Medical Treatment of Aortic Stenosis

Untreated, severe, symptomatic aortic stenosis is associated with a dismal prognosis. The only treatment shown to improve survival is aortic valve replacement; however, before symptoms occur, aortic stenosis is preceded by a silent, latent phase characterized by a slow progression at the molecular, cellular, and tissue levels. In theory, specific medical therapy should halt aortic stenosis progression, reduce its hemodynamic repercussions on left ventricular function and remodeling, and improve clinical outcomes. In the present report, we performed a systematic review of studies focusing on the medical treatment of patients with aortic stenosis. Lipid-lowering therapy, antihypertensive drugs, and anticalcific therapy have been the main drug classes studied in this setting and are reviewed in depth. A critical appraisal of the preclinical and clinical evidence is provided, and future research avenues are presented.

[1]  P. F. Kauff Group , 2000, Elegant Design.

[2]  K. Toutouzas,et al.  Inhibition of Aortic Valve Calcification by Local Delivery of Zoledronic Acid—an Experimental Study , 2018, Journal of Cardiovascular Translational Research.

[3]  Y. Bossé,et al.  Systolic hypertension and progression of aortic valve calcification in patients with aortic stenosis: results from the PROGRESSA study , 2017, European heart journal cardiovascular Imaging.

[4]  Wing W. Chan,et al.  Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction. , 2016, JAMA cardiology.

[5]  Akshay S. Desai,et al.  Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. , 2016, Journal of the American College of Cardiology.

[6]  J. Leipsic,et al.  One-Year Clinical Outcomes With SAPIEN 3 Transcatheter Aortic Valve Replacement in High-Risk and Inoperable Patients With Severe Aortic Stenosis , 2016, Circulation.

[7]  M. Desai,et al.  Association of Abnormal Postoperative Left Ventricular Global Longitudinal Strain With Outcomes in Severe Aortic Stenosis Following Aortic Valve Replacement. , 2016, JAMA cardiology.

[8]  G. Thanassoulis Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis , 2016, Journal of Lipid Research.

[9]  Jeroen J. Bax,et al.  Natural History, Diagnostic Approaches, and Therapeutic Strategies for Patients With Asymptomatic Severe Aortic Stenosis. , 2016, Journal of the American College of Cardiology.

[10]  M. Mack,et al.  Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. , 2016, The New England journal of medicine.

[11]  K. Yutzey,et al.  Cardiac Fibrosis: The Fibroblast Awakens. , 2016, Circulation research.

[12]  Akshay S. Desai,et al.  Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial. , 2016, Circulation. Heart failure.

[13]  J. Tardif,et al.  Resting heart rate as a predictor of aortic valve stenosis progression. , 2016, International journal of cardiology.

[14]  Cuihong Xie,et al.  Angiotensin II promotes an osteoblast-like phenotype in porcine aortic valve myofibroblasts , 2016, Aging Clinical and Experimental Research.

[15]  Y. Bossé,et al.  Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease , 2015, Circulation. Cardiovascular genetics.

[16]  C. Macaya,et al.  Incidence, Causes, and Predictors of Early (≤30 Days) and Late Unplanned Hospital Readmissions After Transcatheter Aortic Valve Replacement. , 2015, JACC. Cardiovascular interventions.

[17]  G. Cioffi,et al.  See Clinical Perspective See Editorial by Barasch and Reichek , 2022 .

[18]  J. Witztum,et al.  Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study , 2015, The Lancet.

[19]  Y. Bossé,et al.  AUTOTAXIN ENHANCES AORTIC VALVE MINERALIZATION THROUGH A NF-κB / IL-6 / BMP-2 DEPENDENT INFLAMMATORY PATHWAY , 2015 .

[20]  J. Tardif,et al.  ALTERATIONS OF APOA-I/HDL TARGET RECEPTOR SR-BI AND LOX-1 IN PATIENTS WITH AORTIC VALVE STENOSIS , 2015 .

[21]  J. Després,et al.  SYSTOLIC HYPERTENSION AND PROGRESSION OF AORTIC VALVE CALCIFICATION IN PATIENTS WITH AORTIC STENOSIS - RESULTS FROM THE PROGRESSA STUDY , 2015 .

