current large clinical trial in which beta blockers are administered in the ambulance, before reperfusion treatment, to try to reduce infarct size.

Improving treatment speed and efficiency system wide

Carlos Macaya of the Hospital Clínico San Carlos in Madrid reinforced the idea that the best strategy to limit myocardial tissue death during acute MI is early reperfusion. He described studies from recent years which have led to the conclusion that interventional methods, in which the occluded artery is mechanically opened (also known as angioplasty) generally have higher success rates than using fibrinolytic drugs to break up the clot. This conclusion reinforces the necessity for MI patients to reach facilities where interventional techniques can be employed as rapidly as possible.

Macaya noted that current quality of care measures for acute MI are focused on the time from entry of the patient into the hospital to coronary reperfusion. However, he pointed out that patient transport from the site of MI diagnosis to the hospital also delays MI treatment, contributing to an overall system delay that covers the time from first medical contact to coronary reperfusion. Multiple studies have shown that the longer the system delay, the higher the mortality for MI victims. Most MI patients are reperfused by percutaneous coronary intervention (PCI), a type of angioplasty that is highly complex and technical, requiring careful multi-disciplinary teamwork and smooth transitions between emergency medical systems, hospitals, and interventional cardiology laboratories. Some countries have already reduced system delay substantially, but in others much work remains to be done.

Time course of treatment of ST-segment elevated myocardial infarction (STEMI) and potential periods when delays might occur. (Image courtesy of Carlos Macaya)

Several other aspects of this process are also targets for improvement. Patients often delay seeking help, contributing to an overall treatment delay that spans from the initial onset of symptoms to reperfusion. Some patients also choose to transport themselves rather than use an ambulance. The proportion of patients who use emergency medical services varies considerably among different European countries. Additional delays may accrue if the patient arrives at a facility without the capacity to perform PCI and needs to be transferred to a PCI-capable facility. This situation occurs quite often in some European countries, particularly in rural areas.

Macaya described several programs addressing these aspects of treatment delay that are now underway in Europe. One study is looking at the possibility of pre-hospital MI diagnosis by electrocardiography while the patient is still in the ambulance, which could help ensure that patients with acute MI are transported directly to a PCI-capable facility. In Spain, public health authorities are developing regional networks with one emergency medical service and one PCI center for every 300 thousand to 1 million people. Public awareness campaigns are also being used to emphasize the importance of recognizing the symptoms of an acute MI and of seeking proper treatment without delay. These efforts will continue to require considerable support from politicians, health care payors, and other public health stakeholders.

Antithrombotic progress—evolving oral agents

One way to prevent both first and subsequent MIs is to prevent inappropriate blood clot formation. Steen E. Husted of Aarhus University Hospital in Denmark, synthesized considerable evidence on new antithrombotic drugs, which are used in a wide range of cardiovascular settings. These new agents, which are primarily taken orally, target multiple points in the clotting cascade and in the process of platelet aggregation. The development of these drugs has been motivated by a continuing search for alternatives to warfarin, an oral agent that has been used for many years. While effective, warfarin is difficult to dose properly, raises bleeding risk, and interacts with many types of foods, necessitating careful attention to diet. To replace it, new agents should be just as effective but have lower bleeding risks, fewer side effects, and better dosing properties.

Multiple new agents target the proteins of the clotting cascade, whose activities lead to blood coagulation. These new drugs include the direct thrombin inhibitor dabigatran etexilate, as well as the direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban. All of them are in late clinical development for use in a range of settings, including thromboprophylaxis (clot prevention), atrial fibrillation, venous thromboembolism, and acute coronary syndromes. These drugs have shown promising efficacy and similar or sometimes lower bleeding risk compared to standard therapies, without the need for frequent laboratory monitoring as with warfarin. However, some of these agents increase the risk of gastrointestinal bleeding and the risk of an MI.

