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The Role of Cardiovascular Pathology in the Clinical

                                 Decision Making

                  ...
techniques is compulsory to establish an infective aetiology and to set up a

causative based therapy.

      Nonetheless,...
medical knowledge. In vivo diagnosis was mostly invasive, by angiography

investigation, with a poor knowledge of anatomy ...
cardiovascular electro-mechanical physiopathology of the heart was mandatory

before my definitive professional choice of ...
neonates, a sound knowledge of the anatomy of complex congenital heart diseases

appeared a prerequisite for optimising cl...
decreased drastically with time. Any tissue resected at cardiac surgery started

undergoing routine histological analysis,...
be the main cause of failure by cusp stiffening or disruption. This awareness

stressed the need to find a solution for pr...
of   new   morbid   entities   like   non-compacted   myocardium   and   restrictive

cardiomyopathy, so as to require a W...
connect the atrial with ventricular myocardium, allowing the electrical impulse to

by-pass the specialized AV junction th...
morphological investigation at subcellular level. However, there are offending

organisms or structural defects that escap...
terms of clinical decision making, the finding of a viral etiology entails strategic

therapeutic implications, since anti...
CARDIOVASCULAR PATHOLOGY IN THE FUTURE :   still a need for ?

      Death is an unavoidable outcome of human life and the...
concerted action with the cardiologist, cardiac surgeon, and the genetist and

molecular biologist with the ultimate goal ...
in the diagnostic fields are being educated and trained in a period not only of

declining incidence of autopsy, but, wors...
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Role of Cardiovascular Pathology in Clinical Decision Making.doc

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Role of Cardiovascular Pathology in Clinical Decision Making.doc