[22]  J. Afilalo,et al.  Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis. , 2015, Annals of emergency medicine.

[23]  Y. Bossé,et al.  Oxidized Phospholipids, Lipoprotein(a), and Progression of Calci fi c Aortic Valve Stenosis , 2017 .

[24]  T. Akasaka,et al.  Risk Factors for Progression of Degenerative Aortic Valve Disease in the Japanese- The Japanese Aortic Stenosis Study (JASS) Prospective Analysis. , 2015, Circulation journal : official journal of the Japanese Circulation Society.

[25]  M. Dweck,et al.  Calcification in Aortic Stenosis: The Skeleton Key. , 2015, Journal of the American College of Cardiology.

[26]  Jiawei Shi,et al.  Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1β-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-κB pathway , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[27]  M. Mack,et al.  5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial , 2015, The Lancet.

[28]  M. Mack,et al.  5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial , 2015, The Lancet.

[29]  C. Held,et al.  EACPR country of the month initiative: Sweden. , 2015, European heart journal.

[30]  Yu Kataoka,et al.  Impact of statins on serial coronary calcification during atheroma progression and regression. , 2015, Journal of the American College of Cardiology.

[31]  Marie-Chloé Boulanger,et al.  Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. , 2015, Cardiovascular research.

[32]  B. Prendergast,et al.  A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial) , 2015, European heart journal cardiovascular Imaging.

[33]  P. Kovanen,et al.  Is Blockade of the Renin-angiotensin System Able to Reverse the Structural and Functional Remodeling of the Left Ventricle in Severe Aortic Stenosis? , 2015, Journal of cardiovascular pharmacology.

[34]  N. Weissman,et al.  Hemodynamic outcomes of transcatheter aortic valve replacement and medical management in severe, inoperable aortic stenosis: a longitudinal echocardiographic study of cohort B of the PARTNER trial. , 2015, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[35]  Y. Bossé,et al.  Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis: the PROGRESSA study. , 2015, JACC. Cardiovascular imaging.

[36]  Vilmundur Gudnason,et al.  Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. , 2014, JAMA.

[37]  M. Enriquez-Sarano,et al.  Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis: results of an international registry study. , 2014, Journal of the American College of Cardiology.

[38]  Akshay S. Desai,et al.  Angiotensin-neprilysin inhibition versus enalapril in heart failure. , 2014, The New England journal of medicine.

[39]  L. Køber,et al.  Renin-angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis. , 2014, International journal of cardiology.

[40]  Thoralf M Sundt,et al.  2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. , 2014, Circulation.

[41]  Thoralf M Sundt,et al.  2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. , 2014, Circulation.

[42]  M. Enriquez-Sarano,et al.  Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations. , 2014, JACC. Cardiovascular interventions.

[43]  Maurice Buchbinder,et al.  Transcatheter aortic-valve replacement with a self-expanding prosthesis. , 2014, The New England journal of medicine.

[44]  P. Barter,et al.  Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT, IDEAL, and SPARCL). , 2014, The American journal of cardiology.

[45]  C. Hassager,et al.  Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: a placebo-controlled, randomized study. , 2014, American heart journal.

[46]  M. Sandhu,et al.  Lipoprotein(a) levels, genotype and incident aortic stenosis: a prospective Mendelian randomization study and replication in a case-control cohort , 2013 .

[47]  B. Nordestgaard,et al.  Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. , 2013, Journal of the American College of Cardiology.

[48]  P. Pibarot,et al.  The complex nature of discordant severe calcified aortic valve disease grading: new insights from combined Doppler echocardiographic and computed tomographic study. , 2013, Journal of the American College of Cardiology.

[49]  P. Pibarot,et al.  Impact of hypertension and renin–angiotensin system inhibitors in aortic stenosis , 2013, European journal of clinical investigation.

[50]  J. Chambers,et al.  Effect of overweight and obesity on cardiovascular events in asymptomatic aortic stenosis: a SEAS substudy (Simvastatin Ezetimibe in Aortic Stenosis). , 2013, Journal of the American College of Cardiology.

[51]  R. Nishimura,et al.  Systemic Hypertension in Low-Gradient Severe Aortic Stenosis With Preserved Ejection Fraction , 2013, Circulation.

[52]  A. Bogers,et al.  Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. , 2013, Journal of the American College of Cardiology.

