(Circulation. 1997;96:1745-1749.)
© 1997 American Heart Association, Inc.
Articles |
High Homocysteine Levels Are Independently Related to Isolated Systolic Hypertension in Older Adults
From the Department of Epidemiology (K.S.-T., C.Z.-J.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa; and the Vitamin Bioavailability Laboratory (A.B., J.S.), Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts New England Medical Center, Boston, Mass.
Correspondence to Kim Sutton-Tyrrell, DrPH, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St, Pittsburgh, PA 15261. E-mail Tyrrell{at}edc1.gsph.pitt.edu
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Abstract |
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Background The association between homocysteine and isolated systolic hypertension in older adults was evaluated using a case-control design, and the relationship between homocysteine and clinical or subclinical atherosclerosis was explored.
Methods and Results Cases were 179 adults 
60 years with a
systolic blood pressure of 160 mm Hg and
diastolic blood pressure <90 mm Hg. One hundred
seventy-one control subjects had the same criteria except
systolic blood pressures were <160 mm Hg. All had normal
creatinine levels. Homocysteine levels were performed on
fasting blood samples that had been stored at -70°C.
Atherosclerosis was defined as either a history of
clinical disease, an internal carotid stenosis of 40% by
duplex scan, or an ankle/arm pressure ratio of <0.9. The median
homocysteine value was 11.5 µmol/L for cases and 9.9 for control
subjects (P<.001). After control for potential confounders,
homocysteine remained significantly associated with systolic
hypertension (P=.019). For the hypertensive group, there was
no apparent association between level of homocysteine and prevalence of
atherosclerosis. However, among the normotensive group,
the prevalence of atherosclerosis went from 22% in the
lowest quintile of homocysteine values to 53% in the fifth quintile,
with an odds ratio of 4.1 (fifth quintile in comparison to the first,
P<.05). After adjustment for age, sex, systolic
blood pressure, cholesterol, and smoking, this odds ratio
increased to 6.4 (P<.01).
Conclusions Elevated levels of homocysteine may be related to the cause of isolated systolic hypertension in some individuals. In normotensive older adults, homocysteine appears to be an independent risk factor for atherosclerosis.
Key Words: aging • atherosclerosis • elasticity • hypertension • peripheral vascular disease
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Introduction |
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Homocysteine is a sulfhydryl amino acid; its precursor, the essential amino acid methionine, is derived from dietary protein.1 In 1969, McCully2 first linked severe hyperhomocysteinemia to precocious arteriosclerosis in children with distinct inborn errors of metabolism. During the intervening 27 years, subsequent studies have associated more mild-to-moderate elevations in homocysteine with angiographically diagnosed coronary disease,3 MI,4 cerebrovascular disease,5 carotid intima-media thickness,6 and arterial disease of the lower extremities.7 A recent review8 summarized the convincing body of evidence associating elevated homocysteine levels and vascular disease. Based on these pooled observational data, the authors concluded that each 5-µmol/L increase in total homocysteine levels conferred the same increase in risk for vascular disease as a 20-mg/dL increase in total cholesterol level.
Metabolism of homocysteine is dependent on specific B vitamins that function as enzymatic cofactors or substrates.1 It has further been observed in vitro that the activity of the key homocysteine-metabolizing enzyme cystathionine synthase may decline with age.9 Epidemiological studies have demonstrated a negative correlation between homocysteine and plasma vitamin B levels3 10 and a strong positive correlation with age,10 11 which are consistent with these experimental observations. Creatine/creatinine production is directly associated with S-adenosyl-homocysteine/homocysteine production,12 accounting for the positive correlation between creatinine and homocysteine levels observed within a creatinine range reflective of normal renal function.13 Finally, recent in vivo evidence has been provided that the kidneys normally play a major role in plasma homocysteine metabolism,14 which explains the refractory mild-to-moderate hyperhomocysteinemia commonly observed in end-stage renal disease.15 16
Definitive, controlled homocysteine-lowering trials for the potential reduction of vascular disease outcomes in adult populations have not been conducted. However, severe hyperhomocysteinemia such as that found in homozygous cystathionine synthase deficiency has been treated with methionine restriction and supraphysiological doses of vitamin B-6, vitamin B-12, folate, and betaine.17 Such treatment lowers homocysteine levels and, more importantly, reduces the incidence of atherothrombotic events and mortality in these patients.18
The mechanism by which hyperhomocysteinemia is atherogenic is unknown. Several studies have reported a positive association between homocysteine levels and both SBP and DBP.18 19 20 Thus, one mechanism of atherogenesis could be through elevations in blood pressure. To evaluate the relationship between homocysteine and SBP, homocysteine levels were measured in 179 subjects enrolled at the Pittsburgh center of the SHEP and in 171 age-similar normotensive control subjects. All subjects underwent an evaluation for subclinical peripheral atherosclerosis, including carotid ultrasound and measurement of ankle blood pressures. Thus, in this report, we also examined the relationship between homocysteine and clinical and subclinical atherosclerosis.
