Author: Dr Tim Glenie
To many, anything that pre-dated 1990 may seem ancient – bygone eras of rock’n’roll, big hair and cheese fondue – however the past 40-years has hailed huge steps forward in cardiovascular technologies. As Dr Tim Glenie explains, breakthrough technologies in yester-years has carved a path for future advances in treatments and measures.
Cardiac catheterisation has an interesting story behind it and maintains a chief position in the history books, explains Dr Glenie. Its roots largely cemented by German doctor, Werner Forssmann, who hypothesised a catheter could be inserted directly into the heart to directly deliver drugs or measure blood pressure. However, there was general fear that intrusion into the heart would be fatal, so he experimented on himself.
“He managed to put a drip into his antecubital fossa and feed a catheter into his right heart, walk downstairs and take an x-ray of the catheter to prove it could be done,” explains Dr Glenie. “He won a joint Nobel Prize some years later for his work on proving cardiac catheterisation was possible.”
Equally as pronounced, and highly acclaimed, is the story behind cholesterol synthesis and the physicians who truly brought it to the fore. Although the molecular formula of cholesterol was founded in 1888 by Austrian botanist Fredrick Reinstar, clinical interest in cholesterol upped its game in the 1950s – largely headed by four biochemists, Konrad Bloch, Feodor Lynen, John Cornforth and George Popjak. Their intense efforts to uncover the pathway by which cholesterol was synthesised in the body, opened doors for those thereafter.
As reported in Wikipedia, they founded four crucial steps in a complex pathway – which involves 30 enzymatic reactions:
(1) Condensation of three acetate units to form a six-carbon intermediate, mevalonate.
(2) Conversion of mevalonate to activated isoprene units.
(3) Polymerization of six five-carbon isoprene units to form the 30-carbon linear squalene.
(4) Cyclization of squalene to form the steroid nucleus, with a further series of changes to produce cholesterol.
“In 1964, Bloch and Lynen won the Nobel prize for describing cholesterol symphysis and the speaker at the time said, ‘Your discoveries may provide us with weapons against some of man’s greatest maladies’,” explains Dr Glenie.
Today, one of the world’s most famous ongoing cardiovascular studies, The Framingham Heart Study, continues to make headway in cholesterol discoveries. It is accredited for revealing the first solid evidence that individuals with higher blood cholesterol levels at the time of a baseline exam, were more likely to experience a myocardial infarction in later years.
Today, millions of statin patients can be thankful for the genius behind the green mould discoveries of late. Inspired by Alexander Fleming, discoverer of penicillin, Japanese researcher Akira Endo, speculated that fungi – like moulds on mushrooms – would produce antibiotics that inhibited HMG-CoA reductase – lethal to microbes.
“In 1976, he (Akira) first discovered the chemical Compactin, which he dubbed the first statin and demonstrated that in humans and dogs, you can successfully lower cholesterol,” explains Dr Glenie. “In the 1980s there were human reports using the same compound, successfully treating familial hypercholesterolemia.”
The success of Akira’s studies prompted him and others to carry out various clinical trials, and for other pharmaceutical companies to search for other strains of Compactin:
- In 1978, Akira and his physician friend Akira Yamamoto treated an 18-year old woman with severe familial hypercholesterolemia. Her serum cholesterol dropped from 1,000 mg per decilitre to ∼700 mg per decilitre during treatment with Compactin at a daily dose of 500 mg.
- Thereafter, Yamamoto treated five heterozygous patients with familial hypercholesterolemia and three patients with combined hyperlipidaemia with Compactin, and on average their cholesterol declined by roughly 30% – with no noted severe side effects.
- In 1979 Merck Research Laboratories, under the direction of Alfred Albert, isolated a statin very similar to Compactin in chemical structure, called Mevinolin.
- 1982, several clinicians, including Roger Illingworth and Scott Grundy and David Bilheimer, treated patients with severe hypercholesterolemia unresponsive to available agents. The drug showed dramatic activity in lowering LDL cholesterol, with very few side effects.
- In 1984, Merck began large-scale clinical trials of lovastatin in patients at high-risk and long-term toxicity studies in dogs. The drug dramatically reduced cholesterol levels and was well tolerated with no tumours detected.
“The first commercial statin was available in 1987 and since then there have been multiple large-scale trials performed worldwide,” says Dr Glenie. “In 2005, 25 billion dollars’ worth of statins were sold. In 2010, 30 million people worldwide were taking them – and all from that green mould you get on fruit!”