A newer approach to antithrombosis is to target platelet aggregation. New compounds in this group include prasugrel and clopidogrel, which are irreversible inhibitors of the platelet receptor P2Y12, an important regulator of aggregation. Several reversible P2Y12 inhibitors, ticagrelor, elinogrel, and cangrelor, are also in clinical development. One of the latest strategies is to target the platelet thrombin receptor protease-activated receptor-1 (PAR-1), an approach that should carry reduced bleeding risk. The PAR-1 antagonist vorapaxar is being tested for clinical efficacy and safety in ongoing trials.

Molecular targets for anticoagulation therapy found on the platelet. (Image courtesy of Steen Husted)

Each of these new agents works at least as well as or better than warfarin, but each has its own profile of side effects. These side effects are likely to play an important role in the choice of agents for specific patients, especially since the trials for each drug were designed differently, making it difficult to compare among them based on efficacy alone. The availability of multiple new choices for antithrombotic therapy will enable clinicians to better customize their care for individuals with the complete range of cardiovascular disorders that require anticoagulation.

The link between complex coronary disease and significant carotid disease, diabetes, or cerebrovascular disease

Valentin Fuster provided further perspective on the links between complex coronary disease, carotid artery disease, and cerebrovascular disease. He noted similarities between recent developments in care for coronary artery disease and carotid artery disease. In both cases, the sum of available evidence suggests that therapeutic approaches to complex disease should account for the anatomical and structural characteristics of the atherosclerotic lesions, patient characteristics and risk factors, and risks associated with the procedure itself, such as operator inexperience. He said that it is increasingly important to take an individualized approach when planning treatment for these conditions.

Fuster also discussed the relationship between cardiovascular disease and Alzheimer's disease. The number of people with Alzheimer's is predicted to rise to 81 million by 2040. The current lifetime risk for developing the disease is estimated to be 10.5% for a 65-year-old. A large body of literature shows a strong association between hypertension and other cardiac risk factors and degenerative brain disease, including Alzheimer's. At the same time, novel imaging studies suggest that individuals with Alzheimer's often have plaque that occludes the cerebral microvasculature. Although the pathology of Alzheimer's largely involves amyloid deposition and other pathologic processes that affect neurons and glial cells, the progression of Alzheimer's is more rapid if there is a vascular component. Researchers estimate that 60% to 90% of Alzheimer's patients have vascular disease. Many of the same factors that increase cardiovascular risk are risk factors for the development of dementia and Alzheimer's, including obesity, smoking, hypertension, and diabetes. These findings suggest that therapeutic approaches that reduce cardiovascular disease risk factors may also delay Alzheimer's progression and help with this coming epidemic as well.

Cardiovascular and other physiologic factors that may be associated with neurodegenerative diseases, including Alzheimer's, in the brain. (Image courtesy of Valentin Fuster)

Fuster presented a number of insights into the role of aging in cardiovascular disease. Older humans and other animals have fewer and less active stem cells. One reason for this is the shortening of the telomeres, which are the ends of the chromosomes that are reduced in size with each cell division, eventually leading to cell apoptosis. Other processes such as stress also cause cells to age, and there is evolving evidence that cardiovascular risk factors like obesity and smoking promote cell aging. Understanding these processes may one day allow the development of agents that prevent them, leading to better aging in which both heart and brain remain healthy.

Ischemia in the elderly: refractory angina and carotid disease

Jonathan L. Halperin of Mount Sinai Medical Center continued on the theme of aging, presenting recent findings on the care of elderly patients with refractory angina, carotid artery disease, and other cardiovascular conditions. Angina is characterized by transient pain or discomfort, occurring while there is an intermittent loss of blood flow to the heart muscle itself. It is often treated with mechanical revascularization, which can be effective in older individuals. However, there are an estimated 14 million older individuals who have refractory angina that is not controlled by drugs, but who are not candidates for surgical revascularization. Uncontrolled angina correlates with higher mortality and also reduces quality of life. One potential new approach is intramyocardial autologous stem cell therapy, which has been shown in clinical trials to reduce angina frequency and improve exercise tolerance.

Halperin discussed other cardiovascular conditions that are common in the elderly, including atrial fibrillation and carotid artery disease. The prevalence of atrial fibrillation rises with age, and untreated, it correlates with a high risk of stroke that also increases with age. Carotid artery disease is also associated with increased risk of stroke. Treatment choices in patients with symptomatic disease and high levels of occlusion include carotid stenting, which is less invasive, or endarterectomy, which involves surgical clearing of the artery. Recent studies have shown that, despite the risks of surgery, endarterectomy is the more effective approach in octogenarians.

