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Of MIs and Men—A Historical Perspective on the Diagnostics of Acute Myocardial Infarction* Gianfranco Cervellin, MD1

Giuseppe Lippi, MD2

1 Emergency Department, Academic Hospital of Parma, Parma, Italy 2 Laboratory of Clinical Chemistry and Hematology, Academic Hospital

of Parma, Parma, Italy

Address for correspondence Gianfranco Cervellin, MD, Emergency Department, Academic Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy (e-mail: [email protected]).

Abstract

Keywords

► myocardial infarction ► acute coronary syndrome ► history ► electrocardiogram ► biomarkers

The history of myocardial infarction (MI) diagnostics has gone through a continuous evolution over the past century, when several new discoveries have contributed to remarkably increase the number of patients appropriately diagnosed with this condition. The tale “of MIs and Men” displays rather a long history, since atherosclerosis was found to be present in humans several centuries before modern civilization and the identification of the most prevalent risk factors. It was only at the end of the 19th century and at the beginning of the 20th century that the physicians acknowledged that MI is principally sustained by coronary thrombosis, and that the clinical picture of MI could be subsequently confirmed at autopsy. With the first description of the electrocardiogram (ECG) in the 1910s and 1920s, the history of modern MI diagnostics really began. Additional important discoveries followed, which are mainly represented by radiography, echocardiography, computed tomography, and magnetic resonance imaging of the heart. Another major breakthrough occurred at the down of the third millennium, with the development of commercial immunoassays for the measurement of cardiac troponin I and T, which represent now the cornerstones for identifying any kind of myocardial injury, thus including MI. The major advancements in the understanding of MI pathophysiology and the progressive introduction of efficient diagnostic tools will be described and discussed in this narrative historical review.

Our species is the only creative species, and it has only one creative instrument, the individual mind and spirit of a man —John Steinbeck (1902–1968), Of Mice and Men In most ancestral cultures, the heart has been considered as a source of heat, and the blood vessels as transporters of the pneuma, that is, the vital spirit animating all living creatures. * Dedicated to Willem Einthoven [1860–1927], a Dutch physician and physiologist who invented the electrocardiogram and received the Nobel Prize in Medicine in 1924. Einthoven was born in Semarang in Java within the Dutch East Indies (now Indonesia), on May 21, 1860, and died in Leiden in the Netherlands, on September 29, 1927.

published online June 26, 2014

Issue Theme A Short History of Thrombosis and Hemostasis: Part I (40th Year Celebratory Issue); Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).

These concepts were theoretically envisioned by the Roman (although of Asian origins) physician Claudius Galenus of Pergamon, in the second century of the Christian era. It is however rather challenging to exactly establish when civilization became first aware of coronary artery disease. Probably, the first description of angina pectoris was formulated around the 1550 BC, when Egyptians reported a realistic description of heart ischemia in the Ebers Papyrus, “if thou examinest a man for illness in his cardia and he has pains in his arms, and in his breast and in one side of his cardia… it is death threatening him.”1 It was not until the Renaissance, when Leonardo da Vinci (1452–1519) investigated coronary arteries and Andreas Vesalius (1514–1564) first described heart anatomy, that the relationships between coronary

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DOI http://dx.doi.org/ 10.1055/s-0034-1383544. ISSN 0094-6176.

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Semin Thromb Hemost 2014;40:535–543.