[53]  F. Tubach,et al.  Progression of aortic valve stenosis is associated with bone remodelling and secondary hyperparathyroidism in elderly patients--the COFRASA study. , 2013, European heart journal.

[54]  B. Lutz,et al.  Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. , 2013, Life sciences.

[55]  P. Pellikka,et al.  Prevention of atrial fibrillation in patients with aortic valve stenosis with candesartan treatment after aortic valve replacement. , 2013, International journal of cardiology.

[56]  Ajit P. Yoganathan,et al.  Aortic Valve: Mechanical Environment and Mechanobiology , 2013, Annals of Biomedical Engineering.

[57]  A. Luttun,et al.  Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling , 2013, PloS one.

[58]  Kathleen F. Kerr,et al.  Genetic associations with valvular calcification and aortic stenosis. , 2013, The New England journal of medicine.

[59]  R. Sacco,et al.  Higher Ambulatory Blood Pressure Is Associated With Aortic Valve Calcification in the Elderly: A Population-Based Study , 2013, Hypertension.

[60]  O. Alfieri,et al.  Guidelines on the management of valvular heart disease (version 2012). , 2012, European heart journal.

[61]  K. Masters,et al.  A time course investigation of the statin paradox among valvular interstitial cell phenotypes. , 2012, American journal of physiology. Heart and circulatory physiology.

[62]  J. Peteiro,et al.  Association of Left Ventricular Mass with All-Cause Mortality, Myocardial Infarction and Stroke , 2012, PloS one.

[63]  M. Dweck,et al.  Osteoporosis is a major confounder in observational studies investigating bisphosphonate therapy in aortic stenosis. , 2012, Journal of the American College of Cardiology.

[64]  P. Pibarot,et al.  Inhibition of ectonucleotidase with ARL67156 prevents the development of calcific aortic valve disease in warfarin-treated rats. , 2012, European journal of pharmacology.

[65]  J. Després,et al.  Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. , 2012, Journal of the American College of Cardiology.

[66]  B. Gage,et al.  Effects of Phosphodiesterase Type 5 Inhibition on Systemic and Pulmonary Hemodynamics and Ventricular Function in Patients With Severe Symptomatic Aortic Stenosis , 2012, Circulation.

[67]  P. Garg,et al.  077 Osteoporosis and bisphosphonate's use associated with reduced progression of calcific aortic stenosis: retrospective observational single centre study , 2012, Heart.

[68]  P. Heidenreich,et al.  The effect of angiotensin-converting enzyme inhibitors and statins on the progression of aortic sclerosis and mortality. , 2012, The Journal of heart valve disease.

[69]  A. Oto,et al.  OP-281 ASSESSMENT OF THE RELATIONSHIP OF CHOLECALCIFEROL, CALCIUM CARBONATE AND ALENDRONATE TREATMENTS WITH AORTIC VALVE CALCIFICATION , 2012 .

[70]  E. Tuzcu,et al.  Do bisphosphonates slow the progression of aortic stenosis? , 2010, Journal of the American College of Cardiology.

[71]  Y. Bossé,et al.  Replication of genetic association studies in aortic stenosis in adults. , 2011, The American journal of cardiology.

[72]  J. Després,et al.  Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves , 2011, European journal of clinical investigation.

[73]  K. Teo,et al.  Lipid lowering on progression of mild to moderate aortic stenosis: meta-analysis of the randomized placebo-controlled clinical trials on 2344 patients. , 2011, The Canadian journal of cardiology.

[74]  J. Pepper,et al.  Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. , 2011, Journal of the American College of Cardiology.

[75]  P. Pellikka,et al.  Noninvasive assessment of filling pressure and left atrial pressure overload in severe aortic valve stenosis: relation to ventricular remodeling and clinical outcome after aortic valve replacement. , 2011, The Journal of thoracic and cardiovascular surgery.

[76]  C. Lang,et al.  Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. , 2011, Journal of the American College of Cardiology.

[77]  B. Mulder,et al.  Effects of rosuvastatin on progression of stenosis in adult patients with congenital aortic stenosis (PROCAS Trial). , 2011, The American journal of cardiology.

[78]  Stuart J Pocock,et al.  Transcatheter versus surgical aortic-valve replacement in high-risk patients. , 2011, The New England journal of medicine.

