The Science of Healing: Optimality and New Understanding of Myocardial Infarction
People who don’t run after the herd
are rare everywhere
Introduction
It's time to gather stones. If I don't collect them, no one will do it for me. A professor from Warsaw once wrote to me, asking me to create a book based on my philosophy, my approaches to disease, and my understanding of it. That was about five years ago. I made that book and sent a copy in electronic format to his address.
Over time, his request has turned into a personal demand for myself to review what I have accomplished in medicine and to summarize my contributions.
This opportunity has arisen, as evidenced by this book. It is interesting in many respects. The discoveries I made with my students regarding myocardial infarction have only begun to be recognized by the contemporary medical world in recent years. If we consider the mid-1970s as the starting point of our research and now at the end of the first quarter of this century, it’s evident that the time gap is approaching half a century. Even today, the medical world still needs time to reach the level of understanding of the phenomenon that I described back then.
This topic is extremely important not only for myocardial infarction. By the way, I do not use the term "acute myocardial infarction" because it is always acute and cannot be chronic, and the term "subacute" does not apply to it. Everything discussed in this book about myocardial infarction, which I will write more about, applies to any other acute inflammation. It is natural for those who deal with such phenomena in their activities to utilize these ideas.
Moreover, this topic allowed me to understand and then formulate the Principle of Disease Optimality, as a component of the Principle of Optimality in Nature in general. This is a very useful concept, mastery of which allows viewing our specialty from new horizons, without which, I am convinced, breakthrough solutions will remain just a good wish.
The research in this direction has cost me too much not to share the special moments associated with it. These came at the height of the totalitarian communist regime in the USSR, where I spent a good half of my life, which I did not accept, and whose impact I felt keenly on my own skin, even though externally everything seemed more than successful. Those who find the strength to reach the end of the book, or, without waiting, go directly to its last pages, will learn about these moments.
I am gathering stones. I collect as I know how. I will be only grateful for any remarks and suggestions.
Chapter 1
How It All Began
The subject discussed in this book, as with all things, was built upon foundational prerequisites. I could never have attained this level of understanding regarding myocardial infarction without these underlying factors. I am profoundly grateful for these prerequisites, as they not only unveiled a previously obscure world of myocardial infarction to me but also expanded my perspective to encompass the broader spectrum of clinical medicine and its philosophical implications.
The first attempt to assemble the mosaic was a fiasco
In our experimental studies of myocardial infarction on dogs and rats, the observations were highly informative. Each healing stage revealed distinct changes not only within the infarct zone but also in the surrounding tissues. Initially, we observed ischemic changes, but rather than a static necrosis zone, the area was dynamically influenced by leukocytes predominantly originating from blood. These leukocytes rapidly altered their composition and ratios within days, highlighting their critical role in the evolving pathology of the infarct zone. This dynamic interplay underscored that the progression from ischemia through to the remodeling of organ-specific structures and the development of connective tissue was intricately linked to leukocyte activity.
However, a challenge presented itself. Regardless of the size of the infarct induced in animals, the result was consistently a well-formed scar. In contrast, human patients exhibited variations such as aneurysms and heart ruptures under similar conditions, which were not adequately explained by existing literature. This discrepancy led me to delve deeper into the pathological mechanisms at play.
Analyzing human pathological samples, I encountered a chaotic and inconsistent pattern of changes across different cases. The orderly progression observed in animal models was absent in human samples, where the morphological states of the infarct and surrounding zones could appear similar across different stages of healing. This variability suggested a significant divergence in the pathological process in living subjects compared to post-mortem findings and emphasized the need to rethink the prevailing understanding of myocardial infarction.
The realization dawned on me that the course of myocardial infarction in living individuals likely differed markedly from the post-mortem condition, akin to what was observed in animal models. It became clear that leukocytes played a pivotal role in the resolution of the infarction, influencing whether the outcome would be resolution or complication.