  1. 1. The Role of Cardiovascular Pathology in the Clinical Decision Making Gaetano Thiene Department of Pathology, University of Padua Medical School, Padua, Italy SUMMARY The advent of cardiac surgery and interventional cardiology has dropped the pathologist in the clinical arena. Once confined to the job of post-mortem investigation of patients dying of cardiovascular diseases, nowadays the pathologist shares routine responsibilities in clinical decision making, by enlarging his or her traditional armamentarium to include immunohistochemistry, electron microscopy and molecular biology. The contribution of surgical pathology, namely the histological examination of any tissue sample resected at time of cardiovascular surgery (pericardium, vessels, myocardium, valves, masses), may be crucial in surgical decision making. This, for instance, is the case for cardiac tumours since accurate histological examination is required for differential diagnosis with malignancies. The major step forward in this setting has been made by cardiac transplantation, where the monitoring of cardiac rejection through endomyocardial biopsy plays a key-role in modulating immunosuppressive therapy. Cardiac biopsy is nowadays a routine diagnostic tool in the evaluation of cardiomyopathies, whether primary or specific, and the use of molecular biology 1
  2. 2. techniques is compulsory to establish an infective aetiology and to set up a causative based therapy. Nonetheless, autopsy still plays a central role. The information coming from a detailed, skilful post-mortem is of vital importance for clinical management of future patients and the clinico-pathological conference represents an irreplaceable rendez vous with clinicians and surgeons. A precise diagnosis is essential in cases of sudden death due to hereditary-familiar cardiovascular disorders, where the autopsy may represent the first opportunity not only to establish the cause of death, but also to guide the clinicians to family investigation, including molecular genetics. INTRODUCTION When in the late 60’s I was still a student and started following the call for cardiovascular pathology, the job was mostly restricted to autopsy. This discipline was the Cinderella within the large family of Anatomic Pathology and the reason was it dealt only with cadavers. My mentor in cardiovascular pathology was a skilled, encyclopedic anatomist, confined to post-mortem investigation of patients dying of cardiovascular disease. He was superb to finely dissect and interpret quite complex congenital heart diseases and was the keeper of the cardiac anatomical collection. Cardiac surgery was at dawn for congenital, valve and coronary diseases with a prohibitive operative mortality. The pathologist was asked to perform post-mortems on surgical fatalities bearing witness of limitations in 2
  3. 3. medical knowledge. In vivo diagnosis was mostly invasive, by angiography investigation, with a poor knowledge of anatomy and pathology by the operators. Cardiopulmonary bypass and cardiac arrest allowed the surgeons to open the heart and correct the defects, being still unaware of elementary morphological notions like the topography of the conduction system. Most of the first septal defects operated at Mayo Clinic with the use of cardiopulmonary by-pass machine weaned out from operation with AV block. There was clearly a great demand and need for anatomy and pathology learning. “Operable” cardiac diseases consisted of gross structural defects and clearly the mission of the pathologist was to support the clinicians and surgeons by transfer the information of post-mortem anatomy into clinical and surgical anatomy knowledge to improve the diagnosis and treatment for the benefits of the patient. The anatomical theatre was still the place “mors ubi gaudet succurrere vitae”. It became soon evident that the cardiologist, the surgeon and the pathologist should possess a similar cultural background despite different professional duties. The haemodynamic lab, the surgical theatre and the autopsy room were places to apply the same teaching and language for fruitful clinicopathologic correlations. The visit I did in 1974 to the Mayo Clinic was inspiring in this perspective. I saw the pathologist with surgeons and cardiologists during clinicopathologic conferences and presentations of clinicopathologic studies, with mutual knowledge of their professional skill so as to make difficult at first sight the identification “who is who”. I realized that clinical training to learn the elementary notions of 3
  4. 4. cardiovascular electro-mechanical physiopathology of the heart was mandatory before my definitive professional choice of pathology. I became first a cardiologist. The call for pathology was reinforced during the clinical training by episodes of which I was witness to patients dying in my arms because of late diagnosis and/or delayed surgical decision making, due to existing restraints in basic knowledge, effective diagnostic tools and surgical facilities. Thus, I started the venture of cardiovascular pathology, eager to implement a service complementary to clinical demands. Lucky enough, I soon received an assistant position in the Faculty of Medicine where circulation was discovered by William Harvey and where the method of clinicopathologic correlations was first introduced in the history of Medicine by Giovanni Battista Morgagni, my predecessor in Pathology, who wrote his book The seats and causes of diseases investigated by Anatomy, thus establishing pathological anatomy as a science and changing the course of medical diagnosis. In this review I would like to draw your attention to the changing role of cardiovascular pathology in the last 30 years, which obviously reflects the development of cardiac surgery and interventional cardiology on one side and of the genetics and molecular biology on the other. CARDIOVASCULAR PATHOLOGY IN THE ‘70 S : the development of surgical therapy and the onset of surgical pathology Following the improvements of anaesthesiology and myocardial-cerebral protection during cardiac arrest, which rendered the operations feasible in 4