Halperin emphasized that medical therapy, less invasive catheter-based interventions, and surgery should be considered complementary interventions in the elderly. Treatment choices should be based on individual patient characteristics, and age alone should not determine the type of intervention. He also noted the importance of including the elderly and those with common co-morbidities in clinical trials, in order to collect the clinical data that will guide future treatment choices in these populations.

Speakers:
Laurence Sperling, Emory University School of Medicine
Robert A. Phillips, University of Massachusetts Medical School
Javier Sanz, Mount Sinai Medical Center
Clyde W. Yancy, Northwestern University Feinberg School of Medicine
Frederick A. Masoudi, University of Colorado Denver

Highlights

• Optimal blood lipid targets for preventing cardiovascular disease are evolving with the release of new clinical trial results and increased understanding of the interactions between lipoproteins.
• Recent guidelines establish optimal blood pressure targets, but these may change with new clinical trial results.
• Visualization of scarring by MRI, nuclear imaging of MIBG, and other new imaging methods are improving diagnosis and prognostication in multiple forms of cardiomyopathy.
• Evidence-based guidelines for managing systolic heart failure are well developed, but effective management of individuals with diastolic heart failure is still under investigation.
• Quality-of-care measurement is an important but difficult component of effective care for cardiovascular conditions such as heart failure.

Optimal lipid targets (OLT) for the new era of cardiovascular prevention

Sessions V and VI focused specifically on clinical challenges, including preventing cardiovascular disease by treating dyslipidemia and hypertension, and advances in the management of cardiomyopathies and heart failure.

One of the most important risk factors for cardiovascular disease is dyslipidemia. Laurence Sperling of Emory University School of Medicine in Atlanta, Georgia, provided an update on optimal lipid targets for preventive therapy. Sperling noted that chimpanzees and human newborns have LDL cholesterol levels of less than 70 mg/dL, and adults living in primitive hunter-gatherer societies tend to have LDL levels that are less than 100 mg/dL. By contrast, the average American adult has LDL levels higher than 190 mg/dL. Considerable scientific evidence connects these high levels of blood lipids to cardiovascular disease, for example, from studies of families with inherited hypercholesterolemia.

Clinical trial evidence further supports the idea that lowering serum LDL reduces the risk of cardiovascular disease. Even in patients with established heart disease, lowering LDL from over 100 mg/dL to less than 70 mg/dL reduces the number of subsequent cardiovascular events. Multiple studies suggest that reducing levels below 50 mg/dL continues to help. Sperling emphasized that optimal LDL targets are still under investigation, and that future guidelines may recommend more aggressive lipid lowering, particularly in high-risk individuals. It is unclear whether there is an LDL level at which the cardiovascular disease event rates approach zero.

Optimal levels for triglycerides are still evolving as well. Sperling said that a synthesis of current evidence suggests optimal fasting triglyceride levels of less than 100 mg/dL and nonfasting levels of less than 200 mg/dL. Scientific advances in understanding the different forms of blood lipids have also complicated the picture. Sperling noted that LDL cholesterol, as calculated in current laboratory reports, may have limitations. It may be more useful to think in terms of total non-HDL cholesterol rather than just LDL levels.

Optimal HDL levels are another continuing topic of study. Although higher HDL correlates with reduced risk of cardiovascular disease, clinical trials that have focused on raising HDL levels have been disappointing. HDL has several potentially beneficial effects on atherogenesis. It inhibits the oxidation of LDL, which is an important step in plaque formation, promotes cholesterol efflux from the intima, and inhibits the expression of adhesion molecules that are involved in plaque formation. HDL metabolism is complex, and it has become apparent that some mechanisms for raising HDL levels are not necessarily beneficial in humans. As noted earlier in the meeting by Lina Badimon, it may be important to distinguish among different types of HDL when developing new agents. More research will be needed before optimal HDL targets can be identified.

