Relation of a Postmortem Renal Index of Hypertension to Atherosclerosis in Youth
Abstract In a cooperative multicenter study, Pathobiological Determinants of Atherosclerosis in Youth, of 1164 young men 15 through 34 years of age who died of external causes and were autopsied in forensic laboratories, we measured atherosclerosis of the aorta and the right coronary artery. Using the ratio of intimal thickness to outer diameter of the small renal arteries to predict mean arterial pressure (MAP) during life, we classified the cases as either normotensive (MAP <110 mm Hg) or hypertensive (MAP ≥110 mm Hg). By this criterion, the prevalence of hypertension in blacks was 16%; in whites, 12%. Hypertension was associated directly with blood level of glycohemoglobin (an indicator of blood glucose concentration) and with body mass index (BMI) but inversely with thickness of the panniculus adiposus.
Among hypertensive compared with normotensive cases, the extent of raised lesions (mainly fibrous plaques) was greater in the aortas of 30- to 34-year-old men and in the right coronary arteries of 25- to 34-year-old men. The prevalence of raised lesions involving 5% or more of the intimal surface was twofold greater in the aortas and right coronary arteries of hypertensive men throughout the 15-to-34–year age span of the study cases. The association of hypertension with raised lesions was not accounted for by adjusting for glycohemoglobin level, BMI, or thickness of the panniculus adiposus. Hypertension is associated with accelerated atherosclerosis in youth, particularly fibrous plaques.
Reprint requests to Jack P. Strong, MD, Department of Pathology, LSU Medical Center, 1901 Perdido St, New Orleans, LA 70112.
↵1 A list of participants is given in the Appendix.
- Received August 9, 1995.
- Accepted September 27, 1995.
Hypertension, long known to predispose to the clinical manifestations of atherosclerosis,1 emerged from the longitudinal epidemiological studies of the 1950s as one of the three major predictors, along with serum cholesterol concentration and smoking, of risk of coronary heart disease and stroke.2 3 Hypertension is also associated with the extent and severity of atherosclerosis in both middle-aged and older humans4 5 and experimental animals.6 7 8 9
The augmentation of atherosclerosis by hypertension was thought to be primarily a problem of older persons until surveys showed a considerable range of blood pressures in children10 and tracking of blood pressures as the children matured.11 However, observations on the association of blood pressures with atherosclerosis in young persons were limited to a small number of persons.12 13 A multicenter cooperative study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), of coronary and aortic atherosclerosis in 15- to 34-year-old autopsied young persons showed that serum lipoprotein levels, smoking,14 glycohemoglobin levels, and adiposity15 were associated with atherosclerosis. The availability of kidney samples from these cases provided an opportunity to assess the association of renal vascular changes that are indexes of elevated blood pressure with the extent and severity of atherosclerosis in its early stages.
Fourteen cooperating centers adopted a Standard Operating Protocol and Manual of Procedures to collect specimens and submit them to central laboratories for analysis. A statistical coordinating center received all data pertaining to each case from the collection centers and central laboratories.
Study subjects were persons 15 to 34 years of age, inclusive, who died of external causes (accidents, homicides, or suicides) within 72 hours after injury and were autopsied within 48 hours after death in one of the cooperating medical examiners’ laboratories. Age and race were obtained from the death certificate. Persons of race other than black or white and those with congenital heart disease, Down’s syndrome, acquired immunodeficiency syndrome, or hepatitis were excluded. From a total of 1692 cases collected between June 1, 1987, and August 31, 1990, 160 cases were excluded because they did not meet these inclusion criteria or because of incorrect sampling or incomplete critical information. For this analysis, we did not include females because there were too few cases. Of the 1181 remaining males, kidney samples were available for 1164 cases, which form the basis of this report. The Institutional Review Board of each participating center approved the use of tissue, blood, and data from the human subjects in this study.