  5. 5. neonates, a sound knowledge of the anatomy of complex congenital heart diseases appeared a prerequisite for optimising clinical diagnosis and improving surgical repair. Implementation of a cardiac registry of congenital heart disease specimens, gathered since the origin of paediatric cardiology, allowed the study of the whole anatomical spectrum of various defects. The anatomical collection represented the meeting point of paediatric cardiologists and cardiac surgeons with the pathologist for the quality control of both clinical diagnosis and surgical treatment, as well as for ideating new technical solutions for repair. The segmental approach (atria, ventricles and great arteries) was introduced as the best way to clear up the difficulty of diagnosing complex congenital heart diseases with the aim to reconstruct by surgery separate pulmonary and systemic circulations in a correct segmental manner. The delineation of the precise course of the conduction system through histological serial sections virtually cancelled the risk of AV block during closure of septal defects by guiding the hand of the surgeon in suturing the patch. The early occurrence of pulmonary vascular disease was found to jeopardize the surgical repair of congenital heart disease with septal defects, suggesting the need to anticipate the decision making for operation within the first year of life. This was supported by histological study of lung biopsies taken in vivo at the time of total repair, which demonstrated that advanced pulmonary vascular disease entailed a high risk of fatal outcome following septal closure. It is quite rewarding to realize that thanks to improvement of diagnostic and surgical expertise, with the help of the pathologist, mortality for repair of congenital heart disease, including quite complex forms like univentricular hearts, 5
  6. 6. decreased drastically with time. Any tissue resected at cardiac surgery started undergoing routine histological analysis, thus opening the era of cardiovascular surgical pathology. Valves, vessels, vein or arterial grafts, tumors, pericardium were submitted systematically to a precise microscopic diagnosis, an essential step for establishing the nosography and epidemiology of “operable” cardiovascular disease. Bicuspid aortic valve was found to be not only a substrate of early dystrophic calcification and stenosis, but also a major risk factor for endocarditis, aortic incompetence and spontaneous dissection. Histology of cardiac masses allowed one to distinguish thrombotic from neoplastic tissues. Endocavitary atrial tumors were found to be not only benign myxoma, but even malignancies and the application of immunohistochemistry resulted to be crucial for establishing the histological type. The increasing use of valve prostheses, with an intrinsic propensity to structural failure, required a novel skill. Since the beginning, the cardiovascular surgery at the University of Padua made the choice for biological valves, namely glutaraldehyde fixed porcine xenografts. Differing from mechanical valves, they do not require anti-coagulation and are not noisy, allowing compliance from the patients. The evaluation, made by the pathologists, allowed us to discard prosthetic valves with early failure due to technical deficiencies in design, pointing to the use of more durable devices. Bioprosthetic valves disclosed a limited durability with a half life of only 8-10 years. We cumulated a huge experience with a surgical pathology study of more than 400 Hancock standard porcine valves from patients who were re-operated once or twice for dysfunction. Calcification was proven to 6
  7. 7. be the main cause of failure by cusp stiffening or disruption. This awareness stressed the need to find a solution for preventing or retarding mineralization and for enhancing long term durability. In vivo animal and in vitro experiments were carried out to test anti-calcific agents with the aim to introduce new devices in the clinical practice, with an increase of half-life by 5-7 years. CARDIOVASCULAR PATHOLOGY IN THE ‘80 S and the advent of interventional cardiology, endomyocardial biopsy and cardiac transplantation; the start of clearing up the sudden death mystery In the past it was a common place to say that “the pathologist at autopsy knows everything, but too late”. This limitation changed abruptly in the cardiovascular field with the introduction of endomyocardial biopsy. It was then possible to achieve an in vivo diagnosis of heart muscle disease, thus providing vital information for the clinical decision making. Endomyocardial biopsy is nowadays the diagnostic gold standard for myocarditis, giving to the pathologist the ultimate word. The pivotal role of the cardiovascular pathologist was further enhanced by the beginning of cardiac transplantation program, which requires the use of endomyocardial biopsy for rejection monitoring. 15-20 endomyocardial biopsies in each patient are performed during the first year following transplant. Nearly 40 % of biopsy reports of a Cardiovascular Pathology Service deal with cardiac transplantation. Moreover, the study of heart specimens, resected at the time of transplantation, gave an extraordinary opportunity of research with the discovery 7