Sperling said that as lipid guidelines evolve, new measures of blood cholesterol will need to be considered, along with more aggressive targets. Guidelines should also consider lifetime risk of cardiovascular disease rather than the 10-year risk calculations that were previously used; particularly for intermediate and lower risk individuals, a first heart attack is highly likely to be fatal.

Hypertension and guidelines: whom to believe?

Robert A. Phillips, of the University of Massachusetts Medical School, reviewed guidelines for the identification and management of patients with hypertension, another important risk factor for cardiovascular disease, and also discussed recent advances and controversies.

Current blood pressure guidelines are based primarily on clinical trials that measured patients' blood pressures in a clinic or in a physician's office. For uncomplicated hypertension, the treatment goal is less than 140/90 mmHg for individuals between 18 years old and 79 years old, and systolic blood pressure between 140 mmHg and 150 mmHg for those 80 years or older. Treatment of hypertension in the very elderly has been controversial, but the results of the HYVET trial showed significant reductions in heart failure, stroke mortality, and all-cause mortality with reduction of blood pressure by treatment with a diuretic and an ACE inhibitor in this population. African-Americans often show target organ damage at lower blood pressures than whites, so a lower goal of less than 135/85 mmHg is currently recommended for members of this population.

Another area that needs more clinical evidence is the choice of drugs for initial treatment of hypertension. Most patients with hypertension require two or more antihypertensive agents to reach their blood pressure goal. Studies such as the ACCOMPLISH trial will establish optimal drug combinations for initial therapy.

In patients with coronary artery disease, diabetes, or chronic kidney disease, the recommended blood pressure target is less than 130/80 mmHg. More data are needed, but most high-risk patient populations benefit from lowering blood pressure as much as possible. Phillips noted a potential exception in patients with carotid artery disease. A recent study found that lower blood pressure was associated with worsened outcomes in patients with bilateral carotid stenosis or greater than 70% stenosis on one side. These patients are at high risk of recurrent stroke so it will be important to determine the most effective management approach for them.

Ongoing clinical trials are examining the effects of intensive blood pressure lowering. The very large National Heart, Lung and Blood Institute-sponsored Systolic Blood Pressure Intervention Trial (SPRINT), is testing the hypothesis that intensive lowering of systolic blood pressure to less than 120 mmHg is superior to lowering it to less than 140 mmHg for the prevention of non-fatal MI, stroke, and heart failure. This study is also looking at the effects of intensive blood pressure lowering on the preservation of cognitive function and of normal brain architecture.

Another important area of research is masked hypertension, which is defined as having normal blood pressure when it is measured in the clinic but a high average self-monitored or ambulatory blood pressure. This condition is more prevalent in high-risk individuals with conditions such as chronic kidney disease, diabetes, left ventricular hypertrophy, and obstructive sleep apnea. Masked hypertension is associated with increased target organ damage and additional cardiovascular events. Phillips said that ambulatory and self-monitored blood pressure measurements should be incorporated into new guidelines in order to identify individuals with masked hypertension. New treatments may also be needed to manage these patients more effectively.

Diagnostic and prognostic imaging (MR, CT) of the various cardiomyopathies

Individuals with cardiomyopathy, defined as severe dysfunction of the heart muscle, are at increased risk of dangerous arrhythmias and sudden cardiac death. Javier Sanz of Mount Sinai Medical Center described new noninvasive imaging methods that are providing important diagnostic and prognostic insights into different types of cardiomyopathy.

In dilated cardiomyopathy, the most common form of the disease, the heart muscle is enlarged and weakened. Recent evidence suggests that myocardial scarring is a powerful marker of poor prognosis in both ischemic and non-ischemic forms of this disorder. Sanz described a relatively new imaging technique, delayed enhancement MRI, as an important method for visualizing scarring. The presence of a delayed enhancement signal correlates with poorer survival in these patients.

Another common form is hypertrophic cardiomyopathy, in which the heart muscle is enlarged and thickened, usually in the left ventricle. This disorder is one of the causes of sudden death among young athletes. Several recent studies have shown that scarring is a predictor of heart failure and perhaps of ventricular arrhythmic events in this patient population as well. The presence or absence of scarring on MRI has also emerged as an important diagnostic tool for other conditions that include cardiomyopathy, such as sarcoidosis.