Dissecting and Preserving Arteries
An autopsy technician removed the aorta from a point 2 cm proximal to the ligamentum arteriosum to a point 2 cm distal from the iliac bifurcation. Branching arteries were severed close to the aortic wall, and adventitial fat was removed by sharp dissection. The PDAY technician opened the aorta along a line on the dorsal surface midway between the orifices of the intercostal and lumbar arteries, rinsed the intimal surface with Hanks’ balanced salt solution, and flattened it with the adventitial surface downward. The PDAY technician then bisected the aorta longitudinally along a line on the ventral surface and midway between the intercostal and lumbar ostia, prepared the right half for histochemical and chemical analyses, and placed the left half on a piece of cardboard with the adventitia downward. This left half was covered with absorbent cotton and fixed in 10% neutral-buffered formalin in a flat pan for 48 hours.
The PDAY technician opened the right coronary artery from its origin to the point at which it turned downward along the posterior interventricular sulcus with blunt-point microdissecting scissors, dissected it from the heart, removed the epicardial fat, and fixed it in the same manner as the aorta. The other main branches of the coronary artery system were prepared for other studies.
The collection centers placed each aorta and coronary artery in a plastic bag and shipped accumulated tissues to the central laboratory each month. The central laboratory stained the arteries with Sudan IV16 and packaged each artery with its identification number in a transparent plastic bag with a slight excess of 10% formalin.
The disrobed body was weighed in the units commonly used by the local medical examiner or coroner before organs, liquid, or other material was removed from the body. Weight was recorded to the nearest one-half kilogram or nearest pound. A record was made when an amputation or other operative procedure that might alter weight appreciably was present.
The length of the cadaver, from the vertex of the cranium to the base of the heel, was measured in units commonly used by the local medical examiner or coroner. The measuring instrument was laid parallel to the body, which was in a supine position and with the inferior extremities extended. Measurements were recorded to the nearest centimeter or one-half inch.
The autopsy technician measured subcutaneous fat, including the subcutaneous tissue from the inner edge of the rectus sheath, to the nearest millimeter at a point halfway between the xyphoid process and the umbilicus. For statistical analysis, cases were classified into categories of panniculus thickness corresponding to quartiles of the entire sample.
Body Mass Index
Body mass index (BMI) was computed as weight (kilograms) divided by height (meters) squared. Cases were classified into categories of BMI <25, BMI 25 to 30, and BMI >30 kg/m2.17
Heart Weight and Left Ventricular Thickness
The prosector weighed the heart to the nearest gram after removing blood clots, measured the thickness of the left ventricle to the nearest millimeter at its obtuse margin halfway between the mitral valve and apex, and measured the thickness of the right ventricle at the conus 1 cm from the pulmonary valve. Cases were classified into categories of heart weight/height <2.5 and ≥2.5 g/cm.18
Pathologists blinded to demographic, clinical, or pathological observations and collection site evaluated the right coronary arteries and left halves of the aortas. They visually estimated the extent of intimal surface involved with fatty streaks, fibrous plaques, complicated lesions, and calcified lesions by procedures developed in the International Atherosclerosis Project.16 A fatty streak was defined as a flat or slightly elevated intimal lesion stained by Sudan IV and without other underlying changes. A fibrous plaque was a firm, elevated intimal lesion, sometimes partially or completely covered by sudanophilic deposits. A complicated lesion was a plaque with hemorrhage, thrombosis, or ulceration. A calcified lesion was an area in which calcium was detectable, either visually or by palpation, without overlying hemorrhage, ulceration, or thrombus. The sum of the percentages of surface involved with fibrous plaques, complicated lesions, and calcified lesions by gross visual grading was designated “raised lesions.” Most of the raised lesions were fibrous plaques.19 Consensus grading of lesions was the average of independent gradings by three pathologists. Intraobserver variability was assessed by repeated independent gradings of coded specimens randomly interspersed among new specimens. Agreement among observers was reported previously.19
Dissecting, Preserving, and Processing Kidney Tissue
Kidneys were stripped of perirenal fat and capsule and bisected by the PDAY staff. One section that included cortex and medulla was taken from each kidney, fixed in 10% neutral-buffered formalin, and shipped to the central laboratory. At the central laboratory, blocks perpendicular to the capsular surface were embedded in paraplast, sectioned at 6 μm, and stained with PAS-Alcian blue. The two sections of tissue represented 2 to 4 cm2 of cross-sectional area of the renal cortex.
