Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances.

Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances.

The timeline shows the steady decline in cardiovascular deaths over the late 20th and early 21st centuries, along with major advances in cardiovascular science and medicine. ALLHAT denotes Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, CASS Coronary Artery Surgery Study, GISSI Italian Group for the Study of Streptokinase in Myocardial Infarction, HMG-CoA 1-hydroxy-3-methylglutaryl coenzyme A, ISIS-2 Second International Study of Infarct Survival, MI myocardial infarction, NCEP National Cholesterol Education Program, NHBPEP National High Blood Pressure Education Program, PCI percutaneous coronary intervention, SAVE Survival and Ventricular Enlargement, and TIMI.

Thrombolysis in Myocardial Infarction trials subsequently showed that both primary and secondary prevention was possible when steps were taken to lower blood pressure and serum total cholesterol. Fortunately, drugs to reduce these risk factors safely became available as a result of a series of productive collaborations between industry and academic medicine. Coronary Care Units Until 1961, patients with acute myocardial infarction — if fortunate enough to survive until they reached a hospital — were placed in beds located throughout the hospital and far enough away from nurses’ stations that their rest would not be disturbed.

Patients were commonly found dead in their beds, presumably from a fatal tachyarrhythmia. Indeed, the risk of death occurring in the hospital was approximately 30%. The development of the coronary care unit,12 which provided continuous monitoring of the electrocardiogram, closed-chest cardiac resuscitation, and external defibrillation, reduced in-hospital mortality by half among patients admitted with acute myocardial infarction.

Physiology, Cardiac Catheterization, Angioplast y, and surgery The publication of De Motu Cordis in 1628, William Harvey’s seminal description of the circulation and the function of the heart,13 set the stage for the physiological era several centuries later. The 19th-century French physiologist Claude Bernard catheterized animals and measured the pressures in the great vessels and cardiac chambers.  This experiment led to the first human cardiac catheterization, performed by Werner Forssman — on himself — in 1929,15 which in turn led to the exploration of cardiac hemodynamics by André Frédéric Cournand and Dickinson W. Richards.

All three of these investigators were awarded the Nobel Prize in Physiology or Medicine in 1956. Cardiac catheterization paved the way for the development of coronary arteriography in 1958.17 When combined with left ventriculography, the use of this imaging technique allowed clinicians to elucidate the natural history of coronary artery disease. Coronary arteriography and left ventriculography became the standard diagnostic tool for defining pump function and vessel anatomy and provided the foundation for surgical treatment by means of coronary revascularization. The development and refinement of the technique of open-heart surgery required close collaborations among surgeons, engineers, cardiologists,anesthesiologists, and hematologists.

The field of invasive cardiology soon emerged, built on the pioneering work of Dotter and Judkins, although Andreas Grüntzig is considered the father of percutaneous interventional cardiology The initial technique of balloon angioplasty was followed by the insertion of baremetal stents, and today, drug-eluting stents are used to prevent coronary restenosis.20 Once again, cross-disciplinary collaborations, this time among engineers, cardiologists, radiologists, and pathologists, forged remarkable advances in terms of improved vascular devices and techniques.

Obstructions in the heart and circulation can now be successfully opened, and abnormal openings successfully closed, in the catheterization laboratory. Modern Therapy By the 1970s, in-hospital mortality from acute myocardial infarction was approximately 15%, and in the first year after hospital discharge, roughly 10% of patients died from left ventricular failure associated with large infarctions. Studies in laboratory animals suggested that infarct size could be reduced by rectifying the imbalance between myocardial oxygen supply and demand. In 1976, cardiologists were able to open acutely occluded coronary arteries by intracoronary infusion of the fibrinolytic agent streptokinase.

The Italian Group for the Study of Streptokinase in Myocardial Infarction (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico) (GISSI) trial, one of the first cardiac “mega-trials” (involving more than 10,000 patients), showed that intravenous streptokinase reduced early mortality in patients with acute myocardial infarction.The Second International Study of Infarct Survival (ISIS-2) showed that the addition of aspirin (an antiplatelet drug) led to further reductions in mortality.Coronary angioplasty and stenting,25 together with newer, more potent platelet inhibitors (e.g., P2Y12 and glycoprotein IIb/IIIa platelet–receptor blockers), further reduced in hospital mortality to about 7%. The efficacy of these treatments, including ventricular defibrillation, depends on a short interval between the onset of symptoms and the patient’s arrival at the hospital.