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vessels and heart disease were first suspected. In the same culturally sparkling period, William Harvey (1578–1657), in the fundamental treatise Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus [An Anatomical Exercise on the Motion of the Heart and Blood in Living Beings] published in 1628, definitively unveiled the circulation of blood and the pivotal role of the heart pump. Harvey, quite poetically, stated “The heart of animals is the foundation of their life, the sovereign of everything within them, the sun of their microcosm, that upon which all growth depends, from which all power proceeds.” Nearly one century later, the German physician Friedrich Hoffmann (1660–1742), professor at the University of Halle, recognized that some heart diseases might be related to “reduced passage of the blood within the coronary arteries.” In the same period, the Italian anatomist Giovanni Battista Morgagni (1682–1771), considered as one of the fathers of human pathology, described atherosclerotic changes in coronary arteries.2 Finally, in 1877 Adam Hammer (1818–1878) made the first ever clinical diagnosis of a coronary occlusion, that was subsequently confirmed at autopsy.3 With the aforementioned milestones of medical research, the history of ischemic heart disease finally began.4 The tale “of MIs and Men” displays a longer history, since atherosclerosis was found to be present in humans several centuries before modern civilization and the identification of the most prevalent risk factors. In 1852, the Austrian–German physiologist, Johann Nepomuk Czermak (1828–1873)—who introduced the laryngoscope into clinical medicine—was the first to describe the presence of atherosclerosis in ancient people, when autopsying the mummy of an elderly Egyptian woman in Vienna.5 Several decades later, Marc Armand Ruffer (1859–1917) confirmed Czermak’s discovery, providing evidence of atherosclerotic lesions during autopsies of multiple Egyptian mummies and mummified limbs.6,7 Recently, in our technological era, Murphy et al demonstrated the presence of bilateral carotid calcific atherosclerosis using computed tomography (CT) scanning in an Italian mummy called “Ötzi,” who probably lived around 3300 BC.8 With the same technology, the Horus study team confirmed the presence, extent, and potential etiologies of atherosclerosis in Egyptian and non-Egyptian ancient peoples, by identification of atherosclerotic lesions in 25% of the 51 examined mummies. Interestingly, the estimated age of death of Egyptians affected by atherosclerosis was 42
10 years compared with 32
15 years of those not affected by the disease, and this is probably attributable to the fact that this latter category of subjects died for other and more frequent causes at that time (i.e., infections and wars).9,10 Returning to the clinics, it is generally acknowledged that the first clinically acceptable description of angina pectoris was made by William Heberden (1710–1801) in 1772.11 Nevertheless, almost a century of additional work was necessary for pathologists to begin focusing on coronary arteries and then describing thrombotic occlusions. It was only in 1889 that the American pathologist Ludwig Hektoen (1863– 1951) acknowledged that myocardial infarction (MI) is caused by coronary thrombosis “secondary to sclerotic changes in the coronaries.”12 A few decades later, in 1910, Seminars in Thrombosis & Hemostasis

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two Russian clinicians and pathologists described the cases of five patients presenting with clinical picture of MI, which was subsequently confirmed at autopsy.13 The great Canadian clinician and pathologist William Osler (1849–1919) worked extensively on angina pectoris, and published extensive material about the correlation existing between clinical and pathological findings of coronary thrombosis.14 With the first use of electrocardiogram (ECG) for diagnosing MI, originally made by the American physician James Bryan Herrick (1861–1954) in the second decade of the past century,15,16 we can unquestionably assert that the history of modern MI diagnostics really began.

The Landscape of Myocardial Infarction At the dawn of the new millennium, in the 2000, the First Global Task Force for MI published a new definition of MI, which implied that “any necrosis in the setting of myocardial ischemia should be labelled as MI.”17 This definition is still valid, and has been refined in two subsequent revisions,18,19 culminating in the third universal definition of MI. 19 Since several hours of ischemia are necessary before myocardial necrosis can be identified by macroscopic or microscopic examination, and the subsequent process leading to scaring and healing usually takes not less than 5 to 6 weeks,20 MI can be recognized at different times by means of instrumental features such as ECG findings, biochemical markers of myocardial necrosis, imaging techniques, or, later, by pathology. 19 As such, the aim of this narrative review is to trace the historical perspective of the main diagnostic tools used for detecting MI, mostly the ECG and biomarkers, due to their clinical usefulness in precocious identification of this disease, so allowing the most timely and appropriate clinical management.

History of the Electrocardiogram in Myocardial Infarction Diagnostics The history of ECG dates back to the late Renaissance, coupling with the history of the discoveries in the physics of electricity and their relationships with animal life. In 1600, William Gilbert (1544–1603), physician to Queen Elizabeth I and founding father of the “magnetic philosophy,” introduced the term “electrica” for objects that hold static electricity. He derived the word from the Greek “amber” (ελεχτρα, electra), as it was known from ancient times that amber, when scrubbed, is able to lift light objects.21 More than one and a half century later, in 1769 and in 1773, Edward Bancroft (1744–1821) and John Walsh (1726–1795) suggested that the “shock” from the torpedo fish and from the electric eel Electrophorus Electricus is electrical rather than mechanical in nature. In the 18th century, a leading thought was “water and electricity do not mix,” so that the idea of an “electric fish” was generally refuted.22,23 In 1786, the Italian anatomist Luigi Galvani (1737–1798) showed that a dissected frog’s leg jerked when touched with a metal scalpel. After studying the effects of electricity on animal tissues for months, he concluded the following:

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I had dissected and prepared a frog in the usual way and while I was attending to something else I laid it on a table on which stood an electrical machine at some distance from its conductor and separated from it by a considerable space. Now when one of the persons present touched accidentally and lightly the inner crural nerves of the frog with the point of a scalpel, all the muscles of the legs seemed to contract again and again as if they were affected by powerful cramps.24 Galvani interpreted these results in terms of “animal electricity,” and—fundamental in our context—also showed that electrical stimulation of a frog’s heart led to cardiac muscular contraction.24 Galvani’s name is currently given to the “galvanometer,” an instrument for measuring and recording electricity, which is an essential part of the ECG machinery. In 1842, the Italian physician Carlo Matteucci (1811–1868), professor at the University of Pisa, showed that each heartbeat is accompanied by electrical activity. He later tried to demonstrate the existence of electrical conduction in nerves, but the results were disappointing, because his galvanometers were not sensitive enough.25 A few years later, the German physiologist Emil DuBois-Reymond (1818–1896) described an “action potential” accompanying each muscular contraction by developing a highly sensitive galvanometer.26 The French physicist Gabriel Jonas Lippmann (1845–1921) invented, in the early 1870s, a capillary electrometer, subsequently used by the British physiologists John Burdon Sanderson and Frederick Page, to record the electrical potential of the heart. In 1878, they were able to demonstrate that each cardiac contraction was accompanied by a two-phase electrical variation, so describing ventricular depolarization and repolarization for the very first time.27 In the same period, the British physician Augustus Desiré Waller (1856–1922) began a series of experiments using the capillary electrometer. He connected electrodes attached to the front and back of a human chest to a capillary electrometer, so showing that each heartbeat was “accompanied by an electrical variation,” and ultimately recording the first human ECG.28 The Dutch physiologist and Nobel Prize winner Willem Einthoven (1860–1927), after attending a lecture by Waller at an international physiology meeting, began to investigate the use of the capillary electrometer to record minimal electrical currents and, in 1895, he was able to detect recognizable waves, which he labeled as “P, Q, R, S, and T.”29 The major innovation of Einthoven was the invention of the string galvanometer, in 1903, which made it possible to exactly record what we currently know as “ECG.”30,31 At that time, the self-adhesive electrodes did not exist, and Einthoven asked his patients to immerse each of their limbs into containers of salt solutions from which the ECG could be recorded. He also introduced the term “electrocardiogram” at a meeting of the Dutch Medical Association, but he later admitted that Waller had been the first to use this term.32 In the following years, he described several pathophysiological ECG features, such as bigeminy, complete heart block, right and left ventricular hypertrophy, atrial fibrillation and flutter, as well as ECG changes related to various heart diseases.31,33

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It is generally less known, but it is now of utmost importance, that in 1905 Einthoven started transmitting ECGs through telephone cables from the hospital to his laboratory, located approximately 1.5 km away,34 which can therefore be regarded as the foundation of the current telemedicine. Shortly afterward, two American physicians made pivotal advances in ECG diagnostics of coronary heart disease. Fred Smith (1888–1946) made pioneering observations on the ECG abnormalities associated with experimental coronary artery ligation in 66 anesthetized dogs,35 and George Bousfield described the ECG during an episode of angina.36 These findings paved the way for Harold Pardee (1886–1973) to describe, in New York in the 1920s, the ECG changes associated with MI in humans. He first characterized the very early rise of ST-segment along with the takeoff of the T-wave from the descending R-wave during the early phase myocardial ischemia.37 This ECG finding was later called the “Pardee’s (or, sometimes, Smith-Pardee’s) sign.” Pardee was working with a three standard limb leads, but the way was paved, so that Wolferth and Wood established the clinical use of precordial leads in the early 1930s,38 followed by Wilson who introduced the unipolar leads.39 In the same period, the possibility to obtain useful information not only from a resting ECG, but also while stressing the heart, was evaluated. In 1931, Charles Wolferth and Francis Wood described the use of exercise to trigger attacks of angina pectoris, also investigating the ECG changes induced by exertion, both in normal subjects and in those with angina. The experiments were stopped, however, because it was thought that “to induce anginal attacks indiscriminately” was harmful.40 Their work was then resumed by Goldhammer and Scherf, who proposed the use of ECG after moderate exercise as a tool for the diagnosis of coronary disease.41 The definitive improvement in ECG recording technique was established in 1942, when Emanuel Goldberger (1913– 1994) increased the voltage of Wilson unipolar leads by 50% and created the augmented limb leads named augmented vector right, left, and feet (i.e., aVR, aVL, and aVF) as they are currently used.42,43 Adding the augmented limb leads to Einthoven three limb leads and to the six chest leads, the ECG recording technique achieved the 12-lead ECG which is still presently used. In 1959, the American cardiologist Myron Prinzmetal (1908–1987) described a variant form of angina, in which the ST segment is elevated rather than depressed, so potentially confounding the diagnosis by mimicking an acute MI.44 The familiarity with ECG abnormalities and their meaning have continuously grown, and it was only in 1976 that Erhardt et al described the use of a right-sided precordial lead in the diagnosis of right ventricular infarction, which had previously been thought to be electrocardiographically silent.45 The ECG has also played an important and growing role in acute MI classification and in decision making for the most appropriate care. In the late 1930s, some skilled clinicians raised the attention on what we presently know as non–ST elevation acute coronary syndrome (NSTE-ACS), including both unstable angina and non–ST elevation MI (NSTEMI). The affected patients complained of severe angina pain, even Seminars in Thrombosis & Hemostasis