Another marker of poor prognosis in cardiomyopathy is loss of integrity of the cardiac sympathetic nervous system. This can be demonstrated by newly developed nuclear imaging techniques that detect reduced myocardial uptake of radiolabeled MIBG. Sanz described several other new techniques, including MRI methods for quantifying diffuse interstitial myocardial fibrosis (as opposed to focal scarring) and noncontrast MRI for quantifying iron in the hearts of individuals with iron overload. These new techniques promise to improve diagnosis and prognostication greatly in the cardiomyopathies.

State-of-the-art management of systolic and diastolic heart failure

Heart failure is becoming the most common manifestation of cardiovascular disease, affecting over 20 million people worldwide and over 6 million in the U.S. Clyde W. Yancy of the Northwestern University Feinberg School of Medicine said that the cost of care for these individuals, as well as the loss of quality and quantity of life, makes the development of new treatment approaches to heart failure imperative. It is also important to use current treatment approaches more comprehensively and more effectively.

Heart failure conditions are classified according to the amount of ventricular function retained. Patients with reduced left ventricular function (often described as reduced ejection fraction) are considered to have primarily systolic heart dysfunction, while those with preserved left ventricular function are considered to have primarily diastolic dysfunction. However, abnormalities of systolic and diastolic function can both be found in individuals with either reduced or preserved left ventricular function.

The distinction between patients with reduced and preserved ventricular function is crucial in the choice of treatment regimen. Evidence-based, guideline-driven care has been clearly identified for systolic heart failure, and optimal compliance with quality-of-care measures is associated with improved outcomes. Interventions that have been shown to improve outcomes for patients with systolic heart failure include medical therapies such as ACE inhibitors, angiotensin receptor antagonists, beta blockers, aldosterone antagonists, and others, as well as interventional therapies such as implantable defibrillators and cardiac resynchronization therapy.

Recent studies have shown that some of these treatments, particularly device-based interventions and aldosterone antagonists, are significantly underused in cardiology practice, although usage can be increased with quality improvement programs. Researchers have calculated that optimal implementation of all of the guidelines would save over 60,000 lives per year in the U.S.. Over the past 20 years, the mortality rate for patients with systolic heart failure has dropped by 63% for patients in clinical trials, but this rate has dropped only modestly for patients being treated in the community, illustrating the gap between evidence-based best practices and real world care.

Improvements in outcomes from heart failure made in clinical trials over the past 20 years have not been reflected in community practice. (Image courtesy of Clyde Yancy)

Diastolic heart failure, which is characterized by preserved ejection fraction, is a very different situation. To date, no therapies have been demonstrated to modify the natural history of this type of heart failure, which affects about half of all heart failure patients. Until better therapies are developed, these patients are best managed by treating the multiple co-morbidities often associated with this disorder. Up to 90% of patients with diastolic heart failure also have hypertension, coronary artery disease, diabetes, or atrial fibrillation.

Yancy strongly emphasized the importance of using left ventricular function as a guide to selecting evidence-based therapies for heart failure patients, but he also emphasized the importance of preventing the disease in the first place, through treatment of risk factors such as hypertension, lipid disorders, smoking, and obesity.

Quality control of heart failure treatment

Advances in science have generated effective interventions for heart failure, and current guidelines recommend many of these interventions. However, as Yancy noted, often the best interventions are not used, and opportunities to avoid adverse outcomes are missed. Frederick A. Masoudi of the University of Colorado Denver described recent efforts to measure and improve the care and outcomes of patients with heart failure. He noted that these efforts have evolved in two respects: what is measured and how the measures are employed.

Measurements of health care quality generally include three important dimensions: structures of care, such as staffing and physical plant; processes of care, such as the use of medications and procedures; and outcomes of care, such as mortality, readmission rates, and health status. Structure-based measures are surrogate measures because they assume that institutions that have the most experience in a therapeutic area, i.e., that treat the greatest number of patients, provide the best care. Process measures are based on guideline recommendations that are supported by high levels of clinical evidence. These types of measures calculate the proportion of patients who receive a certain standard of care compared to the number who should receive that standard of care according to the guidelines.

