Circadian rhythm of serum total homocysteine in men

Circadian rhythm of serum total homocysteine in men

pathetic tone, or reversal of endothelial dysfunction.8 Other independent predictors of poor outcome included male gender, history of CHF, higher seru...

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pathetic tone, or reversal of endothelial dysfunction.8 Other independent predictors of poor outcome included male gender, history of CHF, higher serum blood urea nitrogen, lower serum sodium, and ⬎5 discharge diagnoses. A history of systemic hypertension conferred a better outcome. Our study has several limitations. It is a retrospective chart review. Most patients did not have documentation of left ventricular function, although most had radiographic evidence of cardiomegaly or CHF. However, the strength of our study is that to our knowledge, this is the first report that has demonstrated the generalizability of the beneficial effect of ACE inhibitor therapy early after discharge in this older population. Our major finding was that older patients with CHF who were discharged on an ACE inhibitor were significantly less likely to die or be readmitted within 30 days than patients not receiving an ACE

inhibitor. Our data support aggressive treatment of older patients with CHF. 1. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting

enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450 –1456. 2. Wang R, Mouliswar M, Denman S, Kleban M. Mortality of the institutionalized old-old hospitalized with congestive heart failure. Arch Intern Med 1998; 158:2464 –2468. 3. Burns RB, McCarthy EP, Moskowitz MA, Ash A, Kane RL, Finch M. Outcomes for older men and women with congestive heart failure. J Am Geriatr Soc 1997;45:276 –280. 4. Krumholz HM, Parent EM, Tu N, Vaccarino V, Wang Y, Radford MJ, Hennen J. Readmission after hospitalization for congestive heart failure among Medicare beneficiaries. Arch Intern Med 1997;157:99 –104. 5. Havranek E, Abrams F, Stevens E, Parker K. Determinants of mortality in elderly patients with heart failure: the role of angiotensin-converting enzyme inhibitors. Arch Intern Med 1998;158:2024 –2028. 6. Rothman KJ. Modern Epidemiology. Boston: Little, Brown, 1986. 7. Sueta CA, Chowdhury M, Boccuzzi SJ, Smith SC Jr, Alexander CM, Londhe A, Lulla A, Simpson RJ Jr. Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease. Am J Cardiol 1999;83:1303–1307. 8. Mancini GBJ, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard ACG, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: the TREND (Trial on Reversing Endothelial Dysfunction) Study. Circulation 1996;94:258 –265.

Circadian Rhythm of Serum Total Homocysteine in Men W. Fraser Bremner, MD, PhD, Earl W. Holmes, PhD, Eugene L. Kanabrocki, PhD, Ramon C. Hermida, PhD, Diana Ayala, MD, PhD, Jean Garbincius, MS, Jane L.H.C. Third, MD, May D. Ryan, RN, MS, Margaret Johnson, MS, Sharon Foley, MS, Parvez Shirazi, MD, Bernard A. Nemchausky, MD, and Lawrence E. Scheving, PhD omocysteine is a sulfur-containing amino acid involved in vitamin B12 and folate metabolism. H High serum concentrations have been shown to represent an independent risk factor for atherosclerotic clinical events, particularly myocardial infarction and stroke.1 The current hypothesis to explain this finding is that homocysteine in moderate to high concentrations damages the endothelial lining of arteries by as yet ill-defined biochemical effects,2 resulting in enhanced plaque production, particularly during thrombotic events. Moderate homocysteine levels are common in many countries and may have a significant impact on national atherosclerotic burdens. Among fasting subjects, a normal serum level is considered to be 5 to 15 ␮mol/L. Higher levels are classified as moderate (16 to 30 ␮mol/L), intermediate (31 to 100 From the MacNeal Cardiology Group, Berwyn; Department of Pathology, Loyola University, Stritch School of Medicine, Maywood; and Department of Veterans Affairs, Edward Hines, Jr., Hospital, Hines, Illinois; John L McClellan Memorial Hospital, Little Rock, Arkansas; and Bioengineering and Chronobiology Laboratories, University of DeVigo, Vigo, Spain. This study was supported in part by John H. Olwin, MD, and the Vascular Disease Research Foundation, Skokie, Illinois. Dr. Bremner’s address is: MacNeal Cardiology Group, 3231 South Euclid Avenue, Berwyn, Illinois 60402. Manuscript received March 17, 2000; revised manuscript received and accepted May 22, 2000. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 November 15, 2000