  8. 8. of new morbid entities like non-compacted myocardium and restrictive cardiomyopathy, so as to require a WHO re-classification of cardiomyopathies. In particular, restrictive cardiomyopathy featured the paradox of a small heart requiring transplantation because of terminal congestive heart failure in the absence of cardiomegaly, due to elective impairment of the diastolic function. Interventional cardiology with atherectomy, a procedure aimed at relieving obstructed arterial segments, provided intimal coronary artery tissue which enabled one to establish the in vivo substrate and to study the pathogenesis of coronary syndromes. On the autopsy side, a new demand for cardiovascular pathology came from the amazing occurrence of sudden death, even in young people or in athletes collapsing on the play-ground. The absence of coronary artery disease and myocardial infarction in most of the cases appeared intriguing for the pathologist, who was used to considering pump failure as the obvious mode of cardiac death and the left ventricle as the culprit cardiac segment. The physiopathology training, as well as the tight collaboration with clinicians, was of great help for interpretation of the event as an electrical breakdown. The concept that the heart may stop suddenly due to ventricular fibrillation, in an absence of an ischemic milieu, was a revolutionary step forward for the pathologist’s mind. Since the conduction system is the power plant of the heart, we first pointed to this specialized tissue in the search of abnormalities able to explain cardiac arrest due to either tachyarrhythmias or block. This was the case of Wolff-Parkinson-White syndrome where a tiny fascicle of ordinary myocardium (Kent’s fascicle) may 8
  9. 9. connect the atrial with ventricular myocardium, allowing the electrical impulse to by-pass the specialized AV junction thus accounting for ventricular pre-excitation. The precise location of the Kent fascicle close to the endocardium was vital histological information for interventional ablation which is nowadays easily accomplished. However, we soon realized that the working ventricular myocardium itself may be the source of life-threatening arrhythmias, despite the integrity of the conduction system and the coronary arteries. Arrhythmogenic right ventricular cardiomyopathy, which was discovered at autopsy as the major cause of sudden death in young athletes, represented an alarming instance in so far as fibro-fatty replacement of the right ventricular free wall may trigger lethal tachyarrhythmias during effort through re-entrant mechanisms, even in the setting of normal left ventricle and conduction system. By establishing a close collaboration with the Pathology Services of the Veneto Region, as well as with forensic pathologists, we set up a network that was able to collect all the cases of sudden death in the young, a unique opportunity to study the phenomenon on a large scale and to discover a wide spectrum of diseases as a cause of life-threatening cardiac electrical instability. CARDIOVASCULAR PATHOLOGY IN THE ‘90 S : from gross to molecular pathology The traditional tools of the pathologist are the naked eye at the autopsy table for dissection and the light microscope for histological examination. Magnification power increased a lot with electron microscopy allowing 9
  10. 10. morphological investigation at subcellular level. However, there are offending organisms or structural defects that escape even the ultrastructural imaging, emphasizing the limits of traditional morphology. The discovery of new tools like in situ hybridisation and polymerase chain reaction (PCR), linkage analysis and gene sequencing opened extraordinary avenues for getting deep insight into cell and nuclear pathophysiology, as well as genes and coded proteins. The collaboration with clinicians was extended to basic scientists and this policy has been rewarding in so far as in 15 years it was possible to pass from the first post-mortem observation of familiar arrhythmogenic right ventricular cardiomyopathy to the discovery of the culprit gene. Apoptosis was found to be a mode of cell death and to occur in heart failure and cardiomyopathies. By applying TUNEL, an in situ hybridisation technique, on endomyocardial biopsy of patients with arrhythmogenic right ventricular cardiomyopathy, myocyte apoptosis was observed in a high rate so as to probably account for progressive fibro-fatty replacement. The use of PCR or reverse transcriptase (RT) PCR, able to amplify DNA or RNA by 100,000 fold, was a powerful weapon in detecting viral particles, which were detected in nearly 50 % of endomyocardial biopsies from patients with myocarditis. DNA viruses, like adenovirus, were found to be cardiotropic infective agents like RNA enterovirus, accounting for various clinical presentations of myocarditis, from cardiogenic shock to sudden death. PCR is now an essential weapon in endomyocardial biopsy evaluation to achieve a gold standard for diagnosis. In 10