Classification of Hypertension Status
Arterial changes associated with hypertension were measured in histologic sections of kidney by a method developed by Tracy et al.20 The grader used a microscope equipped with ×10 and ×40 objective lenses and an eyepiece ruler marked at units corresponding to 10 μm under the ×10 objective lens. The grader measured the outer diameter, from one outer media to the other, of the least axis of the elliptic profile of all arterial profiles with outer diameters of 80 to 300 μm. The grader then measured the thickness of the intima, also along the least axis, under the ×40 lens. The measurement was made in the better presented of the two opposite walls; if both were equally well presented, an average of the two was used. One observer made all measurements. An average of 36.8 arteries per case were measured (range, 6 to 69). Measurements were grouped into those derived from arteries with outer diameters of 80 through 149 μm (arteries remote from the heart) and those derived from arteries with outer diameters of 150 through 300 μm (arteries more proximal to the heart). A renal measure of hypertension (RMH) was calculated by dividing the average thickness of the intima by the average outer diameter of the artery separately for the measurements made on the smaller (remote) arteries and the measurements made on the larger (proximal) arteries.
Each case was classified as normotensive or hypertensive by an algorithm derived from an equation that predicted mean arterial pressure (MAP) from RMH and age.21 (A typographical error in the published equation was corrected by changing the sign for one coefficient from positive to negative.) The normotensive category included cases with a predicted MAP <110 mm Hg; hypertensive, those with predicted MAP ≥110 mm Hg. These cut points were selected on the basis of analysis of lengthy lifetime records of blood pressure measurements in persons whose kidneys were examined after autopsy.22 The cut points were similar, but not identical, to MAPs computed from systolic and diastolic pressures used as cut points in epidemiological surveys. For example, the frequently used definition of borderline hypertension as systolic blood pressure between 140 and 160 mm Hg and diastolic blood pressure between 90 and 95 mm Hg yields a lower limit of computed MAP (sum of systolic plus twice diastolic divided by 3) of 107 mm Hg; and the definition of hypertension as systolic blood pressure greater than 160 mm Hg and diastolic blood pressure greater than 95 mm Hg yields a limit of computed MAP of 117 mm Hg.23
In repeated classification of subjects as either normotensive or hypertensive, without knowledge of her previous grade, the single observer agreed with herself in 88% of a sample of 97 cases (κ=0.66, P<.0001).24 The observer agreed with an independent observer in 72% of a sample of 65 cases (κ=0.18, P=.0103). These findings indicate acceptable agreement.24
The relation of hypertension classification to atherosclerotic lesions was analyzed by using RMH values derived from proximal and remote arteries separately. The results were similar; therefore, only the results based on measurements of the smaller remote arteries are presented.
The associations of hypertension classification, race, and 5-year age group with percent intimal surface area involved with lesions, heart weight, heart weight/height ratio, and ventricle thicknesses were analyzed by using ANOVA.25 The linear model included the main effects of hypertension classification, race, 5-year age group, and all two-factor interactions. A logit transformation was applied to the proportion of surface area involved with lesions.26 A small constant (0.001) was added to avoid the logarithm of zero. A logarithmic transformation was applied to the heart weight, heart weight/height ratio, and ventricle thicknesses. The transformations made the data better satisfy the assumptions underlying the statistical analysis. The prevalence of cases classified as hypertensive and the prevalence of cases having 5% or more of the intimal surface involved with lesions were analyzed by using logistic regression.27 Tests of hypotheses used the likelihood ratio test. Convergence problems in the logistic regression maximum likelihood analysis of the prevalence of cases having 5% or more of the intimal surface involved with lesions necessitated a model simpler than that used for the ANOVA. Preliminary investigation indicated a main-effects model was adequate.
Distribution of Cases by Blood Pressure Classification
Table 1⇓ shows the number and percentage of cases classified as normotensive and hypertensive by race and age. There is no significant interaction between race and age. The percentage of cases classified as hypertensive is higher among blacks than among whites (blacks, 15.7%; whites, 11.7%; P=.0250).
Extent of Lesions by Blood Pressure Classification
Table 2⇓ shows the percent intimal surface area involved with lesions by age and blood pressure classification. Hypertension is not associated with fatty streaks in the aorta or the right coronary artery but is associated with raised lesions in both segments of the aorta and in the right coronary artery. Hypertension is associated with more extensive raised lesions in the thoracic aorta of blacks but not of whites (race by blood pressure interaction, P=.0006; results not shown). The effect of hypertension on raised lesions is twofold to threefold after age 30.
