For much of the 40 years since the development of coronary artery bypass grafting in 1968, the presence of a 50% diameter stenosis of the coronary artery has been used as the threshold value for therapy. In multiple outcome trials dating from the Veterans Administration (VA) Cooperative Study (1970 to 1974) through the BARI trial (1988 to 1991) to the SYNTAX trial (2005 to 2007), a 50% stenosis was defined as “significant” or “clinically important,” and patient enrolment was restricted to those with a stenosis of that caliber or greater in the left main or other major coronary arteries. Therefore, much of what we understand regarding the merits of medical therapy versus coronary interventions such as angioplasty and coronary bypass surgery is based on the recruitment of patients with or above this specific value.
The published results of the VA Cooperative Study indicating mortality benefits for subsets of patients, particularly those with a ≥50% left main stenosis, reinforced its status as a reliable discriminator of clinically important disease. Two generations of patients have had their therapeutic decisions based upon whether that precise cutoff was exceeded or not. The influence of the 50% diameter stenosis threshold made it 1 of the 2 most important single numbers in modern cardiology, the other being the number of 35% for left ventricular ejection fraction.
Furthermore, the validity of the array of noninvasive tests used to identify myocardial ischemia has been determined by their ability to identify the presence of a 50% coronary diameter stenosis. No matter the modality: single photon emission tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), and computed tomographic angiography (CTA); all were originally benchmarked against their ability to correctly identify a ≥50% coronary stenosis. To this day, a 50% stenosis continues to be the reference marker in studies of the newest imaging technologies.
More recently, a distinction has been made between the anatomic appearance of a stenosis and its functional significance, with a marked discordance between the two. Using methods such as fractional flow reserve (FFR), it has been shown that only about 1/3 of narrowings within a stenosis range of 50% to 70% display provokable myocardial ischemia that merit intervention. The remainder of narrowings can safely be managed medically. As a result, the defining value of a 50% stenosis has shed its critical importance in decision making and has become just one of a series of numbers ranging from 30% to 70%, lumped into a basket labeled “intermediate” stenosis, now undistinguished and of uncertain importance.
If now unjustified, how was such an enduring mandate, a guideline before there were guidelines, arrived at? Also worth questioning is how much of what we believe to be fundamentally true regarding the identification and treatment of coronary heart disease is actually invalid, having been based on a standard which has been discredited. Are there lessons learned which need to be forgotten?
It must certainly have been a challenge to identify early in the development of coronary artery bypass surgery, what degree of stenosis was appropriate to treat with a bypass conduit, whether 30%, 50%, 70%, or 90%. As late as the 1980s, a report titled “Should coronary arteries with less than fifty percent stenosis be bypassed?” examined the favorable evidence for such a strategy. In those gestational days, some surgeons were targeting even 30% narrowings. As the authors noted, “grafts are increasingly being placed to coronary arteries having 50% stenosis or less.”
The VA Cooperative Study
The protocol for the VA Cooperative Study, the first major multicenter randomized trial of bypass surgery, was written in 1969, remarkably only 1 year after Favalaro’s description of the reversed vein bypass procedure. The VA group had already been studying the Vineberg implant procedure but terminated that study after enrolling 75 patients and directed their investigation toward vein conduits. Because they provide no references in their original reports, how they arrived at a 50% diameter stenosis cutoff is a mystery. (Subsequent major randomized trials also do not reference how they chose their threshold value; whether 50% or, in some, 70%.)
In a report published in 1977, the VA group defended why they came to choose a 50% versus a 75% cutoff, indicating that it was based on historical precedent and a theoretical model of blood flow in arteries. However, the citations they provide are dated from 1973 onward, the mathematical model in 1975, and their protocol was written in 1969. Although reluctant to take the credit, in fact they themselves set the precedent for adopting the 50% cutoff which became the standard for clinical trials. But they did not do so in a vacuum, and one can look back and make a reasonable conjecture of why they actually adopted the 50% value.
Much had already been described experimentally regarding the effects of stenosis on blood flow before 1969 and before what is regarded now as the foundational report on that subject in 1974 by Gould et al. That report examined blood flow in canine circumflex coronary arteries at rest and under maximal, hyperemic, flow conditions and established the concept of coronary flow reserve. Because of their research, it is understood that measuring the effects of different degrees of coronary stenosis requires conditions of maximally dilated flow. Their findings launched the technologies which rely on hyperemic flow to detect myocardial ischemia including FFR, PET, and SPECT. Although the report was monumental in its impact and is commonly referenced as the justification for the 50% stenosis cutoff, it actually cannot be used as evidence. Both by direct flow and gamma camera measurement, they found that a 50% stenosis was insufficient to significantly reduce flow. They found that “a short lesion of 45 to 50 percent by diameter probably does not impair coronary flow reserve in man but more severe lesions cause a progressive decrease.” Instead, “marked impairment of coronary flow reserve occurs with progressive stenosis of 65 to 95 percent by caliper determination.” Furthermore, they suggest a hyperemic/baseline flow ratio of 1.5 could possibly be a future cutoff for surgery, which would equate to an 85% diameter stenosis based on their data. Although often cited, the report by Gould et al. is not the source for the adoption of the 50% diameter stenosis. One has to look further back for an answer.
Early Quantitative Studies
The earliest quantitative examination of the effect of stenosis severity on arterial flow was performed by Mann et al. in 1938 on canine carotid arteries. They wanted to answer a practical question: How much can one constrict a blood vessel without decreasing the flow of blood? They demonstrated the previously unappreciated finding that it requires a severe degree of stenosis to reduce resting arterial flow. They reported that “The area of the lumen may be reduced 50 per cent without any change in blood flow, and it can be reduced as much as 90 per cent before a 50 per cent reduction in blood flow occurs.” Explaining that a 50% diameter stenosis equates to a 75% cross-sectional area narrowing, they indicated that “the diameter could be reduced almost 58 per cent without causing more than 20 per cent decrease in blood flow.” For flow to be “reduced significantly,” a 70% diameter or 90% cross-sectional area narrowing had to be created.