Process measures do not measure everything that occurs in the course of patient care. For this reason, it is important to measure patient outcomes as well. Outcome measures are more comprehensive and patient-centered, and they tend to reflect the overall performance of the health care system or institution. However, outcome measures must be adjusted for the level of risk in the patient population under consideration; institutions serving sicker patient populations will not have the same outcomes as those serving a relatively healthy population. Outcome measures can be difficult to determine accurately when they involve subjective symptoms such as pain, and they do not always indicate an obvious pathway to improvement.

Masoudi said that although measuring quality of care is difficult and labor intensive, such measures provide accountability for physicians and institutions to the public and to the government. Quality measures are likely to expand beyond hospital-based measures in the future to include more patient centered outcomes such as health-related quality of life.

Speakers:
Valentin Fuster, Mount Sinai Medical Center and Centro Nacional de Investigaciones Cardiovasculares
Josep Brugada Terradellas, University of Barcelona
Vivek Reddy, Mount Sinai School of Medicine
Josep Rodés-Cabau, Québec Heart and Lung Institute
David H. Adams, Mount Sinai Medical Center

Highlights

• Anticoagulation therapy is an important option in the treatment of atrial fibrillation to reduce the risk of stroke.
• Preventing sudden cardiac death due to ventricular arrhythmias hinges on effective risk calculations and on the identification of individuals most likely to benefit from an implantable cardiac defibrillator.
• Catheter ablation has become an important technique for treating atrial fibrillation, particularly among elderly individuals, but the reliability and durability of this procedure need to improve.
• Transcatheter aortic valve implantation is rapidly becoming accepted as an important alternative to traditional surgical techniques, and outcomes are improving as clinical experience accumulates.
• Current guidelines recommend performing mitral valve repair early in the clinical course of heart failure, because outcomes for this surgery in patients with severe heart failure are very poor.
• Thoracic aortic aneurysm is an understudied condition with different risk factors and underlying pathophysiological events compared to other aortic aneurysm conditions, necessitating a careful therapeutic approach.

Atrial fibrillation, stroke, and quality of life

The final two sessions of the meeting dealt with some of the most challenging cardiovascular conditions, including electrical disturbances of the heart that lead to arrhythmias, structural heart disease such as aortic valve stenosis and mitral valve regurgitation, and the difficult clinical problem of thoracic aortic aneurysm.

In atrial fibrillation, the electrical regulation of the heart becomes disordered, leading to irregular heartbeats. The incidence and prevalence of atrial fibrillation are increasing worldwide, largely as a result of the aging of the population in the Western world. Atrial fibrillation is a major risk factor for ischemic stroke. In many patients, episodes of atrial fibrillation progressively increase in frequency and duration, leading to considerable morbidity and mortality. Strokes in these patients are also more severe than in individuals without atrial fibrillation and lead to worse outcomes.

Anticoagulation therapy is a crucial aspect of managing atrial fibrillation. Valentin Fuster described how measures of risk determine guideline-recommended choices for antithrombotic therapies in these patients. Antithrombotic therapy must be balanced carefully between reducing the risk of clot formation and reducing the risk of bleeding. Fuster described an internet-supervised patient self management system that has shown promise in helping patients manage their therapy. Controlling bleeding risk is particularly important for older patients, who are more likely to experience an intracranial hemorrhage.

Fuster also returned to his theme of microvascular disease in the brain, noting that atrial fibrillation correlates with increased rates of dementia, including Alzheimer's. This correlation might be due to similar risk factors, or it may indicate that microvascular events in the brain, such as thromboemboli, are related to atrial fibrillation. A piece of evidence supporting the latter idea is that oral anticoagulants improve cognitive function in atrial fibrillation patients.

Fuster mentioned that several of the anticoagulants that have been developed in recent years, and those that are still emerging, are likely to be important in treating atrial fibrillation patients. These include novel thrombin receptor antagonists, protease-activated receptor antagonists and others that have shown promise in comparison to the currently used agent warfarin.