Prevalence of Lesions by Blood Pressure Classification
Table 3⇓ gives the estimated prevalence of cases having lesions covering 5% or more of the intimal surface by age and blood pressure classification. Prevalence of fatty streaks covering 5% or more of the aortic intimal surface area is near 100% (results not shown). Prevalence of raised lesions covering 5% or more of the intimal surface is greater in hypertensive persons than normotensive persons for the abdominal aorta and right coronary artery throughout all age groups from 15 to 34 years.
Heart Size and Blood Pressure Classification
Table 4⇓ gives the mean heart weight, heart weight/height ratio, right ventricle thickness, and left ventricle thickness by age and blood pressure classification. There is little or no association between these variables and the blood pressure classification.
Heart Size and Atherosclerosis
Table 5⇓ gives the percent intimal surface area involved with lesions by race and heart weight/height ratio. Heart weight/height ratio ≥2.5 is associated with more extensive fatty streaks and raised lesions in the right coronary artery. Whites having a heart weight/height ratio ≥2.5 have greater involvement with raised lesions in the right coronary artery than blacks. Although heart weight/height ratio is not associated with the blood pressure classification (Table 4⇑), individuals having a large heart weight/height ratio have more extensive coronary lesions.
Relation of Blood Pressure Classification to Glycohemoglobin and Adiposity
Table 6⇓ shows the prevalence of hypertension by glycohemoglobin level, BMI, and thickness of the panniculus. Cases with elevated glycohemoglobin have a higher prevalence of hypertension than those with normal glycohemoglobin levels. Cases with BMI >30 kg/m2 also have a higher prevalence of hypertension. However, as the thickness of the panniculus increases, the prevalence of hypertension decreases.
Relation of Lesions to Blood Pressure, Adiposity, and Glycohemoglobin
When the relation of blood pressure classification to extent of atherosclerotic lesions (as shown in Tables 1 through 3⇑⇑⇑) is adjusted for BMI and glycohemoglobin, the results are similar to those obtained without adjustment (results not shown). The adjustment for glycohemoglobin, which had a substantial effect on raised lesions in the 30- through 34-year age group,15 increases the estimated effect of hypertension on extent of raised lesions in the right coronary artery from about threefold to fourfold. The relation of blood pressure classification to lesions in cases with normal glycohemoglobin levels (that is, <8%) is similar to that in Table 2⇑ (results not shown).
Summary of Results
Hypertension, as measured by the intimal thickness of small renal arteries, is associated with about a twofold greater prevalence of raised lesions in the aortas and right coronary arteries of young white and black men between 15 and 34 years of age (Table 3⇑). Hypertension is associated with a greater extent of raised lesions in aortas of 30- through 34-year-old men, and in right coronary arteries of 25- through 34-year-old men (Table 2⇑). There is no consistent association of hypertension with extent of fatty streaks or with cardiac mass. Although hypertension is associated with elevated blood glycohemoglobin and adiposity, the effect of hypertension on atherosclerosis is not accounted for by those variables.
Validity of Blood Pressure Measured by Renal Intimal Thickness
From 166 subjects whose blood pressure was measured during life and whose renal vessels were measured in kidney samples obtained at autopsy, Tracy et al20 developed an equation that estimated mean arterial blood pressure. This equation took into account the age of the subject. The predictive equation was tested in 154 subjects whose blood pressures were measured in a longitudinal epidemiological study (Honolulu Heart Program) and who were later autopsied.28 The multiple correlation coefficient was .44 (P=.0001). This association is consistent with evidence indicating that increased intrarenal vascular resistance is closely associated with hypertension and that abnormal renal vasoconstriction exists in the prehypertensive state.29
Comparison With Previous Results
Many studies have reported an association of hypertension with more extensive and more severe atherosclerosis in middle-aged and older persons.5 In a small number of subjects between 7 and 24 years of age from the Bogalusa Heart Study whose blood pressures had been measured during life, Newman et al12 reported a borderline-significant association of systolic and diastolic pressure with coronary artery fibrous plaques; and later, in a larger number of cases from the same study, Berenson et al13 reported an association of systolic blood pressure with coronary artery fatty streaks in white males. The results reported here extend those limited observations and indicate that elevated blood pressure begins to accelerate the conversion of fatty streaks to raised lesions as early as the latter part of the second decade of life, even before it leads to cardiac hypertrophy.