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The History of Myocardial Infarction Diagnostics

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at rest, as related to severe, usually multivessel, coronary artery disease. The ECG hence becomes a pivotal tool for classifying MI patients into two major groups, STEMI and NSTEMI.46 The STEMI patients have a critical or complete coronary occlusion, and typically present with a sudden transmural injury of an area that has been previously healthy. These patients also need a timely revascularization. Conversely, NSTEMI patients usually have partially occluded coronary artery/arteries, and the perfused area still receives blood through collateral circulation.47 The ventricle wall injury is thereby not transmural and the risk of necrosis, albeit evident, is usually not impending, so that immediate revascularization is not mandatory. Several ECG abnormalities have been described in the clinical context of NSTEMI, including ST depression with or without final positive T-waves, flat or mild negative T-waves, changes of U-wave, and even normal ECG.19 In 1993, Robert Zalenski, an emergency medicine physician, published an influential article on the clinical use of the 15-lead ECG (i.e., an ECG including routinely the leads V4R, V8, and V9) in the diagnosis of ACSs. After the pivotal advancement consisting in the addition of the six standardized unipolar chest leads in the 1930s, the implementation of these additional leads increases the sensitivity of ECG for diagnosing MI.48 Notably, although the ECG has been successfully used for more than a century for diagnosing MI, the pathophysiological correlations are still not fully understood and further research is needed to completely elucidate the ECG changes that are typically observed in these patients.49 Finally, on the basis of the pioneering work of the Dutch physician Einthoven,34 a team of Danish cardiologists in 2005 reported the successful reduction in the time between onset of chest pain and primary angioplasty (the so-called painto-balloon time) when the ECG of patients could be transmitted wirelessly from ambulance to the cardiologic setting. The immediate classification of the patient (as having STEMI or NSTEMI) allows the attending medical team to make a quick decision to refer patients directly to the catheter laboratory, avoiding time loss in transfers between hospital departments.50

History of Imaging Techniques in Myocardial Infarction Diagnostics The incorporation of imaging techniques, that is, echocardiography, radionuclides, CT, and magnetic resonance imaging (MRI), has represented a major breakthrough for development of in vivo noninvasive study of heart anatomy and function, including noninvasive imaging of the coronary arteries.

History of X-Ray Examination of the Heart The past century has witnessed extraordinary discoveries that have culminated in the current possibility of displaying heart shape and internal anatomy in living subjects. This exciting adventure started in 1895, when Wilhelm Conrad Röntgen (1845–1923), in his article “Über eine neue Art von Strahlen (On a New Kind of Ray),” described the discovery of X-rays. Working with a cathode-ray tube in his laboratory, Seminars in Thrombosis & Hemostasis