Ventricular tachycardia and ventricular dysfunction: which to watch?

Sudden cardiac death affects a significant number of patients after a myocardial infarction. Other causes of sudden cardiac death include dilated or hypertrophic cardiomyopathy, right ventricular dysplasia, and several hereditary syndromes. Josep Brugada Terradellas of the University of Barcelona said that it is important to be able to identify patients at risk of sudden cardiac death in order to prevent it. Individuals with a previous history of ventricular arrhythmias, especially sustained ventricular tachycardia or ventricular fibrillation, are considered likely to have the worst outcomes. However, only a minority of patients who are stricken by sudden cardiac death were previously diagnosed with a ventricular arrhythmia. Left ventricular dysfunction is also a risk factor for sudden cardiac death. Brugada Terradellas said that effective risk prediction for sudden cardiac death requires using of a combination of measures, including age, left ventricular ejection fraction with or without heart failure symptoms, previous arrhythmias, and other factors.

Individuals who are found to be at risk of sudden cardiac death can be managed with an implantable cardioverter defibrillator (ICD). These devices reduce mortality by 30% to 50%. The only test that is currently used to determine whether risk is high enough to warrant ICD implantation is the measurement of ejection fraction, since the risk of sudden death rises as ejection fraction falls. However, trials of ICDs in patients with low ejection fractions show that the device was not triggered in about two-thirds of patients during the study period. This result points to the need to further refine risk calculations in order to ensure that patients who receive the device benefit from it. Potential new risk criteria might use noninvasive imaging techniques, such as MRI, to detect cardiac fibrosis and scarring, and techniques that can visualize the three dimensional architecture of the heart and its patterns of electrical activity. In the future, genetic testing and serum biomarkers may also be employed in risk assessment.

Tackling atrial fibrillation with catheter ablation

Atrial fibrillation is often caused by aberrant electrical signaling that originates near the area where the pulmonary veins enter the heart. Using catheter ablation, cardiologists can isolate the signaling occurring in this area from the rest of the electrical pathways of the heart, relieving or reducing atrial fibrillation. Although relatively new in atrial fibrillation, catheter ablation has become an established therapeutic intervention. Vivek Reddy of the Mount Sinai School of Medicine described recent clinical evidence on the use of this technique as well as emerging evidence and new techniques that will influence how this procedure is used in the future.

Nonpharmacologic approaches to treating atrial fibrillation are largely reserved for patients in whom medications are ineffective or poorly tolerated. Catheter ablation is an important treatment that is more successful than medication for certain types of atrial fibrillation patients. Reddy described current thinking on treatment selection for these patients, which depends on their underlying stroke risk and on whether they are experiencing symptoms. Patients at high risk of stroke generally should receive oral anticoagulants in addition to catheter ablation or to another interventional procedure.

One of the challenges with this technique is that the pulmonary veins are not always isolated completely, so medications may still be needed. Another is that connections to the pulmonary vein area may be re-established, necessitating subsequent ablation procedures. Researchers are developing new ablation techniques as part of ongoing efforts to improve the reliability and durability of this procedure. Improvements include catheters that deliver radiofrequency energy more precisely, improved imaging and electrical mapping technologies, and the use of robotic systems to address the technical demands of the procedure. These new technologies should improve treatment of the growing population of elderly patients who suffer from atrial fibrillation that is not well managed by medical interventions.

Transcatheter aortic valve implantation: the way of the future

Valvular heart disease is also becoming more prevalent, again a result of the aging of the population. Aortic stenosis is the most common acquired valvular heart disease. In addition to being elderly, many individuals with aortic stenosis have significant co-morbidities, such as reduced left ventricular function, impaired renal function, or others, that make them poor candidates for traditional open surgical approaches.