␮mol/L), and severe (⬎100 ␮mol/L) hyperhomocysteinemia.3 Vitamin B6, vitamin B12, and folic acid lower serum homocysteine levels, and because they are inexpensive and safe, there has been pressure to develop national intervention programs. However, the results of several large-scale interventional studies studying this hypothesis are still pending; these studies are not expected to be complete for several years.4 The present study was undertaken to evaluate the circadian characteristics of serum total homocysteine concentration in a group of 7 clinically healthy men and in 5 diabetic subjects. Diabetic subjects were included in the study because they have a profoundly increased risk of developing atherosclerotic complications, a risk that is incompletely explained by standard risk factors (e.g., smoking, hypertension, and dyslipidemia). •••

Twelve men, mean age 61 years (range 51 to 77), volunteered for this study. None were taking folate or B vitamins, which lower homocysteine levels. None were taking diuretics5 and none had irritable bowel disease,6 both of which have been shown to alter homocysteine levels. No diabetic subject was on metformin, which raises homocysteine concentrations.7 No subject was hypothyroid, had high creatinine lev0002-9149/00/$–see front matter PII S0002-9149(00)01181-4


(24.4 to 28.6) and 5 diabetic subjects with average body mass index of 36.1 kg/m2 (33.3 to 40.3). Serum total homocysteine was determined by immunoassay using the IMX Analyzer (Abbott Laboratories, Lake Bluff, Illinois). The IMX Analyzer measures homocysteine levels as slightly higher than high-pressure liquid chromatography, but the correlation coefficient comparing identical samples measured by both methods was very strong.12 The data were analyzed on a microcomputer, Power Macintosh G3 (Cupertino, California), using Chronolab (Vigo, Spain), a software package for biologic time series analysis by linear least-squares estimation. Circadian characteristics of total homocysteine were established by population multiple component analysis—a method designed for analysis of nonsinusoidal hybrid data.13 A p value for rejection of the zero amplitude assumption was determined, with rhythm detection considered statistically significant if the p value was FIGURE 1. Circadian variation in serum total homocysteine in health and diabetic men. ⬍0.05. The arrows from the upper horizontal axis indicate the circadian orthophas for each Serum homocysteine concentragroup. AMP ⴝ amplitude, half the distance between the maximum and the minimum of tions of the subjects are listed in the fitted curve; BATHYPH ⴝ bathyphase, lag from the same reference time point of the Table 1. The mean homocysteine lowest value in the curve fitted to the data (in hours to minutes); CI ⴝ confidence interlevels of the diabetic subjects, howvals; ORTHOPH ⴝ orthophase, lag from a defined reference time point (here, local ever, were only slightly higher than midnight) of the peak time in the curve fitted to the data (in hour to minutes). Clinically those of the healthy subjects healthy subjects (H — H); men with diabetes (D - - - D). *p <0.05, not adjusted for multiple testing (t test). (12.2 ⫾ 1.2 vs 11.7 ⫾ 1.2 ␮mol/L). The population multiple compoels, or had Alzheimer’s disease, all of which have nent analysis indicated a statistically significant circabeen correlated with high homocysteine levels.8 –10 No dian rhythm, which included only the fundamental subject drank beer, because beer contains folate, component with period of 24 hours in homocysteine for obese men with diabetes (p ⫽ 0.035), but not for which reduces homocysteine levels.11 The subjects were housed in a hospital ward. The clinically healthy subjects (p ⫽ 0.343), possibly due to dark phase of the light-dark cycle