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Methods |
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The SHEP was a multicenter randomized clinical trial designed to test the efficacy of the treatment of ISH in adults aged 60 and older. Screening for the study took place at retirement centers, churches, and other locations at which predominantly healthy elderly adults could be found. Qualifications for entry into the study included age
60 years,
SBP of 160 to 219 mm Hg, and DBP of <90 mm Hg. Exclusions
included recent MI, stroke with residual paresis, uncontrolled CHF,
peripheral arterial disease with evidence of
tissue injury or loss, TIAs with associated carotid bruit,
contraindication to study medications, and treatment with insulin.
Complete screening techniques and exclusion criteria have been
reported.21 22 Data were collected on a total of 187 SHEP
participants from January 1989 to November 1990. In addition, a group
of 187 participants with SBP of <160 mm Hg were recruited using
the same screening mechanism from February 1989 to November 1991. All
SHEP exclusion criteria were applied to these subjects except that SBP
was required to be <160 mm Hg and DBP was required to be
<90 mm Hg. To ensure normal renal function, any subjects with a
creatinine of 1.8 mg/dL (159 mmol/L)
were excluded from this analysis. All participants signed an
informed consent that was approved by the Institutional Review Board of
the University of Pittsburgh.
Duplex scanning was used to evaluate carotid disease. Scans were
performed at the Peripheral Vascular Diagnostic
Laboratory located in Montefiore University Hospital, Pittsburgh, Pa,
using a Diasonics DRF 400 duplex scanner with a 10-MHz imaging probe
and a 4.5-MHz Doppler. Doppler measures of blood flow velocity
were used to determine the presence of a carotid stenosis. The
ICA/CCA ratio is a measure of stenosis that controls for
intersubject variation.23 ICA stenosis was defined
as an ICA/CCA ratio of 1.4, based on studies comparing velocity
ratios in normal patients with ratios in patients with angiographically
documented carotid stenosis.24 25 This corresponds
to a luminal diameter reduction of 
40 to 50%.26
Although this definition does not always represent disease
important enough for surgical intervention, it represents the
lowest level of disease that can be reliably detected with Doppler.
The Doppler measures used to determine stenosis were highly
reproducible in participants who had duplicate scans on the same
day.27
The ratio of ankle-to-arm SBP, commonly called the AAI, was used to determine the presence or absence of LEAD. This method has been found to be reliable for detecting stenosis or occlusion in the proximal arteries of the legs.25 28 29 A resting AAI value of <90 in either leg was considered indicative of LEAD.
When evaluating the relationship between
atherosclerosis and homocysteine,
atherosclerosis was defined as either a history of
clinical disease (MI, stroke, TIA, vascular surgery, angina, or CHF),
an ICA stenosis of 40% by Doppler, or an AAI of
<0.9.
Homocysteine measures were performed on fasting blood samples that had been stored at -70°C. Total homocysteine in plasma was determined at the Vitamin Bioavailability Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts New England Medical Center using a modified procedure of Araki and Sako.30 A 100-µL plasma sample is treated with tributylphosphine to reduce the S-S bonds resulting in free homocysteine. After protein precipitation, the supernatant fraction is alkalinized and reacted with SBDF (7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate) a fluorescence probe for SH groups. Homocysteine is then determined after reverse-phase HPLC using isocratic elution that lasts 7.5 minutes (compared with 40 minutes in the original procedure). Interassay coefficient of variation was 8%.