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Röntgen observed a fluorescent glow of crystals on a table near his tube. He concluded that a new type of ray, which he later labeled as X-ray, was emitted from the tube. This ray was capable of passing through most materials, including many human tissues, but not bones or metal objects. Röntgen discovered the potential medical application when he made a picture of his wife’s hand on a photographic plate, so obtaining the first image ever recorded of a part of human body by means of X-rays. When the wife looked at the picture, she could not restrain to say “I have seen my death.”51 Röntgen was awarded the Nobel Prize in Physics in 1901. Röntgen’s discovery was embraced with enthusiastic interest by scientists, and Röntgen replicated his experiment almost everywhere he went, thus initiating several new lines of research to pursue the nature and properties of the mysterious rays. It is noteworthy that the first ever use of X-rays were for an industrial, rather than medical application.52 Like photographs, the radiographs were originally printed on glass photographic plates. X-ray film was only later introduced by George Eastman, the founder of Eastman-Kodak Co., in 1918. As a result of the recent “digital revolution,” radiographic images along with photographs are now digitally recorded. However, radiography has only changed little from the pioneering era, as shadow images are still captured on sensible materials, using procedures and processes that are not so dissimilar from those used in the late 1800s. In April 1896, only 5 months after Röntgen’s discovery, Francis Henry Williams (1852–1936), who is now considered the father of medical radiology, used X-rays to investigate a male patient with severe cardiomegaly. Hundreds of patients were also examined in the next few years, so that Williams could effectively compare heart size estimated with X-rays and that determined by percussion.53,54 The visualization of human blood vessels could be obtained in the same year, when Haschek and Lindenthal injected a mixture essentially composed of calcium carbonate into the blood vessels of an amputated hand.55 In 1910, Franck and Alwens introduced a suspension of bismuth and oil into the hearts of dogs and rabbits directly through the large veins, and observed the passage of droplets from the heart into the lungs.56 In 1923, Berberich and Hirsch reported the first arteriograms and venograms obtained in living humans, using a suspension of strontium bromide.57 Another major breakthrough occurred in 1928, when Forssmann inserted a catheter into his own antecubital vein until he felt—or supposed to feel— that it had reached the right atrium. He then walked through the hospital to the radiographic room, where he obtained a radiograph confirming that the catheter tip had reached the right atrium.58 Because of this essential advancement, he was awarded the Nobel Prize in Medicine and Physiology, in 1958. It was only in 1948, however, that Jönsson et al showed that an aortography could opacify the coronary arteries in humans.59 In 1959, Sones and Shirey successfully attempted to inject the contrast medium directly in the aortic sinuses near the coronary ostia, and short afterward used selective injection via brachial artery, reporting that this selective method was effective.60 In 1964, Paulin studied the

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relationships between arteriographic findings and clinical or ECG data.61 The principles of CT scanning were originally invented by the British engineer Godfrey Hounsfield (1919–2004), who was awarded the 1979 Nobel Prize in medicine and physiology, and the first CT scan was announced in 1972.62 As the characteristics of the internal structure of heart and vessels are readily attainable from CT images, and the recently available scanners are capable of obtaining hundreds of “slices” per rotation,63 this technique is now widely used in coronary disease work-up.64

History of Ultrasound Examination of the Heart Echocardiography has revolutionized cardiovascular medicine due to its accuracy and low cost, so that it is now regarded as one of the most important advances in diagnostic cardiology since the discovery of X-rays. The existence of ultrasounds was first recognized by the Italian scientist Lazzaro Spallanzani (1729–1799), who demonstrated that bats can fly even in darkness by means of echo reflection of emitted inaudible sound. Spallanzani can therefore be considered the real “father of ultrasound.” In 1880, Curie and Curie discovered the piezoelectric effect,65 a peculiar phenomenon observed in certain quartz crystals, which constituted the core of the early ultrasound systems and were subsequently replaced by ferroelectric materials. The first experiments using ultrasonic echo reflection for heart examination were initiated by Inge Edler and Carl Helmuth Hertz in Lund, Sweden. In brief, they obtained the first echocardiograms of the heart in 1953 by using an industrial pulse-echo ultrasonic detector borrowed from a shipyard in Malmö, which allowed them to identify several heart structures.66 An Austrian physicist, Christian Doppler (1803–1853), established the mathematical relationship existing between the frequency shift of sound and the relative motion of sound source and observer. This represented the theoretical basis for the subsequent investigation of blood flow velocity using Doppler frequency shifts to measure motion of cardiac structures, along with the velocity of red blood cells thanks to the precious efforts of Satomura and colleagues in 1957.67 Originally, echocardiography was mainly used for the diagnosis of valve and pericardial diseases. The following technical improvements (i.e., evolution from M-mode to two-dimensional and, recently, three-dimensional echocardiography), allowed a broadening of clinical applications, so that this tool has been increasingly used in the diagnostics of ischemic heart disease, especially in combination with a pharmacological or physical stress. Stress echocardiography, along with stress ECG, have now become one of most widespread types of provocative testing, because they display a high diagnostic and prognostic accuracy.68