Prevalence of Hypertension
The prevalence of hypertension among these young men, which is based on an MAP ≥110 mm Hg, is lower than the prevalence among 18- to 34-year-old men in the NHANES II survey for 1976 to 1980. That survey, using thresholds of 140 mm Hg systolic and 90 mm Hg diastolic (equivalent to an MAP of ≈107 mm Hg), found that 16% of 18- to 24-year-old and 21% of 25- to 34-year-old white men were hypertensive and that 11% of 18- to 24-year-old (small number of cases) and 23% of 25- to 34-year-old black men were hypertensive.30 The prevalence rates had declined since the NHANES I survey of 1971 to 1975.31 Thus, the prevalence of hypertension predicted by renal artery intimal thickness is similar to the prevalence based on measuring blood pressures in samples of the living population.
Association of Blood Pressure With Heart Size
Most32 33 34 but not all35 36 echocardiographic studies in children and adolescents have shown correlations of heart size with blood pressure. Most echocardiographic surveys of adults have obtained similar results.37 38
However, in the largest single population-based study of 946 healthy subjects 18 through 38 years of age, there was no association of borderline hypertension with left ventricular mass, although there were numerous associations with cardiac functional variables.36 Consequently, the lack of a positive association of heart weight, heart weight/height ratio, or ventricular wall thickness with predicted blood pressure classification (Table 4⇑) should not be surprising. This observation suggests that renal artery intimal thickness, which is strongly associated with atherosclerotic raised lesions, may be a marker for an early stage of elevated arterial blood pressure or a precursor of elevated arterial blood pressure, as suggested by Tracy et al.21 It is also possible that both renal arterial intimal hyperplasia and whatever processes convert fatty streaks to fibrous plaques may result from the same humoral agent involved in the early natural history of hypertension.
Intimal thickness of small renal arteries, an anatomic marker for hypertension, is strongly associated with raised lesions (mainly fibrous plaques) of the aortas and right coronary arteries of young adults. The effect of hypertension on atherosclerosis begins in the second decade of life and precedes an effect on cardiac mass. The results suggest that the early stages of hypertension accelerate atherogenesis primarily by accelerating the conversion of fatty streaks to fibrous plaques.
Robert W. Wissler, PhD, MD, University of Chicago; Associate Director: Abel L. Robertson, Jr, MD, PhD, The University of Illinois.
J. Fredrick Cornhill, DPhil, The Ohio State University; Henry C. McGill, Jr, MD, Southwest Foundation for Biomedical Research; C. Alex McMahan, PhD, The University of Texas Health Science Center at San Antonio; Abel L. Robertson, Jr, MD, PhD, The University of Illinois; Jack P. Strong, MD, Margaret C. Oalmann, Dr PH, Gray T. Malcolm, PhD, Louisiana State University Medical Center; Robert W. Wissler, PhD, MD, University of Chicago.
Standard Operating Protocol and Manual of Procedures Committee Chair
Margaret C. Oalmann, Dr PH, Louisiana State University Medical Center.
University of Alabama, Birmingham. Department of Medicine: principal investigator, Steffen Gay, MD; coinvestigators, Renate E. Gay, MD, Guoquiang Huang, MD (HL-33733). Department of Biochemistry: principal investigator, Edward J. Miller, PhD; coinvestigators, Donald K. Furuto, PhD, Margaret S. Vail, Annie J. Narkates (HL-33728).
Albany Medical College, NY. Principal investigator, Assad Daoud, MD; coinvestigators, Adriene S. Frank, PhD, Mary A. Hyer, E. Carol McGovern (HL-33765).
Baylor College of Medicine, Houston, Tex. Principal investigator, Louis C. Smith, PhD; coinvestigator, Faith M. Strickland, PhD (HL-33750).