Statistical Methods
Proportions were compared using the 
2test,
and mean values were compared using a t test when data were
normally distributed and a Wilcoxon test otherwise. Independent
associations with the presence or absence of ISH were determined using
logistic regression. Linear regression was used to determine what
baseline characteristics were associated with homocysteine. A
reciprocal transformation was used to obtain a normal homocysteine
distribution. Because the creatine/creatinine
metabolic pathway is coupled to the
S-adenosyl-homocysteine/homocysteine metabolic pathway,
there is a high degree of colinearity between creatinine
and homocysteine. Because of this and because creatinine is
not in the causal pathway between homocysteine and hypertension or
homocysteine and atherosclerosis,
creatinine was not included in the regression models.
When evaluating the relationship between homocysteine and atherosclerosis, the homocysteine distribution was divided into quintiles. Quintile 1 consisted of homocysteine values of <8.5 µmol/L, quintile 2 included values between 8.6 and 9.8 µmol/L, quintile 3 included values between 9.9 and 11.4 µmol/L, quintile 4 included values between 11.5 and 13.7, and quintile 5 included values of > 13.7 µmol/L. Logistic regression was used to calculate odds ratios comparing the odds of atherosclerosis in each quintile (2 through 5) to the odds of atherosclerosis in the first quintile.
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Results |
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Homocysteine values were available for 356 participants, but 6 participants with creatinine levels of
1.8 mg/dL
(159 mmol/L) were excluded. Of the remaining 350, 179 were
patients with ISH and 171 were normotensive control subjects. For the
entire group, homocysteine values were not normally distributed and
ranged from 4.02 to 98.23 µmol/L, with a median value of
10.7 µmol/L. The median homocysteine value for cases was
11.5 µmol/L compared with 9.9 for control subjects
(P<.001) (Fig 1
). When
subjects were classified according to stage of hypertension using the
JNC V criteria,31 median homocysteine values increased
with each stage. The median homocysteine was 9.7 µmol/L
for normotensive subjects (SBP <140 mm Hg), 10.4
µmol/L for stage I (SBP 140 to 159 mm Hg), 11.3
µmol/L for stage II (SBP 160 to 179 mm Hg), and
13.0 µmol/L for stage III (SBP 180 mm Hg)
(P<.001).
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The baseline characteristics between cases and control subjects were
substantially different (Table 1). In
comparison to control subjects, patients were older
(P<.001), had higher body mass index (P<.001),
lower HDL levels (P=.006), and higher
triglyceride levels (P=.01). Logistic regression
was used to determine whether homocysteine was associated with ISH
independent of these factors. In a model controlling for age, sex, body
mass index, HDL-3, smoking, cholesterol, and alcohol use
(Table 2), homocysteine remained
significantly associated with systolic hypertension
(P=.019). Each 10-µmol/L increment in homocysteine
increased the odds of systolic hypertension by 2.
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Linear regression was used to determine what baseline characteristics were associated with homocysteine; these were older age (P<.01), male sex (P=.02), higher SBP (P<.01), and greater number of pack-years of smoking (P=.05). Within the hypertensive group, treatment with diuretics and/or ß-blockers was not associated with elevated homocysteine levels.
The relationship between homocysteine and
atherosclerosis was next evaluated. For the entire
group, a history of clinical disease was present in 16.6%, ICA
stenosis was present in 15.3%, a low AAI was present
in 16.8%, and any of these conditions was present in 39.1%. The
prevalence of carotid stenosis and a low AAI was significantly
higher among systolic hypertensives than control subjects
(Table 3, P<.001). For both
hypertensive and normotensive groups, the prevalence of any
atherosclerosis by quintile of homocysteine is
presented in Fig 2. For the
hypertensive group, there was no apparent association between level of
homocysteine and prevalence of atherosclerosis.
However, among the normotensive group, the prevalence of
atherosclerosis went from 22% in the lowest quintile
of homocysteine values to 53% in the fifth quintile, with an odds
ratio of 4.1 (fifth quintile in comparison to the first,
P<.05). After adjustment for age, sex, SBP,
cholesterol, and smoking, this odds ratio increased to 6.4
(P<.01).