History of Radionuclide Examination of the Heart Many historians consider the discovery of artificially produced radionuclides by Frédéric Joliot and Irène Curie in 1934 as the most significant milestone in nuclear medicine.69,70 The original idea of medical utilization of radionuclides dates

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back to the mid-1920s, when the Hungarian chemist and Nobel Prize winner, George Charles de Hevesy (1885–1966), performed some experiments with radionuclides administered to rats, unveiling the metabolic pathways of these substances and establishing the tracer principle.71 The origin of modern nuclear medicine should be identified with the work of Ernest Orlando Lawrence (1901–1958). This scientist was awarded the Nobel Prize for physics in 1939 for inventing the cyclotron, the machine that allowed the industrial production of artificial radionuclides. Ernest Lawrence focused his research on bombarding atoms at high speed to produce new particles.72 In 1938, the American scientist Glenn Theodore Seaborg (1912–1999) and the Italian Emilio Segrè (1905–1989), both awarded the Nobel Prize in 1951 and 1959, discovered the isotope technetium 99m, which remains, even today, one of the most commonly used radioisotopes.73 During the first annual meeting of the Society of Nuclear Medicine in 1954, Rex Huff presented a lecture on “Estimates of Cardiac Output by In Vivo Counting of 1-131 Labeled HAS,” thus virtually initiating cardiac nuclear medicine imaging.73 By the 1970s, most organs of the body could be visualized using nuclear medicine procedures and radiopharmaceuticals were specifically designed for use in diagnosis of heart disease in the 1980s. Heart scans are now used to examine both the blood flow to the heart muscle and the mechanical function of this organ. Perfusion studies are very accurate in detecting defects of the coronary arteries flow. The radioisotope, given intravenously to the patient, accumulates in the heart in proportion to the oxygenated blood and nutrients being delivered to the organ, so that a reliable comparison can be made about the degree of uptake in various parts of the heart tissue. The scans can be performed both at rest or after stress (i.e., by exercising on a treadmill).73 Nuclear medicine differs from other imaging modalities in that it primarily shows the physiological function of the system being investigated, as opposed to traditional anatomical imaging such as CT or MRI.

History of Magnetic Resonance Imaging Examination of the Heart MRI is a sophisticated imaging technique that has been adopted as a clinical diagnostic tool during the past 30 years. This field of research was so exciting that five researchers were awarded Nobel Prizes for various discoveries related to this technique. Nevertheless, the origins of MRI, or nuclear magnetic resonance (NMR) as it was formerly termed, can be traced back to more than a century ago. At the beginning of the 19th century Jean Baptiste Joseph Fourier (1768–1830), a French mathematician, developed a mathematical equation for analysis of heat (i.e., energy) transfer between solid bodies.74 His equation was first used for magnetic resonance signal analysis and image reconstruction by Richard Ernst in 1975, as reported in the following part of the article, and is still used in all modern MRI scanners.75 At the dawn of the past century, Nikola Tesla (1856–1943), a Serbian-born, US-immigrated, inventor and researcher, discovered the rotating magnetic field, which is Seminars in Thrombosis & Hemostasis

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the basis of most alternating current machinery, as well as of the modern MRI scanners.76 His discovery has been considered so important that the measure unit of a magnetic field is now named Tesla in his honor, where 1 T ¼ 1 N/A·m. In the same period, Sir Joseph Larmor (1857–1942), an Irish physicist, was the first to calculate the rate at which energy is radiated by an accelerated electron. He is essentially famed for the equation that carries his name (i.e., the Larmor equation), and that is still widely used in MRI because it describes the frequency at which the nucleus absorbs energy.77 In the 1930s, Isidor Rabi (1898–1988), an Austrian scientist, identified and measured the single states of rotation of atoms and molecules, thus calculating the magnetic moments of the nuclei.78 The term “nuclear magnetic resonance” is now attributed to his work. In 1946, two American scientists in the United States, Felix Bloch and Edward Purcell, independently found that certain nuclei absorbed energy in the electromagnetic spectrum when placed in a magnetic field, and reemitted this energy upon returning to their original state, according to the Larmor equation.79,80 For their discovery, they were jointly awarded the Nobel Prize in physics in 1952. It was only in 1974 that Paul C. Lauterbur in the United States, and Peter Mansfield, in England, independently described the use of magnetic field gradients for spatial localization of NMR signals, thus establishing the basis of MRI.81,82 For their pivotal contributions, Lauterbur and Mansfield were jointly awarded the 2003 Nobel Prize in physiology and medicine. In 1975, the Nobel Prize winner Richard Ernst described the use of Fourier equation to reconstruct two-dimensional images, thus providing a practical method to rapidly reconstruct an image from NMR signals. This advancement represents the basis of current MRI examination.83 It is still uncertain when cardiac MRI was first performed, but in 1981 Hawkes et al published a study specifically directed at NMR imaging of the heart.84 In their article, the authors emphasized the advantages of MRI in terms of avoiding the risks of ionizing radiation, and also recognized the limitations of cardiac and respiratory movements. Two years later, in 1983, Paul Lauterbur’s group first reported ECGgated cardiac MRI in an experiment study in dogs.85 With this major advancement, we leave the historical territories, and land in the present field of current clinical application.

