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Association of the Fibonacci Cascade With the Distribution of Coronary Artery Lesions Responsible for ST-Segment Elevation Myocardial Infarction
C. Michael Gibson, MS, MD, William J. Gibson, MPH, Sabina A. Murphy, MPH, Susan J. Marble, RN, MS, Carolyn H. McCabe, BS, Minang P. Turakhia, MD, Ajay J. Kirtane, MD, Juhana Karha, MD, Julian M. Aroesty, MD, Robert P. Giugliano, MD, and Elliott M. Antman, MD, for the TIMI Study Group
This is the first study to demonstrate the appearance of the Fibonacci Cascade within the distribution of coronary artery lesions in the human heart. The propensity for this ratio to appear in nature may also be because this ratio optimizes the efficiency of packing structures in a limited space in such a way that wasted space is minimized and the supply of energy or nutrients is optimized. ᮊ2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:595–597)
TABLE 1 The Fibonacci Cascade
Multiplication by 1.618 1 ϫ 1.618 ϭ 1.618 1.618 ϫ 1.618 ϭ 2.618 2.618 ϫ 1.618 ϭ 4.236 4.236 ϫ 1.618 ϭ 6.854 6.854 ϫ 1.618 ϭ 11.09 Division by 0.618 1/0.618 ϭ 1.618 1.618/0.618 ϭ 2.618 2.618/0.618 ϭ 4.236 4.236/0.618 ϭ 6.854 6.854/0.618 ϭ 11.09

imilar to the number ␲ (pi), the number 1.61804 (␾, phi, “The Golden Mean”) plays a prominent S role in mathematics. The Golden Mean and the

Fibonacci series are intimately connected. The Fibonacci series is named after the thirteenth-century mathematician, Fibonacci (also known as Leonardo of Pisa), who introduced the Arabic, or decimal system of numbering to the West. He also posed a very special number series to originally answer a mathematical problem regarding the breeding patterns of animals. The Fibonacci series is a series of numbers in which each number is the sum of the 2 previous numbers: 1 ϩ 1 ϭ 2; 1 ϩ 2 ϭ 3; 2 ϩ 3 ϭ 5; 3 ϩ 5 ϭ 8; 5 ϩ 8 ϭ 13; 8 ϩ 13 ϭ 21, and so forth. The formula to find the nth term of the sequence is F(n) ϭ F(n Ϫ1) ϩ F(n Ϫ 2), where F(0) ϭ 1 and F(1) ϭ 1. The ratio is then [F(n)/F(n Ϫ 1)]. The ratio of each
From the TIMI Study Chairman’s Office, the Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts. This study was supported in part by grants from Centocor and Eli Lilly Inc., Malvern, Pennsylvania, and Indianapolis, Indiana (TIMI 14); Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (INTEGRITI); Merck & Co. Inc, Blue Bell, Pennsylvania (FASTER); and Aventis Pharma, Antony, France (ENTIRE). Dr. C.M. Gibson’s address is: TIMI Data Coordinating Center, 350 Longwood Avenue, First Floor, Boston, Massachusetts 02115. E-mail: mgibson@perfuse.org. Manuscript received March 5, 2003; revised manuscript received and accepted May 21, 2003.
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 September 1, 2003

The series of numbers above shows a geometric progression on the left-hand side, where each number, starting from 1, is multiplied by 1.618. On the right-hand side, there is a third geometric progression where the first number is divided by 0.618, giving the identical result for each line. There is a third arithmetic progression running through the geometric series, which is arrived at by adding the products of multiplication together as follows: 1.618 ϩ 2.618 ϭ 4.236 which added to 2.618 to obtain 6.854, and so forth. This number is the addition of the previous 2 terms, which is the Fibonacci Series.

term to the previous term in the Fibonacci series is equal to the Golden Mean. At higher numerical values, the Fibonacci series more and more closely approximates the ratio of the Golden Mean or 1.618 . . . designated as ⌽, and 1/⌽, which is designated as ␾ (0.618 . . .).

The Fibonacci Cascade is shown in Table 1. In these 3 series of numbers, different mathematical operations (multiplication, division, and addition), when performed on related numbers, yield the same result. For instance, 1 ϫ 1.618 ϭ 1.618 yields the same results as 1/0.618 ϭ 1.618. Likewise, in a third arithmetic progression 1 ϩ 1.618 ϭ 1.618 ϫ 1.618 ϭ 2.618, which is the next number in the other 2 series, and so forth. Thus, the multiplicative, divisive, and arithmetic progression of these series yields the same results. The following critical ratios appear in this cascade: 1.618, 2.618, 4.236 (Table 1). The ratio of 1.61804. . . is frequently observed in botanic and anatomic structures. In the structure of
0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00731-8