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Discussion |
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In this study, we found homocysteine to be strongly and independently associated with ISH. Elevated homocysteine may thus be part of the cause of ISH in some older individuals. The primary underlying disorder in ISH is stiffening of the central arteries. There are a number of pathophysiological mechanisms that might explain a relationship between homocysteine and vascular stiffness. There is evidence that elevated homocysteine is related to impaired nitric oxide–mediated relaxation of the vessel32 and to smooth muscle cell proliferation.33 Perhaps the most interesting possibility is that elevated homocysteine may stimulate elastinolytic processes in the arterial wall. Rolland et al33 used a high-methionine diet to model hyperhomocysteinemia in Götingen minipigs. In addition to hyperhomocysteinemia, these pigs developed both systolic and diastolic hypertension. Histological examination of the arterial vessels revealed major elastic lamina dislocations, including splitting and fragmentation of the elastic fibers. In addition, hypertrophy and reorientation of smooth muscle cells were observed. Elastic fiber splitting occurred primarily in the presence of focalized smooth muscle cell hyperplasia. The authors point out that dividing muscle cells are known to have the capacity to release elastases and collagenases.34 35 A biochemical analysis of elastin contained in the subrenal aorta wall of the minipigs showed significantly lower levels of elastin in the hyperhomocysteinemic minipigs compared with control animals.36 Further evidence for this hypothesis comes from an in vitro study of smooth muscle cells37 showing that homocysteine induces synthesis and secretion of serine elastase from vascular cells. If elevated homocysteine does in fact cause a stiffening of the arterial wall, this may be one mechanism by which it may lead to atherosclerosis.
In this population of older adults, homocysteine was found to be related to atherosclerosis only among normotensive individuals. ISH was such a potent risk factor for atherosclerosis that elevated homocysteine appeared to confer no added risk within the hypertensive group. However, elevated homocysteine may contribute to causal pathways for the development of both hypertension and atherosclerosis, rendering it more difficult to discern an independent effect of homocysteine on atherosclerosis within a group of hypertensive individuals. Among the normotensive group, the association with atherosclerosis was primarily seen in the top 20% to 25% of the homocysteine distribution. This is consistent with other reports.6 38
Five prospective studies4 39 40 41 42 examined the association between homocysteine levels and the incidence of MI and/or stroke. Three of these investigations4 41 42 reported strong, independent associations between elevated homocysteine and incident MI4 41 or stroke.42 One study reported a marginal association with incident stroke, essentially confined to events occurring before age 60 years,40 and one39 reported no association with either incident MI or incident stroke. In sum, these initial prospective studies appear to support the contention that homocysteine is an independent risk factor for the development of atherosclerotic outcomes. Additional longitudinal studies are required to confirm whether the putative association between homocysteine and incident atherosclerosis persists in cohorts that include adequate numbers of women and minorities. Ultimately, controlled clinical intervention trials demonstrating that lowering homocysteine levels reduces the incidence of atherosclerotic events will be necessary to substantiate the homocysteine-atherosclerosis hypothesis.
In conclusion, elevated levels of homocysteine may be related to the cause of ISH in some individuals. A possible mechanism for this is through a degradation of elastin in the arterial wall, resulting in increased arterial stiffness. In normotensive older adults, homocysteine appears to be a risk factor for atherosclerosis. This association did not hold for hypertensive individuals, most likely because they are already at substantially increased risk.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-39871 and HL-50439. This work was done during the tenure of an Established Investigatorship from the American Heart Association (Dr Sutton-Tyrrell).
Received December 31, 1996; revision received April 9, 1997; accepted April 18, 1997.