[79]  P. Willeit,et al.  Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. , 2011, Journal of the American College of Cardiology.

[80]  Yuan Zhang,et al.  Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations , 2011, British journal of pharmacology.

[81]  A. Innasimuthu,et al.  Effect of Bisphosphonates on the Progression of Degenerative Aortic Stenosis , 2011, Echocardiography.

[82]  R. Arena,et al.  PDE5 Inhibition With Sildenafil Improves Left Ventricular Diastolic Function, Cardiac Geometry, and Clinical Status in Patients With Stable Systolic Heart Failure: Results of a 1-Year, Prospective, Randomized, Placebo-Controlled Study , 2011, Circulation. Heart failure.

[83]  W. Keeling,et al.  Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery , 2011 .

[84]  K. Linhartová,et al.  Bisphosphonates in Calcific Aortic Stenosis: Association with Slower Progression in Mild Disease – A Pilot Retrospective Study , 2010, Cardiology.

[85]  L. Schurgers,et al.  Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis , 2010, Journal of internal medicine.

[86]  S. Pocock,et al.  Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. , 2010, The New England journal of medicine.

[87]  D. Koumoundourou,et al.  Aldosterone receptor blockade inhibits degenerative processes in the early stage of calcific aortic stenosis. , 2010, European journal of pharmacology.

[88]  P. Pellikka,et al.  Effect of candesartan treatment on left ventricular remodeling after aortic valve replacement for aortic stenosis. , 2010, The American journal of cardiology.

[89]  Mario J. Garcia,et al.  Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model. , 2010, European heart journal.

[90]  L. Schurgers,et al.  The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[91]  K. Teo,et al.  Effect of Lipid Lowering With Rosuvastatin on Progression of Aortic Stenosis: Results of the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) Trial , 2010, Circulation.

[92]  M. Cheitlin,et al.  Hydroxymethylglutaryl Coenzyme-A Reductase Inhibitors Delay the Progression of Rheumatic Aortic Valve Stenosis: A Long-Term Echocardiographic Study , 2010 .

[93]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[94]  W. Aronow,et al.  Warfarin use and the risk of valvular calcification , 2009, Journal of thrombosis and haemostasis : JTH.

[95]  P. Pibarot,et al.  Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. , 2009, Journal of the American College of Cardiology.

[96]  V. Persy,et al.  Vascular calcification and bone disease: the calcification paradox. , 2009, Trends in molecular medicine.

[97]  P. Kostenuik,et al.  Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. , 2009, The American journal of pathology.

[98]  I. Kronzon,et al.  Osteoporosis treatment and progression of aortic stenosis. , 2009, The American journal of cardiology.

[99]  S. Young,et al.  Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice , 2009, Circulation.

[100]  A. Mahnken,et al.  Relation of circulating matrix Gla-protein and anticoagulation status in patients with aortic valve calcification , 2009, Thrombosis and Haemostasis.

[101]  M. Criqui,et al.  Association of coronary artery and aortic calcium with lumbar bone density: the MESA Abdominal Aortic Calcium Study. , 2008, American journal of epidemiology.

[102]  J. Chambers,et al.  Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. , 2008, The New England journal of medicine.

[103]  G. Feuchtner,et al.  Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg). , 2008, The American journal of cardiology.

[104]  H. White,et al.  A randomized trial of the aldosterone-receptor antagonist eplerenone in asymptomatic moderate-severe aortic stenosis. , 2008, American heart journal.

[105]  J. Després,et al.  Association Between Plasma LDL Particle Size, Valvular Accumulation of Oxidized LDL, and Inflammation in Patients With Aortic Stenosis , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[106]  G. Filippatos,et al.  [Guidelines on the management of valvular heart disease]. , 2013, Revista espanola de cardiologia.

[107]  J. Després,et al.  Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis , 2007, Heart.

[108]  J. Zamorano,et al.  Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. , 2007, Journal of the American College of Cardiology.

[109]  N. Kostomitsopoulos,et al.  The effects of enalapril on p53 expression in left ventricular cardiomyocytes after aortic stenosis. , 2006, In vivo.

[110]  J. Després,et al.  Metabolic syndrome negatively influences disease progression and prognosis in aortic stenosis. , 2006, Journal of the American College of Cardiology.