These findings were confirmed and greatly amplified by May et al. in 1962 in 2 wide-ranging reports, the first using canine iliac arteries and the second using intraoperative pressure measurements in humans. After finding that both flow and pressure decreased in unison beyond a stenosis, they predicted “From a practical standpoint, the significance of any stenosis can probably be determined as accurately with pressure studies as with flow studies.” They reviewed findings from previous human investigations that indicated a cross-sectional area narrowing of 75% to 97% was necessary to reduce distal vascular pressures, in agreement with their own intraoperative results. They provided the fundamental insight that the “surprising” finding that a severe stenosis was required to produce a significant reduction in flow could be explained using “the classical laws of fluid mechanics in construction of a mathematical model.” They then derived a formula to predict the pressure decrease across a stenosis which recognized that the greater the prestenotic flow velocity the greater the trans-stenotic pressure decrease. Their formula explained conceptually what they found empirically that there was a “critical stenosis” threshold which must be reached before flow begins to decline and beyond which flow drops “precipitously.” The graphs of their findings and those earlier from Mann et al. are superimposable and indicate that flow begins to decrease at a “critical stenosis” diameter of 60% and are reduced by half at a diameter of 70%. The reliance on predictive formulas, the concept of critical stenosis, and the potential equivalence of pressure and flow were all necessary precursors for the future science of FFR.
Of great interest in this era are the pathologic studies of Zoll et al. Before coronary arteriograms were performed on the living, they were performed by pathologists on cadavers. Although comments regarding angina pectoris or myocardial ischemia are rare in our present-day autopsy reports, they were a focus for Zoll et al. They deduced that the presence of coronary collaterals indicated that myocardial ischemia had been present and correlated that with premortem angina pectoris. Using an injection technique developed by Schlesinger, they indicated by their measurements that a 75% diameter stenosis of the coronary artery was usually required to produce the finding of collaterals at autopsy, thus indicating the subject suffered from myocardial ischemia. (Paradoxically, the presence of collaterals normalizes the FFR measurement and produces a reading indicating that no myocardial ischemia actually is present despite the visual appearance of a significant stenosis. This discrepancy can be reconciled mathematically. The “no ischemia” aspect would perhaps be disputed by the subjects of Zoll et al.)
Early Quantitative Studies
The earliest quantitative examination of the effect of stenosis severity on arterial flow was performed by Mann et al. in 1938 on canine carotid arteries. They wanted to answer a practical question: How much can one constrict a blood vessel without decreasing the flow of blood? They demonstrated the previously unappreciated finding that it requires a severe degree of stenosis to reduce resting arterial flow. They reported that “The area of the lumen may be reduced 50 per cent without any change in blood flow, and it can be reduced as much as 90 per cent before a 50 per cent reduction in blood flow occurs.” Explaining that a 50% diameter stenosis equates to a 75% cross-sectional area narrowing, they indicated that “the diameter could be reduced almost 58 per cent without causing more than 20 per cent decrease in blood flow.” For flow to be “reduced significantly,” a 70% diameter or 90% cross-sectional area narrowing had to be created.
These findings were confirmed and greatly amplified by May et al. in 1962 in 2 wide-ranging reports, the first using canine iliac arteries and the second using intraoperative pressure measurements in humans. After finding that both flow and pressure decreased in unison beyond a stenosis, they predicted “From a practical standpoint, the significance of any stenosis can probably be determined as accurately with pressure studies as with flow studies.” They reviewed findings from previous human investigations that indicated a cross-sectional area narrowing of 75% to 97% was necessary to reduce distal vascular pressures, in agreement with their own intraoperative results. They provided the fundamental insight that the “surprising” finding that a severe stenosis was required to produce a significant reduction in flow could be explained using “the classical laws of fluid mechanics in construction of a mathematical model.” They then derived a formula to predict the pressure decrease across a stenosis which recognized that the greater the prestenotic flow velocity the greater the trans-stenotic pressure decrease. Their formula explained conceptually what they found empirically that there was a “critical stenosis” threshold which must be reached before flow begins to decline and beyond which flow drops “precipitously.” The graphs of their findings and those earlier from Mann et al. are superimposable and indicate that flow begins to decrease at a “critical stenosis” diameter of 60% and are reduced by half at a diameter of 70%. The reliance on predictive formulas, the concept of critical stenosis, and the potential equivalence of pressure and flow were all necessary precursors for the future science of FFR.
Of great interest in this era are the pathologic studies of Zoll et al. Before coronary arteriograms were performed on the living, they were performed by pathologists on cadavers. Although comments regarding angina pectoris or myocardial ischemia are rare in our present-day autopsy reports, they were a focus for Zoll et al. They deduced that the presence of coronary collaterals indicated that myocardial ischemia had been present and correlated that with premortem angina pectoris. Using an injection technique developed by Schlesinger, they indicated by their measurements that a 75% diameter stenosis of the coronary artery was usually required to produce the finding of collaterals at autopsy, thus indicating the subject suffered from myocardial ischemia. (Paradoxically, the presence of collaterals normalizes the FFR measurement and produces a reading indicating that no myocardial ischemia actually is present despite the visual appearance of a significant stenosis. This discrepancy can be reconciled mathematically. The “no ischemia” aspect would perhaps be disputed by the subjects of Zoll et al.)
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