University of Chicago, Ill. Principal investigator, Robert W. Wissler, PhD, MD; coinvestigators, Dragoslava Vessellinovitch, DVM, MS, Akio Komatsu, MD, PhD, Yoshiaki Kusumi, MD, Gregory M. Culen, DPM, Alyna Chien, BA, Alexis Demopoulos, BA, Gertrud Friedman, BA, R. Timothy Bridenstein, MS, Robert J. Stein, MD, Robert H. Kirschner, MD, Manuela Bekermeier, ASCP, Blanche Berger, ASCP, Laura Hiltscher, ASCP (HL-33740, HL-45715).
The University of Illinois, Chicago. Principal investigator, Abel L. Robertson, Jr, MD, PhD; coinvestigators, Robert J. Stein, MD, Edmund R. Donoghue, MD, Robert J. Buschmann, PhD, Yoshihisa Katsura, MD, Tae Lyong An, MD, Eupil Choi, MD, Nancy Jones, MD, Mitra S. Kalelkar, MD, Yuksel Konakci, MD, Barry Lifschultz, MD, V. Ramana Gumidyala, MD, Rose M. Harper, BS, Francis Norris, HTL (ASCP) (HL-33758).
Louisiana State University Medical Center, New Orleans. Principal investigator, Jack P. Strong, MD; coinvestigators, Gray T. Malcom, PhD, William P. Newman, III, MD, Margaret C. Oalmann, Dr PH, Paul S. Roheim, MD, Ashim K. Bhattacharyya, PhD, Miguel A. Guzman, PhD, Ali A. Hatem, MD, Conrad A. Hornick, PhD, Carlos D. Restrepo, MD, Richard E. Tracy, MD, PhD, Cecilia C. Breaux, MS, Stephanie E. Hubbard, Cynthia S. Zsembik, DeAnne G. Gibbs, Dana A. Troxclair (HL-33746, HL-45720).
University of Maryland, Baltimore. Principal investigator, Wolfgang Mergner, MD, PhD; coinvestigators, James H. Resau, PhD, Robert D. Vigorito, MS, PA, Q-C Yu, MD, J. Smialek, MD (HL-33752, HL-45693).
Medical College of Georgia, Augusta. Coprincipal investigators, A. Bleakley Chandler, MD, Raghunatha N. Rao, MD; coinvestigators, D. Greer Falls, MD, Ross G. Gerrity, PhD, Benjamin O. Spurlock, BA; associate investigators, Kalish B. Sharma, MD, Joel S. Sexton, MD; research assistants, K.K. Smith, HT (ASCP), G.W. Forbes (HL-33772).
University of Nebraska Medical Center, Omaha. Principal investigator, Bruce M. McManus, MD, PhD; coinvestigators, Jerry W. Jones, MD, Todd J. Kendall, MS, Jerrold A. Remmenga, BS, William C. Rogler, BS (HL-33778).
The Ohio State University, Columbus. Principal investigator, J. Fredrick Cornhill, DPhil; coinvestigators, William R. Adrion, MD, Patrick M. Fardel, MD, Brian Gara, MS, Edward Herderick, John Meimer, MS, Larry R. Tate, MD (HL-33760, HL-45694).
Southwest Foundation for Biomedical Research, San Antonio, Tex. Principal investigator, James E. Hixson, PhD (HL-39913).
The University of Texas Health Science Center at San Antonio. Principal investigator, C. Alex McMahan, PhD; coinvestigators, George M. Barnwell, PhD (deceased), Henry C. McGill, Jr, MD, Yolan Marinez, MA, Thomas J. Prihoda, PhD, Herman S. Wigodsky, MD, PhD (HL-33749, HL-45719).
Vanderbilt University, Nashville, Tenn. Principal investigator, Renu Virmani, MD; coinvestigators, James B. Atkinson, MD, PhD, Charles W. Hartland, MD, Linda Gleaves, RA, Crystal Gleaves, HT, Manik Paul, RA (HL-33770, HL-45718).
West Virginia University Health Sciences Center, Morgantown. Principal investigator, Singanallur N. Jagannathan, PhD; coinvestigators, Bruce Caterson, PhD, James Frost, MD, K. Murali K. Rao, MD, Syamala Jagannathan, Peggy Johnson, Nathaniel F. Rodman, MD (HL-33748).
Grants from the National Institutes of Health (National Heart, Lung, and Blood Institute) supporting this research are listed after the name of the recipient in the “Appendix.”
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