This insight set the stage for a deeper investigation into the relationship between blood leukocyte responses and the clinical outcomes of myocardial infarction. Observing the variable infiltration of leukocytes in deceased patients underscored the potential impact of individual patient conditions on the infarction's resolution.
This critical phase of my research underscored the necessity to explore how leukocyte dynamics in living patients affected the trajectory of myocardial infarction, leveraging my position at the therapeutic department of the Donetsk Medical Institute. This setting provided direct access to a wealth of clinical data and patient histories, enabling a comprehensive study of the interplay between leukocyte behavior and myocardial infarction outcomes.
Leukocyte Reactions in Blood in the First Hours Determine Myocardial Infarction Outcomes
The hypothesis that leukocyte reactions in blood in the first hours determine myocardial infarction outcomes was confirmed. In this work involving archived medical histories, my former student, now one of the top doctors in Israel, Boris Tsarbaev, played an active role. Notably, this was the topic of his doctoral thesis.
The task initially appeared quite routine. It involved creating and then processing a database of all patients treated for myocardial infarction, with data on leukocyte levels and subpopulations of leukocytes (granulocytes, agranulocytes), and the outcomes of myocardial infarction—favorable without complications with post-infarction scarring and heart aneurysm, fatal without and with heart rupture, also considering the timing of death from the onset of the illness.
The database was created and the analysis results were more than expected. In the overwhelming majority of cases where leukocyte levels were either too high or too low, the expected predominant outcome was death. Among the deceased, in most cases again with maximum leukocytosis and leukopenia, the cause was heart rupture. In milder cases, a heart aneurysm was found upon autopsy.
An even greater degree of correlation was established between the leukocyte shift index I proposed (the ratio of the percentage of granulocytes to the percentage of agranulocytes in the blood). An intermediate rise in the index corresponded to favorable outcomes, while low and high were linked to fatal outcomes. The idea of the index is very simple—granulocytes provide the first phase of myocardial infarction, associated with the elimination of dying structures in the infarct zone, while agranulocytes facilitate the second phase, associated with the creation and organization of connective tissue in their place. This index is widely used in the post-Soviet space, as I see from publications not only on myocardial infarction but also referencing my work.
The results raised questions about modeling myocardial infarction in animals with disturbances in leukocyte reactions in blood in the first hours of its development. The hypothesis required experimental confirmation. Such experiments were conducted and fully confirmed it.
Leukocyte reactions in the blood in the first hours determine the outcomes of myocardial infarction
The hypothesis positing that leukocyte reactions in the blood during the initial hours post-event critically influence the outcomes of myocardial infarction has been substantiated. In this investigative endeavor, Boris Tsarbaev, a former student of mine who is now acclaimed as one of the top doctors in Israel, played a pivotal role. This topic was also the focus of his dissertation.
Initially, the work might appear routine—it entailed compiling and analyzing a database containing comprehensive information on patients treated for myocardial infarction. This included data on leukocyte counts, subpopulations (granulocytes, agranulocytes), and clinical outcomes ranging from uncomplicated recoveries with post-infarction scarring or aneurysms to fatalities either with or without cardiac rupture, also factoring in the timing of death relative to the onset of the infarction.
The analysis yielded insights that surpassed expectations. In a significant majority of cases, extreme leukocyte levels—either too high or too low—predominantly led to fatal outcomes. In those deceased, cardiac rupture was frequently observed, particularly in instances of extreme leukocytosis or leukopenia. In less severe cases, autopsies revealed heart aneurysms.
A more pronounced correlation was established with the leukocyte shift index I devised, which is the ratio of granulocytes to agranulocytes percentage-wise in the blood. A moderate increase in this index typically indicated favorable outcomes, whereas both excessively high and low readings generally predicted fatal outcomes. The rationale behind the index is straightforward: granulocytes manage the initial inflammatory response, clearing dying structures in the infarct zone, while agranulocytes aid in the subsequent phase of connective tissue formation and organization. This index has gained traction in post-Soviet regions, evident from its frequent citation in scholarly articles on myocardial infarction.
