Adventures in Cardiovascular Research

This article, derived from an invited Distinguished Scientist lecture presented at the American Heart Association Scientific Sessions in 2007, reviews 4 themes (adventures) in clinical cardiovascular research carried out over a period of 58 years. It begins with the author’s introduction to cardiovascular hemodynamics during a medical school elective in 1951. The 4 adventures include valvular heart disease, hypertrophic cardiomyopathy, heart failure (HF), and myocardial ischemia. In each of these adventures, the author describes briefly what was known when he entered each field, followed by the author’s contribution to the field (the adventure), and ends with comments about the current status of the field. Of particular interest are the changes in the technologies used in clinical cardiovascular research over the past half century, commencing with pressure tracings in left heart chambers with the use of needle puncture in the operating room to genetic technologies designed to understand differences between drugs that inhibit platelet activation. The article ends with some general comments on conducting research and the rewards that can come with this activity.

[1]  M. Keltai,et al.  Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial , 2008, The Lancet.

[2]  A. Stratone.  [The heart--an endocrine organ]. , 1989, Physiologie.

[3]  C. Chidsey,et al.  Biosynthesis of Norepinephrine in Isolated Canine Heart , 1963, Science.

[4]  J. Ross,et al.  Left Heart Catheterization by the Transseptal Route: A Description of the Technic and Its Applications , 1960 .

[5]  J. Ross,et al.  Studies on Starling's law of the heart. V. Left ventricular function in man. , 1961, The Journal of clinical investigation.

[6]  J. Cohn,et al.  C-Reactive Protein in Heart Failure: Prognostic Value and the Effect of Valsartan , 2005, Circulation.

[7]  M. Pfeffer,et al.  Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. , 2005, Journal of the American College of Cardiology.

[8]  E. Braunwald,et al.  Myocardial salvage after intracoronary thrombolysis with streptokinase in acute myocardial infarction. , 1981, The New England journal of medicine.

[9]  E. Braunwald,et al.  Studies on Starling's Law of the Heart: VIII. Mechanical Properties of Human Myocardium Studied in Vivo , 1962, Circulation.

[10]  E. Braunwald.  Hypertrophic cardiomyopathy--the benefits of a multidisciplinary approach. , 2002, The New England journal of medicine.

[11]  J. Ross,et al.  Effects of Beta Adrenergic Blockade on the Circulation, with Particular Reference to Observations in Patients with Hypertrophic Subaortic Stenosis , 1964, Circulation.

[12]  E. Varnauskas,et al.  Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. , 1975, British heart journal.

[13]  B. Gersh.  Intensive oral antiplatelet therapy for reduction of ischemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial , 2009 .

[14]  E. Braunwald,et al.  Six- and twelve-month follow-up of the phase I Thrombolysis in Myocardial Infarction (TIMI) trial. , 1988, The American journal of cardiology.

[15]  E. Braunwald,et al.  Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. , 1957, The American journal of physiology.

[16]  E. Braunwald,et al.  Training the clinician investigator. , 2008, Circulation research.

[17]  E. Braunwald,et al.  Idiopathic Hypertrophic Subaortic Stenosis: II. Operative Treatment and the Results of Pre‐ and Postoperative Hemodynamic Evaluations , 1964, Circulation.

[18]  E. Braunwald,et al.  Circulatory Effects of Electrical Stimulation of the Carotid Sinus Nerves in Man , 1969, Circulation.

[19]  E. Braunwald,et al.  Functional Aortic Stenosis: A Malformation Characterized by Resistance to Left Ventricular Outflow without Anatomic Obstruction , 1959, Circulation.

[20]  E. Braunwald,et al.  Augmentation of the plasma nor-epinephrine response to exercise in patients with congestive heart failure. , 1962, The New England journal of medicine.

[21]  Andrew S. Wechsler,et al.  Relief of Angina Pectoris by Electrical Stimulation of the Carotid-Sinus Nerves , 1967 .

[22]  J. Seidman,et al.  Genetic Basis of Hypertrophic Cardiomyopathy: From Bench to the Clinics , 2007, Journal of cardiovascular electrophysiology.

[23]  E. Braunwald,et al.  Determination of Fraction of Left Ventricular Volume Ejected per Beat and of Ventricular End‐Diastolic and Residual Volumes: Experimental and Clinical Observations with a Precordial Dilution Technic , 1962, Circulation.

[24]  R. Lasser,et al.  The Hemodynamics of the Left Side of the Heart as Studied by Simultaneous Left Atrial, Left Ventricular, and Aortic Pressures; Particular Reference to Mitral Stenosis , 1955, Circulation.

[25]  E. Braunwald,et al.  Hemogynamic alterations in idiopathic hypertrophic subaortic stenosis induced by sympathomimetic drugs. , 1962, The American journal of cardiology.

[26]  E. Antman,et al.  Prasugrel Compared With High Loading– and Maintenance–Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 Trial , 2007, Circulation.

[27]  E. Antman,et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes. , 2007, The New England journal of medicine.

[28]  E. Braunwald,et al.  CATECHOLAMINE EXCRETION AND CARDIAC STORES OF NOREPINEPHRINE IN CONGESTIVE HEART FAILURE. , 1965, The American journal of medicine.

[29]  E. Braunwald,et al.  Contractile State of Cardiac Muscle Obtained from Cats with Experimentally Produced Ventricular Hypertrophy and Heart Failure , 1967, Circulation research.

[30]  E. Braunwald,et al.  THE CONTRACTILE PROPERTIES OF HUMAN HEART MUSCLE: STUDIES ON MYOCARDIAL MECHANICS OF SURGICALLY EXCISED PAPILLARY MUSCLES. , 1965, The Journal of clinical investigation.

