Correspondence

Cardiovascular Medicine at the Turn of the Millennium

N Engl J Med 1998; 338:919-920March 26, 1998

Article

To the Editor:

The Shattuck Lecture by Dr. Braunwald (Nov. 6 issue)1 provided an outstanding overview of cardiovascular medicine and science. In the section entitled “Transgenic Techniques,” apolipoprotein (apo) A-I– and apo E–deficient mice are described as genetically engineered mouse models of atherosclerosis. Though that is true for apo E–deficient mice, it is not for apo A-I knockouts.

Lipoprotein risk factors for atherosclerosis include low levels of high-density lipoprotein (HDL) or high levels of apo B–containing lipoproteins, such as low-density lipoprotein (LDL) or remnant lipoproteins. In humans and mice, apo A-I levels determine HDL levels, whereas apo E is necessary for clearance of remnant lipoproteins. Though they are few, apo A-I–deficient and apo E–deficient humans exist, and both groups appear to have an increased susceptibility to atherosclerosis. Apo A-I–deficient humans have minimal or no HDL, which probably accounts for their increased susceptibility; apo E–deficient humans have high circulating levels of a class of lipoprotein remnant termed β very-low-density lipoprotein (VLDL), which probably accounts for theirs.

Like humans, mice lacking apo E accumulate high plasma levels of β-VLDL, and humanlike atherosclerosis develops.2,3 Atherosclerosis, however, does not develop in apo A-I–deficient mice, as it does in humans lacking apo A-I.4 With gene targeting, the mouse has become the primary animal model for most human disease, but we must recognize that mice are different from people. Apo A-I–deficient mice have low but appreciable levels of HDL and, like normal mice but unlike humans, have almost no LDL or VLDL. We have explained the absence of atherosclerosis in apo A-I–deficient mice primarily on the basis of the lack of atherogenic lipoproteins in this model. This hypothesis has been tested. When a human apo B gene is introduced into mice, appreciable levels of humanlike LDL accumulate. Atherosclerotic lesions develop in these animals with their high LDL cholesterol — lesions that are substantially larger on the low-HDL, apo A-I–deficient background.5

One further point regarding these models: When expressed in apo E–deficient mice, human apo A-I leads to high HDL levels and a dramatic reduction in the degree of atherosclerosis. The suggestion from these studies is that HDL is an atherosclerosis modifier and perhaps not a primary determinant — an interpretation supported by the absence of atherosclerosis in the apo A-I knockout mice. These animals have provided great insight into the genetic and environmental determinants of atherosclerosis, and as we approach the next century they should continue to aid our understanding of this deadly disease.

Andrew Plump, M.D., Ph.D.
University of California, San Francisco, San Francisco, CA 94143

5 References

1. 1

   Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-1369
   Full Text | Web of Science | Medline

2. 2

   Plump AS, Smith JD, Hayek T, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 1992;71:343-353
   CrossRef | Web of Science | Medline

3. 3

   Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992;258:468-471
   CrossRef | Web of Science | Medline

4. 4

   Li H, Reddick RL, Maeda N. Lack of apo A-I is not associated with increased susceptibility to atherosclerosis in mice. Arterioscler Thromb 1993;13:1814-1821
   CrossRef | Medline

5. 5

   Hughes SD, Verstuyft J, Rubin EM. HDL deficiency in genetically engineered mice requires elevated LDL to accelerate atherogenesis. Arterioscler Thromb Vasc Biol 1997;17:1725-1729
   CrossRef | Web of Science | Medline

To the Editor:

It is disturbing to find that one of the major figures in cardiovascular research disregards the important role of psychosocial and emotional distress in coronary heart disease. Depression,1 anxiety,2 and anger3 have each been found to be a major risk factor for cardiovascular events in multiple prospective studies, and several plausible biobehavioral mechanisms have been demonstrated. In fact, the risk ratios for each of these factors are as strong as or stronger than the risk ratios observed for the traditional risk factors.

Mark W. Ketterer, Ph.D.
Henry Ford Hospital, Detroit, MI 48202

3 References

1. 1

   Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999-1005
   Web of Science | Medline

2. 2

   Kawachi I, Colditz GA, Ascherio A, et al. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994;89:1992-1997
   Web of Science | Medline

3. 3

   Kawachi I, Sparrow D, Spiro A III, Vokonas P, Weiss ST. A prospective study of anger and coronary heart disease: the Normative Aging Study. Circulation 1996;94:2090-2095
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Luisa Mestroni. (2003) Genomic medicine and atrial fibrillation. Journal of the American College of Cardiology 41:12, 2193-2196
   CrossRef