equivocal pathological Q waves and/or ST segment elevation or depression in serial recordings; (2) history of typical or atypical angina pectoris, along with equivocal changes on the ECG and elevated enzymes; (3) history of typical angina pectoris and elevated enzymes with no changes on the ECG or not available; (4) fatal cases, whether sudden or not, with naked eye appearances of fresh MI and/or recent coronary occlusion at necropsy (antemortem thrombus, hemorrhage into an atheromatous plaque or embolism).87 Rather understandably, the role of cardiac biomarkers was rather limited at that time, and this could be attributed to the fact that the available tests (i.e., aspartate aminotransferase [AST] or lactate dehydrogenase [LDH] or creatine kinase [CK]) were poorly cardiospecific and, especially, were characterized by a kinetics of post-MI release that was mostly unsuitable for early diagnosis (►Fig. 1).88 A major breakthrough only occurred with the introduction of methods for measurement of the isoenzyme MB of CK (i.e., CK-MB). The first report about the potential usefulness of this test was published by Wagner et al in 1973,89 but the use of this biomarker become widespread only a decade later, favored by transition from measurement of enzyme activity to ligand-binding assays.90 It is undeniable that the diagnosis of MI underwent a paradigm shift with the routine introduction of CK-MB, as this biomarker is characterized by a much greater myocardial specificity than AST, LDH, and CK, is released after myocardial necrosis after 3 to 6 hours, reaches a peak of concentration in only 12 to 24 hours (►Fig. 1), and returns to baseline values much earlier than the conventional enzymes, thus allowing early discharge from the cardiac critical care unit. The scenario remained virtually unchanged for a rather long time, until the development of commercial methods for the measurement of myoglobin, in the 1990s.91 The kinetics of this novel biomarker, which is poorly cardiospecific, was however particularly suitable for combination with CK-MB, as the very early release after cardiac injury (►Fig. 1) allowed early rule out of MI in the presence of nondiagnostic test results. At the dawn of the third millennium, a revolution occurred in the diagnostic approach to MI, when the assessment of the

Biomarkers of Myocardial Infarction As for any other diagnostic area, the use of biomarkers represent a cornerstone for diagnosis and even for prognostication of patients with ischemic heart disease.86 The World Health Organization has historically played a major role in the formulation of diagnostic criteria for MI since the early 1970s. The first document published in 1976, conventionally known as “European Myocardial Infarction registry criteria,” established that the diagnosis of MI could be made on the basis of clinical history, ECG findings, cardiac enzymes, and postmortem findings. In particular, the diagnosis of MI could be established in the presence of one of the following: (1) ECG showing unSeminars in Thrombosis & Hemostasis

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Fig. 1 Kinetics of cardiac biomarkers in the diagnostics of myocardial infarction. AST, aspartate aminotransferase; CK, creatine kinase; LDH, lactate dehydrogenase.

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The History of Myocardial Infarction Diagnostics

Conclusions The history of MI diagnostics has gone through a continuous evolution in the past century, when several new discoveries have contributed to notably increase the number of appropriately diagnosed patients. It is now undeniable that no single “magic bullet” exists for definitely diagnosing an MI, but the clinical reasoning should be guided by a combination of information emerging from the history and the clinics, along with results of a limited array of diagnostics tests, mainly represented by the ECG and the assessment of cardiospecific troponins. In the recent years, the introduction of high-sensitive troponin immunoassays has also contributed to revolutionize our understanding of the pathophysiological continuous that characterize an MI, starting from myocardial ischemia and culminating with myocardiocyte necrosis. The current possibility to detect minimal amount of troponin released from the injured myocardium has been in fact associated with a remarkable increase of diagnosis of “true” MI, wherein a large number of previously classified “unstable anginas” are now effectively recognized as NSTEMI. Several lines of evidence attest that the implementation of highsensitivity troponin testing in chest pain evaluation protocols in emergency department would increase the diagnosis of MI by approximately 50%.96 Although it is always challenging to predict what the future will hold in science and medicine, it seems reasonable