[31]  E. Braunwald,et al.  Amelioration of Angina Pectoris in Idiopathic Hypertrophic Subaortic Stenosis with Beta‐Adrenergic Blockade , 1967, Circulation.

[32]  T COOPER,et al.  Complete replacement of the mitral valve. Successful clinical application of a flexible polyurethane prosthesis. , 1960, The Journal of thoracic and cardiovascular surgery.

[33]  E. Braunwald,et al.  The effects of acutely increased systemic resistance on the left atrial pressure pulse: a method for the clinical detection of mitral insufficiency. , 1958, The Journal of clinical investigation.

[34]  H. S. Mueller,et al.  The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. , 1985, The New England journal of medicine.

[35]  C. Vassanelli,et al.  [Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban]. , 2001, Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology.

[36]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[37]  W. Ganz,et al.  The thrombolysis in myocardial infarction (TIMI) trial. , 1985, The New England journal of medicine.

[38]  M. Pfeffer,et al.  Influence of Chronic Captopril Therapy on the Infarcted Left Ventricle of the Rat , 1985, Circulation research.

[39]  G. Lamas,et al.  Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. , 1988, The New England journal of medicine.

[40]  Thomas Weber,et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes. , 2004, The New England journal of medicine.

[41]  E. Braunwald,et al.  Hemodynamic determinants of coronary flow: effect of changes in aortic pressure and cardiac output on the relationship between myocardial oxygen consumption and coronary flow. , 1957, The American journal of physiology.

[42]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[43]  E. Braunwald,et al.  Modification of myocardial infarction size after coronary occlusion. , 1973, Annals of internal medicine.

[44]  E. Braunwald,et al.  MYOCARDIAL FORCE-VELOCITY RELATIONS STUDIED IN INTACT UNANESTHETIZED MAN. , 1965, The Journal of clinical investigation.

[45]  J. Ross,et al.  Effects of Changes in Body Position on the Severity of Obstruction to Left Ventricular Outflow in Idiopathic Hypertrophic Subaortic Stenosis , 1966, Circulation.

[46]  M. Pfeffer,et al.  Hemodynamic benefits and prolonged survival with long-term captopril therapy in rats with myocardial infarction and heart failure. , 1987, Circulation.

[47]  E. Braunwald,et al.  A Hemodynamic Technic for the Detection of Hypertrophic Subaortic Stenosis , 1961 .

[48]  Jessica L Mega,et al.  Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes , 2009, Circulation.

[49]  J. Ross,et al.  EFFECTS OF MITRAL-VALVE REPLACEMENT ON THE PULMONARY VASCULAR DYNAMICS OF PATIENTS WITH PULMONARY HYPERTENSION. , 1965, The New England journal of medicine.

[50]  A. Mazaev,et al.  [Intracoronary administration of fibrinolysin in acute myocardial infarct]. , 1976, Terapevticheskii arkhiv.

[51]  E. Braunwald.  Thirteenth Bowditch lecture. The determinants of myocardial oxygen consumption. , 1969, The Physiologist.

[52]  M. Cheitlin.  Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes , 2010 .

[53]  E. Antman,et al.  Cytochrome p-450 polymorphisms and response to clopidogrel. , 2009, The New England journal of medicine.

[54]  K. Karsch,et al.  Acute myocardial infarction: Intracoronary application of nitroglycerin and streptokinase , 1979, Clinical cardiology.

[55]  J. Ross.  Transseptal left heart catheterization a 50-year odyssey. , 2008, Journal of the American College of Cardiology.

[56]  R. Califf,et al.  Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. , 2008, American heart journal.

[57]  J. Ross,et al.  The Circulatory Response of Patients with Idiopathic Hypertrophic Subaortic Stenosis to Nitroglycerin and to the Valsalva Maneuver , 1964, Circulation.

[58]  J. Covell,et al.  Factors Influencing Infarct Size Following Experimental Coronary Artery Occlusions , 1971, Circulation.

[59]  J. Youmans.  The manner of expressing serum protein values. , 1949, The American journal of medicine.

[60]  C. Lambrew,et al.  Idiopathic Hypertrophic Subaortic Stenosis: I. A Description of the Disease Based Upon an Analysis of 64 Patients , 1964, Circulation.

[61]  E. Braunwald,et al.  Left Heart Catheterization by the Transbronchial Route: Technic and Applications in Physiologic and Diagnostic Investigations , 1957, Circulation.

[62]  J. Ross,et al.  Effects of Drugs and of Counterpulsation on Myocardial Oxygen Consumption: Observations on the Ischemic Heart , 1969 .

[63]  E. Braunwald,et al.  MYOCARDIAL NOREPINEPHRINE CONCENTRATION IN MAN. EFFECTS OF RESERPINE AND OF CONGESTIVE HEART FAILURE. , 1963, The New England journal of medicine.

[64]  J F Williams,et al.  Effects of exercise on myocardial force-velocity relations in intact unanesthetized man: relative roles of changes in heart rate, sympathetic activity, and ventricular dimensions. , 1965, The Journal of clinical investigation.

[65]  H. F. Wood,et al.  A study of C-reactive protein in the serum of patients with congestive heart failure. , 1956, American heart journal.

[66]  J. Ross,et al.  Velocity of contraction as a determinant of myocardial oxygen consumption. , 1965, The American journal of physiology.

[67]  Chazov Ei,et al.  Intracoronary administration of fibrinolysin in acute myocardial infarct , 1976 .