Role of Cardiovascular Pathology in Clinical Decision Making.doc
The Role of Cardiovascular Pathology in the Clinical
Department of Pathology, University of Padua Medical School, Padua, Italy
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
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
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
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
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
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,
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
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
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
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
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
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
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
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
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
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.
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
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
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).