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 K. Sutton-Tyrrell, R. Wildman, A. Newman, and L. H. Kuller Extent of Cardiovascular Risk Reduction Associated With Treatment of Isolated Systolic Hypertension Arch Intern Med, December 8, 2003; 163(22): 2728 - 2731. [Abstract] [Full Text] [PDF]
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 R. Rodrigo, W. Passalacqua, J. Araya, M. Orellana, and G. Rivera Homocysteine and Essential Hypertension J. Clin. Pharmacol., December 1, 2003; 43(12): 1299 - 1306. [Abstract] [Full Text] [PDF]
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 Z. Bagi, C. Cseko, E. Toth, and A. Koller Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2277 - H2283. [Abstract] [Full Text] [PDF]
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 N. Inamoto, T. Katsuya, Y. Kokubo, T. Mannami, T. Asai, S. Baba, J. Ogata, H. Tomoike, and T. Ogihara Association of Methylenetetrahydrofolate Reductase Gene Polymorphism With Carotid Atherosclerosis Depending on Smoking Status in a Japanese General Population Stroke, July 1, 2003; 34(7): 1628 - 1633. [Abstract] [Full Text] [PDF]
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H. S. Sood, M. J. Hunt, and S. C. Tyagi Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L333 - L341. [Abstract] [Full Text] [PDF]
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 U. Lim and P. A. Cassano Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., December 15, 2002; 156(12): 1105 - 1113. [Abstract] [Full Text] [PDF]
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 C. D. Bushnell and L. B. Goldstein Homocysteine testing in patients with acute ischemic stroke Neurology, November 26, 2002; 59(10): 1541 - 1546. [Abstract] [Full Text] [PDF]
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 M. J. Hunt and S. C. Tyagi Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1073 - C1079. [Abstract] [Full Text] [PDF]
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H. Adachi, Y. Hirai, Y. Fujiura, H. Matsuoka, A. Satoh, and T. Imaizumi Plasma Homocysteine Levels and Atherosclerosis in Japan: Epidemiological Study by Use of Carotid Ultrasonography Stroke, September 1, 2002; 33(9): 2177 - 2181. [Abstract] [Full Text] [PDF]
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 C.-H. Yen and Y.-T. Lau Vascular Responses in Male and Female Hypertensive Rats With Hyperhomocysteinemia Hypertension, September 1, 2002; 40(3): 322 - 328. [Abstract] [Full Text] [PDF]
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R. A.J.M. van Dijk, J. A. Rauwerda, M. Steyn, J. W.R. Twisk, and C. D.A. Stehouwer Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 2072 - 2079. [Abstract] [Full Text] [PDF]
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M. Domanski, J. Norman, M. Wolz, G. Mitchell, and M. Pfeffer Cardiovascular Risk Assessment Using Pulse Pressure in the First National Health and Nutrition Examination Survey (NHANES I) Hypertension, October 1, 2001; 38(4): 793 - 797. [Abstract] [Full Text] [PDF]
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 A. M. Dart and B. A. Kingwell Pulse pressure--a review of mechanisms and clinical relevance J. Am. Coll. Cardiol., March 15, 2001; 37(4): 975 - 984. [Abstract] [Full Text] [PDF]
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L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [Abstract] [Full Text] [PDF]
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L. A. Bortolotto, M. E. Safar, E. Billaud, C. Lacroix, R. Asmar, G. M. London, and J. Blacher Plasma Homocysteine, Aortic Stiffness, and Renal Function in Hypertensive Patients Hypertension, October 1, 1999; 34(4): 837 - 842. [Abstract] [Full Text] [PDF]
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P. M. Kanani, C. A. Sinkey, R. L. Browning, M. Allaman, H. R. Knapp, and W. G. Haynes Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans Circulation, September 14, 1999; 100(11): 1161 - 1168. [Abstract] [Full Text] [PDF]
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A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]
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T. J. Smilde, F. W. P. J. van den Berkmortel, G. H. J. Boers, H. Wollersheim, T. de Boo, H. van Langen, and A. F. H. Stalenhoef Carotid and Femoral Artery Wall Thickness and Stiffness in Patients at Risk for Cardiovascular Disease, With Special Emphasis on Hyperhomocysteinemia Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1958 - 1963. [Abstract] [Full Text] [PDF]
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V. S. Mujumdar, C. M. Tummalapalli, G. M. Aru, and S. C. Tyagi Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR Am J Physiol Cell Physiol, May 1, 2002; 282(5): C1009 - C1015. [Abstract] [Full Text] [PDF]
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