Considerable progress has been achieved since the 1970s through massive public and professional education programs led by partnerships among the NHLBI, the American Heart Association, and the American College of Cardiology. It was also in this era that randomized, controlled clinical trials became the paradigm for the advancement of clinical cardiovascular therapeutics. Based on studies in animals showing the benefits of angiotensin-converting–enzyme inhibitors in experimentally induced myocardial infarction, the Survival and Ventricular Enlargement (SAVE) trial showed that long-term administration of these inhibitors reduced mortality among patients with left ventricular dysfunction after infarction.26

The use of beta-adrenergic blockers and aldosterone blockers in these patients further reduced mortality. Despite these notable advances, however, life-threatening heart failure still occurs late in patients with extensive ventricular scarring as a consequence of large infarcts. Implantable defibrillators,27 cardiac resynchronization therapy with pacemakers,28 and left ventricular assist devices29 have improved the prognosis for such patients. Cardiomyocytes from patients with severe heart failure have been found to be deficient in sarcoplasmic reticulum

Ca2+ ATPase (SERCA2a). In a pilot study, an adenoassociated virus has been used to deliver the gene for SERCA2a by intracoronary infusion, with seemingly beneficial results.30 Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction In the late 1930s, alert clinicians called attention to what we now refer to as unstable angina and non–ST segment elevation acute coronary syndrome. Patients with this disorder have severeanginal pain, usually at rest, often with biochemical evidence of some myonecrosis and severe, multivessel, obstructive coronary artery disease.

These patients now outnumber those with STsegment elevation myocardial infarction by about 3 to 1 and account for about million hospitaladmissions yearly in the United States. Patients with non–ST-segment elevation acute coronary syndrome have improvement with prompt coronary revascularization and require inhibition of the two clotting-system pathways with aspirin and a platelet P2Y12-receptor antagonist (e.g., clopidogrel), together with an anticoagulant (low-molecular-weight heparin). Their course after hospital discharge is improved by an intensive reduction in low-density lipoprotein (LDL) cholesterol levels31 and administration of an anticoagulant.

The clinical problems of coronary artery disease and myocardial infarction are still being actively investigated and reported in a lot of medical publications. Coronary Atherosclerosis; The ability to access vascular and cardiac tissue rapidly led to the development of animal models of vascular disease, as well as clinical studies in humans. Two lines of investigation in the 1970s and 1980s forged the field of vascular biology: the observations that thrombotic occlusion of a ruptured or eroded atherosclerotic plaque led to acute myocardial infarction and that nitric oxide was a physiological dilator of blood vessels, a discovery for which Furchgott, Ignarro, and Murad received the 1998 Nobel Prize in Physiology or Medicine.

This pioneering work transformed our understanding of the cellular interactions in both normal and diseased blood vessels and influenced the direction of subsequent research. Investigators shifted their attention from animal preparations of intact vessels to molecular and cellular regulation and, ultimately, to the genes that encode the growth factors, enzymes, other proteins, and RNAs responsible for the development of normal or diseased vessels. On the basis of these and other studies, we now understand that atherosclerosis is a chronic inflammation of arteries, which develops over decades in response to the biologic effects of risk factors.

Atherogenesis begins as a qualitative change to intact endothelial cells; when subjected to oxidative, hemodynamic, or biochemical stimuli (from smoking, hypertension, or dyslipidemia) and inflammatory factors, they change their permeability to promote the entry and retention of blood-borne monocytes and cholesterol-containing LDL particles. Inflammation and biochemical modifications ensue, causing endothelial and smooth-muscle cells to proliferate, produce extracellular matrix molecules, and form a fibrous cap over the developing atheromatous plaque.

Plaques lead to clinical symptoms by producing flow-limiting stenoses (causing stable angina) or by provoking thrombi that interrupt blood flow on either a temporary basis (causing unstable angina) or a permanent one (causing myocardial infarction). Physical disruption (rupture) of the plaque exposes procoagulant material within the core of the plaque to coagulation proteins and platelets, triggering thrombosis. Evidence of the causative role of LDL cholesterol in atherosclerosis is threefold: first, genetic mutations that impair receptor-mediated removal of LDL cholesterol from plasma cause fulminant atherosclerosis; second, animals with low LDLcholesterol levels have no atherosclerosis, whereas increasing these levels  experimentally leads to disease; and third, human populations with low LDL-cholesterol levels have minimal atherosclerosis, and the process increases in proportion to the level of LDL cholesterol in the blood.

Remarkable victory for patients with coronary artery disease came when the LDL-cholesterol pathway was delineated and the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), discovered by Akira Endo,  was developed to lower LDL-cholesterol levels. Brown and Goldstein’s discovery of the LDL-receptor pathway, for which they were awarded the 1985 Nobel Prize.

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