The compelling results prompted further investigation into the animal models of myocardial infarction, particularly focusing on the impact of altered leukocyte responses within the first few hours of onset. This hypothesis necessitated experimental validation, which was subsequently carried out and affirmed the initial findings.
Significant Artificial Influence on Leukocyte Reactions in Blood in Experimental Animals Models Myocardial Infarction Complications in Humans
To empirically ascertain the impact of disturbances in blood leukocyte reactions on myocardial infarction outcomes, we carried out additional animal experiments. The procedure mirrored previous ones, but with a crucial variation: from the onset of myocardial infarction modeling, drugs known to significantly alter blood leukocyte responses were administered parenterally.
We induced hyperreactive leukocytosis using pyrogenal and hyporeactive leukocytosis with amidopyrine. It's worth noting that amidopyrine is no longer available in pharmacies due to its severe risk of agranulocytosis and the availability of safer non-steroidal anti-inflammatory alternatives. At the time, however, it was a common choice.
As anticipated, administration of pyrogenal prompted a marked increase in leukocytosis, while amidopyrine significantly suppressed leukocyte activity. The animals survived, but the myocardial infarction was complicated by the formation of substantial heart aneurysms. Notably, pyrogenal triggered the formation of aneurysms within the first three days, whereas amidopyrine's effects became apparent over the subsequent five days—aligning with my predictions.
Valeriy Sokrut, a diligent collaborator in these studies, extended this research to various drugs affecting specific leukocyte subpopulations, consistently validating their impact on outcomes. Despite my concerns about the ethical implications of such extensive animal testing, he was determined to proceed. His rigorous investigations culminated in his successful defense of his doctoral dissertation in Medical Sciences and he is now a distinguished professor in Ukraine.
These comprehensive experiments solidified the pivotal role of leukocyte dynamics in myocardial infarction outcomes, affirming the hypothesis I had proposed. This work laid the groundwork for developing the Principle of Disease Optimality, an extension of the broader Principle of Optimality in Nature, which presumes that biological processes strive towards the most favorable outcomes under given conditions.
Is There Necrosis in the Infarct Zone?
In clinical settings, myocardial infarction is commonly associated with cellular death and necrosis due to significant reduction or complete cessation of blood flow to a portion of the heart wall. Conventionally, necrosis entails the death of body tissues, which subsequently lose all functionality.
For the heart, necrosis implies a critical loss of functional strength—a scenario that should, theoretically, lead to fatal outcomes due to high pressures exerted during cardiac contractions that could rupture the necrotic wall. If this were invariably the case, then myocardial infarction would consistently result in heart rupture and high mortality. However, the reality is different: the vast majority of myocardial infarction patients survive, with current mortality rates below five percent.
This observation suggests that in cases of myocardial infarction survival, true necrosis in the myocardial zone might not actually occur. Instead, what typically unfolds in the affected zone is an activation of inflammation—a protective and compensatory mechanism. Therefore, myocardial infarction in survivors is not merely a process of necrosis but predominantly one of inflammation. This revised understanding aligns with my developed theory on the healing dynamics of myocardial infarction.
In deceased patients, what is observed are disruptions in the inflammatory process, leading to misinterpretations of myocardial infarction's nature. A critical error has been the extrapolation of post-mortem findings in infarct zones to living patients.
Indeed, disruption of circulation in the infarct zone leads to tissue death, but this is not an uncontrolled necrosis. It is a regulated process, heavily mediated by leukocytes that migrate from the bloodstream into the infarct zone. In survivors, this regulation balances necrotic and restorative processes, maintaining the structural integrity of the heart and preventing aneurysms or ruptures.
Moreover, it’s important to acknowledge that even in deceased individuals, the infarct zone does not exhibit pure necrosis. From the initial moments post-infarction, the area is infiltrated by various types of leukocytes—some catalyzing destruction and others promoting restoration. In these cases, necrotic processes simply dominate over restorative ones, but the necrosis is not complete.