FIGURE 1. The median length of all arteries in the series was 15.3 cm (IQ range 13.2/17.7, 1,533 lesions) (see text).

branches in ferns, in animal population studies, and in the shells of crustaceans, this ratio plays a prominent role. The ratio is particularly prevalent in branching structures. It has been speculated that this arrangement forms an optimal packing of seeds, so that no matter how large the seed head, they are uniformly packed at any stage, all the seeds being the same size; there is no crowding at the center and there is no sparseness at the edges. In humans, the ratio plays a prominent role in facial features. For instance, the ratio of the base of the nose to the width of the lips is ideally ⌽ and the ratio of the first to second incisor is ⌽. In the hand, the ratio of the longest bone in a finger to the middle bone approximates ⌽ and the ratio of the middle bone to the shortest bone (at the end of the finger) also approximates ⌽. With respect to human stature, the ratio of the distance from the ground to the umbilicus is ⌽ times the distance from the umbilicus to the top of the head. The goal of this study was to extend these previous observations to examine if the distribution of lesions responsible for ST-segment elevation myocardial infarction (STEMI) are associated with the mathematical pattern of the Fibonacci Cascade. Given that human coronary arteries are a branching structure, we hypothesized that the ratios identified in the Fibonacci Cascade (1.618, 2.618, 4.236) would be observed in the location of coronary artery lesions relative to the length of the epicardial coronary artery. Anatomic data were pooled from the Thrombolysis In Myocardial Infarction (TIMI) 14, 20, 23, and 24 trials. The TIMI 14 trial was a 1,187 patient trial comparing a full-dose thrombolytic (alteplase or reteplase) with abciximab plus a reduced dose thrombolytic for treatment of STEMI.10,11 Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI)-TIMI 20 was a 418 patient trial evaluating the safety and efficacy of eptifibatide in conjunction with varying doses of tenecteplase for treatment of STEMI.12 The Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction (ENTIRE)-TIMI 23 trial was a 488 patient phase II trial comparing enoxaparin to unfractionated heparin in patients receiving tenecteplase or reduced-dose tenecteplase plus eptifibatide for treatment of STEMI.13
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Fibrinolytics and Aggrastat in ST Elevation Resolution (FASTER)-TIMI 24 was a phase II trial evaluating the efficacy of a combination of tirofiban, tenecteplase, and unfractionated heparin for treatment of acute STEMI. The distance from the ostium to the middle of the lesion was planimetered as was the distance from the ostium to the bifurcation in most distal branch in the coronary artery. Measurements were performed using manual hand-held planimeters (Scale Master II, Calculated Industries Inc., Carson City, Nevada). All analyses were performed using Stata version 7.0 (StataCorp, College Station, Texas). Because the length data were not normally distributed, all continuous variable values are reported as medians and interquartile ranges (IQ). Figure 1 shows the predicted and observed location of human coronary lesions. The median length of all arteries in the series was 15.3 cm (IQ 13.2/17.7, 1,533 lesions). This length divided by the ratio of 4.236 identified in Fibonacci Cascade yielded a predicted value of 3.62 cm (IQ range 3.11/4.18, 1,533 lesions), which is 24% of the distance down the artery from the origin or 76% of the distance from the distal terminus of the artery. The median location of human coronary artery lesions responsible for ST-segment elevation lies nearly precisely at the predicted distance down the artery at 3.78 cm (24.7%) of the distance down the artery from the origin.

This is the first study to demonstrate the appearance of the Fibonacci Cascade and the Golden Mean within the distribution of coronary artery lesions in the human heart. The appearance of this ratio is most likely related to the location of branch points within the arborizing coronary anatomy. This ratio may reflect the mathematical efficiency of fractal geometry: the smaller is to the larger as the larger is to the whole. Such a self-replicating system is efficient because the information required for the future scale independent growth of a structure is encoded within the existing structure. The propensity for this ratio to appear in nature may also be because this ratio optimizes the efficiency of packing structures in a limited space in such a way that wasted space is minimized and the supply of energy or nutrients is optimized. In branching structures such as plants and seed heads, a mathematically efficient single-fixed angle would produce the optimal design, no matter how large a branching structure a plant grows. Such an optimal angle would ensure that each leaf receives maximum exposure to light, rain, and insects for pollination while simultaneously minimizing the probability of obscuring the leaves below. This angle also minimizes the probability of being obscured by any future leaves above, no matter what stage of growth. The optimal fixed angle of turn is ⌽ (1.618 . . .) leaves (structures) per turn or alternatively ␾ (0.618 . . .) turns per new leaf (structure), which was proved mathematically in 1992 by Douady and Couder, 2 French mathematicians.4 Even as early as 1837, the