  11. 11. terms of clinical decision making, the finding of a viral etiology entails strategic therapeutic implications, since antiviral and not immunosuppression therapy should be accomplished in PCR positive cases. 6-10 % of young people dying suddenly present with a normal heart ( mors sine materia). Molecular genetics demonstrated that many of these cases are ascribable to genes encoding defective proteins and/or receptors of cell/sarcoplasmic membranes, where sodium-potassium channels, Ca++ uptake- release or cell junctions are located. Clearly these defects are beyond the microscopic resolution power. For the pathologist was frustrating and difficult to accept that hearts from patients who died suddenly had a normal heart even after extensive morphological examination including the conduction system. Some of them were proven by molecular genetics to be affected by lone pinpoint mutations of the gene encoding the Ryanodine II receptor, responsible for Ca++ release from the smooth sarcoplasmic reticulum for excitation-contraction coupling. A single mutation of one base accounts for an altered coded protein with only one different amino acid, enough to impair the receptor function and Ca++ release, jeopardizing the electrical stability during effort. One may wonder whether this infinitesimal change of a gene sequence is enough to deserve the name of congenital heart disease - namely a structural defect present at birth. Most probably so. With the advent of molecular genetics, the meaning of congenital disease is changing from phenotype to genotype. 11
  12. 12. CARDIOVASCULAR PATHOLOGY IN THE FUTURE : still a need for ? Death is an unavoidable outcome of human life and there will be always a need for autopsy, whether clinical or forensic. Since cardiovascular diseases account for nearly half of the causes of death, an increasing demand for pathologists with specific expertise in cardiac anatomy and pathology is expected. Autopsy is basically our job and morphological skills will be a prerequisite in professional training, despite the declining rate of post-mortem for in-hospital deaths. The anatomical theatre will continue to be the main lab of cardiovascular pathology. However, it is becoming more and more evident that the ability in interpreting the morphologic alterations, featuring the natural history of the human body, is based on a solid clinical background. The information coming from a thorough autopsy examination is of vital importance for clinical management of future patients. A precise autopsy diagnosis is essential in cases of sudden death due to hereditary/familial disorders, where the autopsy may represent the first opportunity not only to establish the cause of death but also to guide clinicians to family investigation, including molecular genetics. It may be that, as I did, the cardiovascular pathologist in the future should start training in a clinical milieu to become confident with presentation, diagnosis and treatment of the diseases and then move to Pathology for the final occupation. Anyway, he or she will never be alone and powerless, as it was in the past, witnessing the defeat of Medicine in the silence of the mortuary. The interdisciplinary approach to diagnosis and therapy and prevention of cardiovascular diseases, will see the cardiovascular pathologist working in a 12
  13. 13. concerted action with the cardiologist, cardiac surgeon, and the genetist and molecular biologist with the ultimate goal to achieve improvement in the quality of life of human kind. Nowadays, a large spectrum of diagnostic weapons are at the disposal of the pathologist, some of them avoiding the traditional microscope. They render update and more useful our job and the figure of cardiovascular pathologist should stand and appear intellectually appealing to the young generation of doctors as a protagonist in the fight against heart diseases. Their strategic position between the bed and the bench endows him or her with the potential of remaining crucial in the study of cardiovascular disease. Historically, human pathology has paid more attention to morphological substrates and pathogenesis than to etiology of diseases. We know which morbid entities affect heart and vessels and we know signs and symptoms of the disease as well as their natural history. We know which medical or surgical therapy, even extreme like transplantation, may best applied. It is time for cardiovascular pathology to make a step forward. The extraordinary technology breakthroughs in molecular biology provide exciting opportunities for investigating the causes besides the substrates of the diseases. However, returning to autopsy and its irreplaceble value, let me finish quoting Jesse Edwards, “The father of Modern Cardiovascular Pathology”: “At this point in the history of medicine, the leaders in the field of diagnostic aids have come from a class of people familiar with the autopsy, and development of these tests and many others have been supported by anatomic observations made by pathologists and clinicians working together at the autopsy. Now, persons 13
  14. 14. in the diagnostic fields are being educated and trained in a period not only of declining incidence of autopsy, but, worse than that, absence of the clinician from the few autopsies that are being performed... ...Unless that trend reverses itself, it is my prediction that the day will come when current and future teachers will miss the fundamental instruction on which the practice of medicine has been built. To overcome the deficiency, there will need to be a return to the autopsy with a promise for future developments in the field of diagnostic testing” (Mayo Clin Proc 1999;74:739). 14

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