Elucidation of the Correct Structure of Cholesterol in 1932

The most significant breakthrough in linking cholesterol to atherosclerosis occurred in 1913 when Nikolai Anitschkow, a young student under the direction of the prominent histologist Alexander Maximal at the Military Medical Academy in St. Petersburg, Russia, found through a series of feeding experiments in rabbits that cholesterol led to atherosclerosis. He first fed the rabbits whole eggs, then egg yolks, and finally just purified cholesterol from the egg yolks dissolved in sunflower oil; all feedings resulted in atherosclerosis.

The purified cholesterol dissolved in the sunflower oil caused atherosclerosis, while the sunflower oil alone did not. He went on to make a make a number of seminal discoveries that has stood the test of time; he first described fatty streaks and drew foam cell-rich lesions in the rabbit aortas as the earliest manifestations of atherosclerosis. Anitschkow’s dictum was “No atherosclerosis without cholesterol” even though he was aware that other factors could exacerbate the disease process and used the term “combination theory” to explain the phenomenon.

Unfortunately, his work was largely ignored by the global medical research community. His experiments could not be replicated in dogs or rats, which are resistant to cholesterol-induced atherosclerosis because their plasma cholesterol is predominately high-density lipoproteins (HDLs); therefore, most experts believed that cholesterol-induced atherosclerosis was exclusively a phenomenon in rabbits. In addition, the prevailing view at the time was that human atherosclerosis was part of the inevitable process of aging.

After many years of promoting his cholesterol hypothesis through publications and lectures throughout the world, he died in 1964 at age 79 of myocardial infarction. His initial mentor Alexander Maximal, following the Russian Revolution, immigrated to the United States and became a professor of anatomy at the University of Chicago, dying in 1928 at age 54 of severe coronary atherosclerosis. Anitschkow was studying in Freiburg under Aschoff when he was performing his studies in 1913. He was arrested and put in prison in 1914 when the war broke out. Aschoff helped him get out and escape through Sweden to return to Russia.

The Norwegian physician Carl Muller first associated the physical signs and high cholesterol levels with autosomal dominant inheritance in 1938. In his seminal paper in Acta Medica Scandinavica, he referred to Fritz Harbitz describing xanthomas in 1925 and the Norwegian medical literature describing 8-10 cases of patients with xanthomas, in which five died suddenly of “paralysis of the heart.” In cases in which necropsy was performed, the cause of death proved to be “vessel changes, viz. deposits of xanthomatous masses in the aorta, on the aortic valves and in the coronary arteries.”

He went on to confirm the autosomal dominance pattern of xanthomatosis or hypercholesterolemia in 76 cases from 17 Norwegian families. This was the first linkage of severe hypercholesterolemia to atherosclerosis derived from a genetic cause and paved the way four decades later for the discovery of the low-density lipoproteins (LDL) receptor.