[111]  T. Fleming,et al.  Sildenafil citrate therapy for pulmonary arterial hypertension. , 2005, The New England journal of medicine.

[112]  D. Srivastava,et al.  Mutations in NOTCH1 cause aortic valve disease , 2005, Nature.

[113]  S. Stock,et al.  Atorvastatin Inhibits Hypercholesterolemia-Induced Calcification in the Aortic Valves via the Lrp5 Receptor Pathway , 2005, Circulation.

[114]  Damien Garcia,et al.  Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. , 2005, Journal of the American College of Cardiology.

[115]  D. Hardie,et al.  Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase* , 2005, Journal of Biological Chemistry.

[116]  O. Florey,et al.  Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways: A Vicious Cycle of Inflammation and Arterial Calcification? , 2005, Circulation research.

[117]  R. Prescott,et al.  A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. , 2005, The New England journal of medicine.

[118]  W. Zapol,et al.  Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. , 2005, Chest.

[119]  M. Budoff,et al.  Angiotensin-converting enzyme inhibitors and change in aortic valve calcium. , 2005, Archives of internal medicine.

[120]  B. Popescu,et al.  Progression of aortic valve sclerosis and aortic valve stenosis: what is the role of statin treatment? , 2005, Italian heart journal : official journal of the Italian Federation of Cardiology.

[121]  D. Kass,et al.  Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy , 2005, Nature Medicine.

[122]  M. Mäyränpää,et al.  Induction of local angiotensin II-producing systems in stenotic aortic valves. , 2004, Journal of the American College of Cardiology.

[123]  M. Schemper,et al.  Statins but Not Angiotensin-Converting Enzyme Inhibitors Delay Progression of Aortic Stenosis , 2004, Circulation.

[124]  M. Enriquez-Sarano,et al.  Evaluation and Clinical Implications of Aortic Valve Calcification Measured by Electron-Beam Computed Tomography , 2004, Circulation.

[125]  P. Ridker High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: from concept to clinical practice to clinical benefit. , 2004, American heart journal.

[126]  R Alagesan,et al.  Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: Symptomatic Cardiac Obstruction-Pilot Study of Enalapril in Aortic Stenosis (SCOPE-AS). , 2004, American heart journal.

[127]  A. Urtti,et al.  Effect of Liposomal and Free Bisphosphonates on the IL-1β, IL-6 and TNFα Secretion from RAW 264 Cells in Vitro , 1995, Pharmaceutical Research.

[128]  B. Popescu,et al.  Effect of statins on the progression of bioprosthetic aortic valve degeneration. , 2003, The American journal of cardiology.

[129]  K. Fox,et al.  Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study) , 2003, The Lancet.

[130]  Karl Swedberg,et al.  Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial , 2003, The Lancet.

[131]  M. Pfeffer,et al.  Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial , 2003, The Lancet.

[132]  Philippe Ravaud,et al.  A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. , 2003, European heart journal.

[133]  D. Lamontagne,et al.  Endocannabinoids protect the rat isolated heart against ischaemia , 2003, British journal of pharmacology.

[134]  J. Goding,et al.  Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. , 2003, Biochimica et biophysica acta.

[135]  E. Tuzcu,et al.  Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. , 2003, The New England journal of medicine.

[136]  M. Enriquez-Sarano,et al.  Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. , 2002, Journal of the American College of Cardiology.

[137]  P. Vandervoort,et al.  Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. , 2002, Journal of the American College of Cardiology.

[138]  R. Bonow,et al.  Atorvastatin Inhibits Hypercholesterolemia-Induced Cellular Proliferation and Bone Matrix Production in the Rabbit Aortic Valve , 2002, Circulation.

[139]  J. Cohn,et al.  A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. , 2001, The New England journal of medicine.

[140]  G. Ertl,et al.  Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. , 2001, Journal of the American College of Cardiology.

[141]  M. Lauer,et al.  Effect of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors on the Progression of Calcific Aortic Stenosis , 2001, Circulation.

[142]  W. Aronow,et al.  Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. , 2001, The American journal of cardiology.