Thus, the conventional definition of myocardial infarction as simple coronary necrosis is misleading. My theory redefines it, providing a nuanced perspective that underscores the intricate interplay of destructive and restorative processes within the infarct zone. This theory offers a more accurate description of myocardial infarction, challenging the traditional views and opening up new avenues for understanding and treatment.
Strength of the Heart Wall in the Infarct Zone
The integrity of the heart wall in the infarct zone and the surrounding area is crucial for understanding the frequency, causes, and mechanisms behind the formation of aneurysms and heart ruptures. These complications were particularly significant until the 1980s, when the introduction of various reperfusion technologies such as thrombolysis, stenting, and arterial reconstructive surgery began to mitigate their incidence. While these complications have not been completely eradicated, their occurrence has significantly decreased—heart ruptures by threefold and aneurysm formation by twofold—thanks to these advancements. Nonetheless, for individuals with risk factors, the threat of these complications remains substantial.
Risk factors influencing these complications include the size and location of the infarct zone—with larger infarcts and those located on the anterior wall of the left ventricle posing higher risks—along with the patient's age and gender. Older individuals and females are considered at higher risk, partly due to a greater propensity for cardiac muscle atrophy. Moreover, a lack of prior ischemic heart disease and existing arterial hypertension, which places additional stress on heart walls weakened by an infarct, elevates risk levels.
Regarding the mechanisms of rupture, it has been traditionally understood that loss of structural integrity due to necrosis could prompt such events. However, my research, conducted in collaboration with my then-student and now close colleague Volodymyr Shliakhover, suggests a more nuanced view. We discovered that while necrosis is a component of every myocardial infarction, the inflammatory processes that occur during infarction are not inherently weakening. Instead, disruptions in these inflammatory processes may lead to weakening and potential rupture. Our studies have shown that inflammation following infarction serves as an evolutionarily optimized compensatory mechanism that aids in the restoration of the infarct zone with connective tissue.
In our research, we further explored the strength of the heart wall during myocardial infarction. We established that under normal conditions, the human heart maintains a strength margin more than tenfold that of the highest arterial pressure experienced during a lifetime. This strength significantly increases during the ischemic stage of infarction when myocardial contracture occurs due to disruptions in the calcium pump. Consequently, in an uncomplicated infarction, the structural strength of the heart wall never drops below physiological norms at any disease stage. This robustness inherently guards against complications like aneurysms and ruptures unless the inflammatory process is disturbed, leading to drastic reductions in heart wall strength and, ultimately, severe complications.
Volodymyr Shliakhover's doctoral dissertation on this topic was groundbreaking and remains, to my knowledge, the only comprehensive academic work dedicated solely to the structural dynamics of the heart during myocardial infarction. More details on our findings and their implications will be discussed in the subsequent chapter.
The Reason for Disorders in the Healing of the Infarct Zone Became Clear or the Mosaic Was Successfully Assembled
The findings from these studies fundamentally shift our understanding of myocardial infarction from being merely necrotic to predominantly inflammatory. This inflammation acts as a reparative mechanism, restoring the heart wall's structure in the infarct zone. Disturbances in this inflammatory process are what lead to many of the complications, some of which can be fatal.
The examination of infarct zones in deceased individuals over various stages of myocardial infarction initially clouded my understanding of the processes at play. The disparate data prevented me from forming a coherent overall picture of the pathology based on these observations alone.
Collectively, these studies not only clarified the nature of myocardial inflammation, but also helped to create a comprehensive theory of both uncomplicated and complicated myocardial infarction. These insights have allowed us to piece together a detailed mosaic, providing a clearer picture of the inflammatory mechanisms at work and how they serve as a protective, compensatory-adaptive response to cardiac injury.
Furthermore, the mechanisms underlying complications observed in myocardial infarction are broadly applicable to other types of acute inflammation. This translational aspect of my research has been extensively developed and will be detailed later with specific examples.