Bravais brothers observed this angle, known as the “divergence angle” or the “Golden angle,” which is close to 137.5°.7 The angle that divides a complete turn by the Golden ratio is 360°/⌽ ϭ 222.5°. Because this is more than half a circle (180°), the observed angle is actually obtained by measurement from the “end” of the circle. In other words, 222.5° is subtracted from 360° yielding the observed angle of 137.5°. This ubiquitous example from nature is germane to the present study because the relation was observed by measuring from the “end” of the coronary artery. With respect to the coronary tree, such a sequence may not simply optimize packing of the vasculature, but more likely, if the Fibonacci relation identified here is a surrogate for branch location, then it may be speculated that this relation may optimize the branching pattern in such a way that the coronary tree maximizes perfusion of the myocardial bed (this is akin to myocardial perfusion being the “sunlight” that plant leaves receive when leaves are optimally distributed in a Fibonacci pattern). In some plants, the numbers do not belong to the sequence of f’s (Fibonacci numbers) but to the sequence of g’s (Lucas numbers), or even to the still more anomalous sequences 3, 1, 4, 5, 9... or 5, 2, 7, 9, 16... . The Lucas numbers are formed in the same way as the Fibonacci numbers— by adding the latest 2 to get the next, but instead of starting at 0 and 1 (Fibonacci numbers) they start with 2 and 1 (the Lucas numbers). The other 2 sequences above have other pairs of starting values but then proceed with the same rule as the Fibonacci numbers. An interesting fact is that, for all series that are formed from adding the latest 2 numbers to get the next, and, starting from any 2 values (Ͼ0), the ratio of successive terms will always tend to be 1.618 . . . (⌽). Clinically, these data imply that careful consideration should be given to percutaneous therapy in the region noted to be at risk in this study (approximately 24% of the way down the artery).14 It should be noted that the data apply only to those patients who survive to reach the hospital. This is the first study to demonstrate, in the setting

of STEMI, that the Fibonacci Cascade and the Golden Mean are present within the distribution of coronary artery lesions in the human heart. Given the arborizing coronary anatomy of the heart, the presence of the ratio is likely related to the location of branch points. As has been shown with other structures in nature, the ratio may reflect the mathematical efficiency of fractal geometry, in which the smaller is to the larger as the larger is to the whole.
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Quarterly 1963;1:53–64. 3. Coexeter HSM. The golden section, phyllotaxis, and Wythoff’s game. Scripta Mathematica 1953;19:135–143. 4. Douady S, Couder Y. Phyllotaxis as a physical self-organized process. Physic Rev Lett 1992;68:2098 –2101. 5. Hoffer W. A magic ratio occurs throughout art and nature. Smithsonian 1975:110 –120. 6. Jean RV. Mathematical Approach to Pattern and Form in Plant Growth. New York: John Wiley & Sons, 1984. 7. Livio M. The Golden Ratio: The Story of Phi, The World’s Most Astonishing Number. New York: Broadway Books, 2002. 8. Rivier N, Occelli R, Pantaloni J, Lissowdki A. Structure of Binard convection cells, phyllotaxis and crystallography in cylindrical symmetry. J Physique 1984; 45:49 –63. 9. Grunbaum, Branko, Shephard GC. Tilings and Patterns. New York: W. H. Freeman & Co., 1987. 10. Antman EA, Giugliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, Vahanian A, Adgey AAJA, Menown I, Rupprecht HJ, et al, for the TIMI 14 Investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 Trial. Circulation 1999;99:2720 –2732. 11. Antman EA, Gibson CM, de Lemos JA, Giugliano RP, McCabe CH, Coussement P, Menown I, Nienaber CA, Rehders TC, Frey MJ, et al, for the TIMI 14 Investigators. Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. Eur Heart J 2000;21:1944 –1953. 12. Antman EA, Giugliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, Vahanian A, Adgey AAJA, Menown I, Rupprecht HJ, et al, for the TIMI 14 Investigators. Combination reperfusion therapy with eptifibatide and reduced dose tenecteplase for ST-elevation myocardial infarction: results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial. J Am Coll Cardiol 2003;41:1251–1260. 13. Antman EA, Louwerenburg HW, Baars HF, Wesdorp JCL, Hamer B, Bassand JP, Bigonzi F, Pisapia G, Gibson CM, Heidbuchel H, Braunwald E, Van de Werf F. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 trial. Circulation 2002;105:1642–1649. 14. Kirtane AJ, Murphy SA, Karha J, Wong GC, Giugliano RP, Antman EM, Gibson CM. A mathematical model of preventing plaque rupture with drug eluting stents based upon distance from the ostium to the culprit lesion in ST elevation MI (abstr). J Am Coll Cardiol 2003;41:20A.