Josep Rodés-Cabau of the Québec Heart and Lung Institute described transcatheter aortic valve implantation (TAVI), which has been developed as a less invasive means of treating these patients. In TAVI, the patient receives a new aortic valve that is delivered to the heart through a blood vessel in the arm or leg, without conventional surgery. The first human TAVI procedure for the treatment of symptomatic severe stenosis was performed in 2002, and use of the technique has since become widespread. Several multicenter patient registries have collected clinical experience with TAVI, confirming the safety and efficacy of both balloon-based and self-expanding TAVI devices. Success rates for this procedure are greater than 90% and 30-day mortality rates are less than 10% in most case series, despite a very high-risk patient population. Complications include stroke, major vascular complications, or electrical conduction disturbances that necessitate permanent pacemaker implantation.

Potential transvascular routes for repair of the aortic valve. (Image courtesy of Josep Rodés-Cabau)

Recently, the large randomized PARTNER trial in high-risk or inoperable patients confirmed the superiority of TAVI compared to standard care in patients who are not candidates for the standard valve replacement surgery. Continued improvements in transcatheter valve technology, optimization of procedures, and data regarding the long-term durability of transcatheter valve prostheses may allow TAVI to be expanded to a broader range of patients with severe aortic stenosis in the future.

Severe mitral regurgitation: challenges to surgical intervention

Mitral regurgitation is a condition in which the mitral valve does not close properly, allowing blood to leak from the left ventricle back into the left atrium. David H. Adams of Mount Sinai Medical Center described some of the challenges surrounding surgical intervention for this condition, and discussed current evidence-based guidelines.

Mitral regurgitation often occurs early in patients with heart failure, but is usually asymptomatic. Clinicians often wait to repair it until symptoms appear or until the condition has become much more severe. In the meantime, the patient's heart failure becomes more severe as well, with the ejection fraction dropping to below 50%. Patients with severe heart failure and ejection fractions of less than 50% have poor prognoses after mitral valve surgery. Current guidelines therefore recommend, and Adams concurred strongly, that it is important to perform this repair early while the patient's heart function is still relatively high.

In symptomatic patients, Adams said that it is important to correct mitral regurgitation as soon as clinical manifestations appear, in order to avoid deleterious physiological and structural changes in the heart. In asymptomatic patients with preserved left ventricular function, the main indications for mitral surgery are the onset of symptoms and left ventricular dysfunction. Current guidelines recommend early mitral valve repair based on two factors: a greater than 90% probability that the repair will be successful, based on preoperative assessment of the valve anatomy, and a mortality rate less than or equal to 1%. Adams said that indications, referral patterns, and timing of surgery for severe mitral regurgitation are evolving rapidly, and the guidelines will likely be refined further in the future.

The dilated aorta and its consequences

Valentin Fuster gave the final talk of the meeting, focusing on pathological conditions that arise when the thoracic aorta, the portion of the aorta that is closest to the heart, becomes dilated and enlarged. The resulting weakening of the aortic wall can form a thoracic aortic aneurysm, which in turn can rupture in a life-threatening thoracic aortic dissection. Pathophysiological factors that work together to create this condition include genetic predisposition, cardiovascular risk factors, and the effects of hemodynamic forces on the blood vessel wall.

Computed tomography (CT) image of a dissected (internally ruptured) thoracic aortic aneurysm. (Image courtesy of Valentin Fuster)

Fuster described recent advances in our understanding of aortic aneurysms, which are derived from the study of thoracic aortic aneurysms as well as of abdominal aortic aneurysms and of inherited conditions such as Marfan's syndrome. Studies of these conditions have led to insights into molecular changes in the blood vessel wall, largely involving extracellular matrix proteins, that lead to weakening and dilation. Identifying these molecular changes reveals potential targets for new drugs. In addition, new imaging techniques are providing important structural information about this condition, which will lead to improved diagnostic and prognostic methods for these patients.

Fuster noted that thoracic aneurysms involve different genes, risk factors, and pathophysiologic processes from other similar aortic conditions. He said that extrapolation of data from one aneurysmal disease process to another is ill-founded and potentially harmful to patients. Clinical trials will need to be done specifically in thoracic aortic aneurysm patients before treatments that have been tried in other aortic aneurysms, such as beta-blockers, angiotensin receptor blockers, statins, and macrolide antibiotics, can be recommended. In the meantime, researchers are identifying surgical methods and devices that can be used to repair these aneurysms, preferably before they rupture and threaten the patient's life.