Ultimately, these concerted research efforts have laid the groundwork for the Principle of Optimality of Disease, affirming it as a fundamental philosophical principle governing recovery processes in various diseases. This principle underscores the body's inherent ability to optimize healing, reflecting a deeper, systemic resilience within the biological processes of recovery.
The Significance of Quantitative Research Methods or How the Mechanisms of Uncomplicated and Complicated Myocardial Infarction Were Established
Why others failed, but I and my team succeeded, is also clear. Before we began our research on myocardial infarction, E. Weibel's book 'Morphometry of the Human Lung' was published. I was captivated by this book and, with my students, reproduced it for the lungs of dogs. At that time, we were involved in lung transplantation in dogs and began using quantitative methods in our research.
The experience was successfully transferred to myocardial infarction when we started studying it. Particularly, the quantitative data on leukocyte infiltrates in the infarct zone and peri-infarct zone in animal experiments and on the pathological material of the deceased puzzled me with their inconsistency and complete chaos with the pathological material. The result was the development of a theory of uncomplicated and complicated healing of myocardial infarction.
Georgiy Avtandilov was a leader in introducing quantitative methods in morphology in the former USSR. I fondly remember him because my Ph.D. thesis, my first attempt at defending a doctoral thesis (which I will discuss at the end of the book), and finally passing through the Higher Attestation Commission of the USSR on the third try are significantly associated with his special support. We accomplished much together, evidenced by our joint numerous articles and books on this topic.
A significant contribution to understanding the phenomenon and building its theory was made, I believe, by the results of productive collaboration with Yuriy Dimashko and Boris Kantor.
Yuriy Dimashko's father was hospitalized in the myocardial infarction department of a clinic in Donetsk, where I worked as an assistant in the department of internal diseases. Fate arranged that we met, and this acquaintance gifted both him and me with a model of myocardial infarction, which involved everything—stress mechanisms of its healing, the interrelationship of necrotic and reparative processes in the infarct zone, and the dynamics associated with the changes in the heart wall strength in the infarct zone, as well as the biomechanics of the heart. This model encompassed all phenomena and described both uncomplicated and all variants of complicated courses of myocardial infarction. This model was published in the journal 'Cardiology,' of course, in the USSR.
Unfortunately, this fruitful collaboration between us was quickly interrupted because I had to move to Kharkov, where I worked as the deputy director at the Institute of Therapy under Lyubov Malaya. She invited me and taught me a lot—in management, science, clinic, and fair treatment of people. The next two attempts to defend a doctoral thesis under her supervision, the last of which was successful, are also a result of her support.
Continuing to deal with myocardial infarction problems, I faced the need for mathematical modeling of heart strength. From the literature, I learned about Arnold Volmir in Moscow, a guru in such matters. I asked him for help, and he welcomed me at his home. I remember, his apartment had not a single free spot from filled bookshelves, and one huge one was his own works. He told me a lot of interesting things, but when asked to help with modeling the strength of the heart during myocardial infarction, he simply said—I'm not needed, you have Boris Kantor in Kharkov, and no one can help you better than him.
In Donetsk, working at the department of internal diseases, I studied at the evening department of the Physical Faculty at the University. When I moved to Kharkov, there was no such department at the Physical Faculty, but there was at the Mechanical-Mathematical Faculty. There, many guys were getting additional education from the Institute of Machine Building Problems, where Boris Kantor worked. At their request, they helped me meet him.
Thus began a fruitful collaboration with this outstanding personality. We did a lot of interesting things together, evidenced by pioneering articles and books on heart biomechanics. The concepts of anatomical and pathological stress concentrators in the heart, mathematical models of heart biomechanics, nerve regulation by biomechanics, and much more were our joint achievements. We collaborated with and successfully defended doctoral dissertations on heart biomechanics in medicine, including the aforementioned Volodymyr Shliakhover, and in mathematics, Aleksandr Martynenko. Fruitful cooperation with Boris Kantor evolved into many years of strong friendship between our families.
Regarding the theory of uncomplicated and complicated healing of myocardial infarction, it is described in the next chapter.
You can learn more by reading my e-book
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