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to believe that no major breakthroughs will occur in the diagnostic approach of MI in the immediate future. Some recent studies have shown that the assessment of cardiac microRNAs holds premise, especially in combination with cardiospecific troponins, but the current technical and analytical limitations still largely overcome the potential clinical benefits of this approach.97

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arteries of the heart. Wien Med Wohnsch 1878;28:102 (English translation in: Major RH, eds. Classic Descriptions of Disease. Springfield, IL: Charles C. Thomas, 1965;426–428) Fye W. A historical perspective on atherosclerosis and coronary artery disease. In: Fuster V, Topol EJ, Nabel EG, eds. Atherothrombosis and Coronary Artery Disease. Philadelphia, PA: Lippincott Williams and Wilkins; 2005:1–14 Czermak J. Description and microscopic findings of two Egyptian mummies. Meeting of the Academy of Science 1852;9:27 Ruffer MA. On arterial lesions found in Egyptian mummies (1580 BC–535 AD). J Pathol Bacteriol 1911;16:453–462 Ruffer MA. Preliminary note on the histology of Egyptian mummies. BMJ 1909;1(2521):1005 Murphy WA Jr, Nedden Dz Dz, Gostner P, Knapp R, Recheis W, Seidler H. The iceman: discovery and imaging. Radiology 2003; 226(3):614–629 Allam AH, Thompson RC, Wann LS, Miyamoto MI, Thomas GS. Computed tomographic assessment of atherosclerosis in ancient Egyptian mummies. JAMA 2009;302(19):2091–2094 Thompson RC, Allam AH, Lombardi GP, et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013;381(9873):1211–1222 Heberden W. Some account of a disorder of the breast. Medical Transactions 1772;2:59–67 Hektoen L. Embolism of the left coronary artery; sudden death. Med Newsl (Lond) 1892;61:210 Obrastzov WP, Straschesko ND. Zur Kenntnis der Thrombose der Koronararterien des Herzens. Z Klin Med 1910;71: 116–132 Wearn J. Thrombosis of the coronary arteries with infarction of the heart. Am J Med Sci 1923;165(2):250–275 Herrick JB. Certain clinical features of sudden obstruction of the coronary arteries. JAMA 1912;59:2015–2020 Herrick JB. Thrombosis of the coronary arteries. JAMA 1919; 72:387–390 Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36(3):959–969 Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28(20): 2525–2538 Thygesen K, Alpert JS, Jaffe AS, et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation 2012;126(16):2020–2035 Jennings RB, Ganote CE. Structural changes in myocardium during acute ischemia. Circ Res 1974;35(Suppl 3):156–172 Seminars in Thrombosis & Hemostasis

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highly cardiospecific troponin I and T was introduced into clinical practice. The consensus document published by the European Society of Cardiology/American College of Cardiology Committee for the redefinition of MI17 first introduced the concept that MI can be diagnosed in presence of a typical rise (or gradual fall) of cardiospecific troponin I or T, without the need to perform additional laboratory investigations. This criterion was then reiterated in two additional documents, published in 200718 and 2012.19 The measurement of cardiospecific troponins introduced several clinical and technical advantages over any previous biomarker, which are basically represented by the virtually absolute specificity for cardiac injury, the early release after the onset of myocardial ischemia (i.e., 2–4 hours), the remarkable increase of concentration over the upper limit of the reference range (►Fig. 1), along with their availability as urgent tests for a vast array of laboratory and point of care instrumentation.92 The development of a new generation of cardiac troponin immunoassays, conventionally defined as “highly sensitive,” has subsequently represented a further analytical refinement of this biomarker, as these novel methods allow to identify minor increases of troponin concentration at an earlier time after the onset of symptoms and, especially, to reduce the time of serial sampling for identifying the suggestive increase that typically occurs after an MI.93 According to recent guidelines, the measurement of cardiospecific troponin I or T represent the current gold standard for the diagnosis of MI,94 and their measurement also provide prognostic information that may be useful for the clinical decision making.95

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The History of Myocardial Infarction Diagnostics

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