Longevity is a vascular question
A man is only as old as his arteries
A man of forty may present vessels as much degenerated as they should be at eighty…the arterio-sclerosis results from the bad use of good vessels.
These words are from the 1921 edition of Sir William Osler’s classic textbook, The Principles and Practice of Medicine. They are prescient given that cardiovascular disease would not become the leading killer on the planet for many years. Indeed, myocardial infarction and stroke are not even mentioned in the textbook’s index, although angina pectoris and cerebral hemorrhage are.
Osler’s insight was undoubtedly gained during his performance of 948 autopsies. If one of these included a postmortem examination on a neonate, he would have noted that the neonatal aorta is highly flexible—reminiscent of a rubber tourniquets used by phlebotomists. In contrast, the aorta of an 80 year-old is often no more elastic than any other tissue.
Recent data from the Multi-Ethnic Study of Atherosclerosis corroborate Osler’s observation. The investigators noted a higher resting heart rate is associated with an increased arterial stiffness independent of atrioventricular nodal blocker use and physical activity level, consistent with the notion that the aorta behaves like any other material and is subject to mechanical fatigue and failure of the elastic elements over time.
Insights on Aging from Progeria
A profound insight into the role of aortic elasticity in aging and cardiovascular disease is provided by patients with Hutchinson-Gilford progeria syndrome, a condition often known simply as progeria. This rare genetic disorder is marked with symptoms resembling accelerated aging, and on average, progeria patients die at the age of thirteen.
Ninety percent of deaths are due to myocardial infarction and stroke, even though serum cholesterol, LDL, HDL and C-reactive protein levels are no different from controls. Interestingly, progeria patients have markedly stiffer aortas than controls. In a 2012 study, a population of progeria patients with an average age of seven had the aortic stiffness expected in a 60-69 year old. The exciting thing about that study was that administration of an inhibitor of the enzyme farnesyltransferase improved aortic stiffness to that of a 40 to 49 year old.
I‘m optimistic that this therapy will prolong the lifespan of progeria patients, and as a result, will raise awareness of the role of hemodynamics in aging and human disease.
What are the deleterious effects of aortic stiffness? In the short run, increased aortic stiffness increases vascular impedance (that is, opposition to pulsatile flow, in distinction to opposition to constant flow, which is resistance). Increased impedance decreases cardiac output, decreases perfusion and power output of skeletal muscle, with the result that physical performance declines, increasing the likelihood that an animal will end as prey.
What about the effect of aortic stiffness in humans, who can hope to live for several decades past their physical prime? The result is cardiovascular disease, as seen in progeria patients. The increased stiffness results in increased peak blood velocity, resulting in creation of larger areas of disturbed flow in the vascular tree. These areas of disturbed flow develop atherosclerosis, whether by friction caused by increased shear stress, or organization of mural thrombi.
Finally, appreciation of the role of aortic stiffness elucidates why central obesity imparts a greater risk of cardiovascular disease than generalized obesity. Previously, it was obscure why the “apple” shape was more closely related to cardiovascular disease than the “pear” shape. Increased intraabdominal obesity will increase intraabdominal pressure, limiting expansion of the aorta during systole, decreasing aortic compliance with the same end result as fatigue and failure of the elastic elements of the aorta.
For Further Reading:
1. The Principles and Practice of Medicine, Osler and McCrae, 9th Ed., p. 102, 1921.
4. Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: clues to the biology of premature atherosclerosis in Huthchinson-Gilford Progeria syndrome. The Journal of Pediatrics 2005; 146(3): 336-41.
5. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford Progeria syndrome. Proceedings of the NationalAcademy of Sciences of the United States of America 2012; 109(41):16666-71.
6. Ectopic fat deposition and global cardiometabolic risk: new paradigm in cardiovascular medicine. The Journal of Medical Investigation 2013;60(1-2): 1-14.
Last Updated: 2014-12-30