[143]  P. Price,et al.  Bisphosphonates Alendronate and Ibandronate Inhibit Artery Calcification at Doses Comparable to Those That Inhibit Bone Resorption , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[144]  F. Ohme,et al.  Lack of association among five genetic polymorphisms of the renin-angiotensin system and cardiac hypertrophy in patients with aortic stenosis. , 2001, American heart journal.

[145]  E Fleck,et al.  Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. , 2001, Journal of the American College of Cardiology.

[146]  R. Choudhury,et al.  New insights into the progression of aortic stenosis: implications for secondary prevention. , 2000, Circulation.

[147]  B. Pitt,et al.  The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure , 2000 .

[148]  R. Pai,et al.  New insights into the progression of aortic stenosis: implications for secondary prevention. , 2000, Circulation.

[149]  S. Adami,et al.  Chronic Intravenous Aminobisphosphonate Therapy Increases High‐Density Lipoprotein Cholesterol and Decreases Low‐Density Lipoprotein Cholesterol , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[150]  S. Yusuf,et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[151]  M. Eriksson,et al.  Angiotensin-converting enzyme gene polymorphism influences degree of left ventricular hypertrophy and its regression in patients undergoing operation for aortic stenosis. , 1999, The American journal of cardiology.

[152]  B. Pitt,et al.  The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. , 1999, The New England journal of medicine.

[153]  P. Libby,et al.  Angiotensin induces inflammatory activation of human vascular smooth muscle cells. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[154]  P. Kaufmann,et al.  Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy. , 1999, Circulation.

[155]  J. Thyberg,et al.  Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[156]  R. Alexander,et al.  Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. , 1998, Circulation research.

[157]  H. Schunkert,et al.  Regulation of extracellular matrix proteins in pressure‐overload cardiac hypertrophy: effects of angiotensin converting enzyme inhibition , 1998, Journal of hypertension.

[158]  R. Behringer,et al.  Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein , 1997, Nature.

[159]  Catherine M. Otto,et al.  Clinical Factors Associated With Calcific Aortic Valve Disease , 1997 .

[160]  Bonnie K. Lind,et al.  Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. , 1997, Journal of the American College of Cardiology.

[161]  S. Yusuf,et al.  Overview of Randomized Trials of Angiotensin-Converting Enzyme Inhibitors on Mortality and Morbidity in Patients With Heart Failure , 1995 .

[162]  S. Yusuf,et al.  Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. , 1995, JAMA.

[163]  A. Urtti,et al.  Effect of liposomal and free bisphosphonates on the IL-1 beta, IL-6 and TNF alpha secretion from RAW 264 cells in vitro. , 1995, Pharmaceutical research.

[164]  W. Aronow,et al.  Prognosis of congestive heart failure in patients aged > or = 62 years with unoperated severe valvular aortic stenosis. , 1993, The American journal of cardiology.

[165]  H. Ikram,et al.  Hemodynamic effects of nitroprusside on valvular aortic stenosis. , 1992, The American journal of cardiology.

[166]  Salim Yusuf,et al.  Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. , 1991, The New England journal of medicine.

[167]  F. Tristani,et al.  A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. , 1991, The New England journal of medicine.

[168]  M. Webb-Peploe,et al.  Echocardiographic left ventricular wall thickness: A poor predictor of the severity of aortic valve stenosis , 1991, Clinical cardiology.

[169]  S. Davies,et al.  Progression of valvar aortic stenosis: a long-term retrospective study. , 1991, European heart journal.

[170]  K. Misono,et al.  Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. , 1990, The Journal of biological chemistry.

[171]  D E Manyari,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.

[172]  K. Swedberg,et al.  Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). , 1988, The American journal of cardiology.

[173]  Franz Schwarz,et al.  The Effect of Aortic Valve Replacement on Survival , 1982, Circulation.

[174]  S. Rahimtoola,et al.  Severe Aortic Stenosis in Patients 60 Years of Age and Older: Left Ventricular Function and 10‐year Survival After Valve Replacement , 1981, Circulation.

[175]  R. Miller,et al.  Beneficial effects of nitroprusside administration on left ventricular dysfunction and myocardial ischemia in severe aortic stenosis. , 1981, American heart journal.

[176]  R. Miller,et al.  Effects of isometric exercise and increased arterial impedance on left ventricular function in severe aortic valvular stenosis. , 1977, British heart journal.