was from 10 P.M. to larger interindividual differences among subjects in 6:30 A.M. with brief awakening for sampling at 1:00 this latter group. Comparison of rhythm characteristics indicated similar circadian parameters for both A.M. and 4:00 A.M. hours. Blood samples were drawn at 3-hour intervals (8/24 hours), were immediately healthy and diabetic men (p ⬎0.294). A statistically significant 24-hour rhythm (p ⫽ 0.030) was evident in centrifuged, serum separated, and frozen at –25°C. Subjects ate general hospital meals at 4:30 P.M., data from 12 subjects with acrophase (peak time) at 10:36 P.M. hours and a Midline Estimating Statistic of 7:30 A.M., and 1:30 P.M. hours. The meals consisted of Rhythm (MESOR) of 12.31 ␮mol/L (Figure 1). 2,298 calories: 75 g of protein (14% of total calories); ••• 322 g of carbohydrates (50%); 98 g of fat (36%); Among the growing number of potential risk facvitamin B6 (113%); vitamin B12 (269%); and folate tors for atherosclerotic sequelae, moderately elevated (123%), which is the daily recommended diet in the levels of homocysteine have attracted particular interUnited States. est because they are common in high-risk populations Physical measurements were taken and the body (and in subjects who have cardiovascular damage mass index calculated as kilograms per square meters. despite a dearth of the more standard risk factors) and For the purpose of data analysis, the 12 men were because B vitamins and folate are potentially simple divided into 2 groups of 7 nondiabetic healthy con- interventions that can lower homocysteine levels. The trols with average body mass index of 26.9 kg/m2 risk factor is not limited to a particular range, but is 1154 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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occur. High-density lipoprotein cholesterol peaks in the late morning. Triglycerides have been shown Data Limits (␮mol/L) to be an independent risk factor for Limits coronary events in the Procam Subjects Age (yrs) Low High Range of Change (%) (mean ⫾ SE) study, where allowance was made Controls for the other lipid and lipoprotein 1 39 10.9 12.0 10 11.5 ⫾ 0.5 risk factors in a multivariate analy2 54 11.6 13.5 16 12.2 ⫾ 0.9 3 55 9.9 22.4 106 12.4 ⫾ 4.5 sis.18 Triglycerides were deter4 55 8.0 10.0 25 8.6 ⫾ 0.8 mined to be a risk factor, but they 5 55 8.4 9.5 13 8.9 ⫾ 0.4 were not synchronized to homocys6 70 11.8 14.0 18 12.9 ⫾ 0.8 teine levels. That study was sup7 76 14.9 16.3 9 15.3 ⫾ 0.5 Average 58 10.8 13.9 31 11.7 ⫾ 1.2 ported by a study of 100 healthy and 529 atherosclerotic subjects in Diabetic 8 52 13.3 15.5 16 14.5 ⫾ 0.7 Prague, Czechoslovakia, where 9 55 8.5 12.4 46 10.1 ⫾ 1.3 correlation coefficients between 10 63 8.1 14.4 78 10.0 ⫾ 2.0 plasma homocysteine levels and 11 72 12.5 17.0 36 14.3 ⫾ 1.5 lipid fractions were low (cholester12 77 14.2 16.5 16 15.6 ⫾ 0.8 ol 0.26, low-density lipoprotein Average 64 11.3 15.1 38 12.9 ⫾ 1.3 cholesterol r ⫽ 0.21, and high-density lipoprotein cholesterol r ⫽ spread across the entire range of serum homocysteine 0.20).19 The correlation coefficent for triglycerides levels.14 The data are particularly strong for risk of was also low at 0.20. Fibrinogen, which peaked at myocardial infarction and stroke. There are many 9:58 A.M. in our subjects, showed a correlation coefstudies that demonstrate a role for homocysteine in ficient of only 0.09. This is also true for lipoprotein(a), reducing normal arterial relaxation and in altering which peaked at 8:44 A.M. in our patients, where the endothelial function. A recent study demonstrating a correlation coefficient was ⫺0.03.19 possible effect of homocysteine on metalloproteinases Elevated serum homocysteine levels are due to geinvolved in connective tissue matrix development may netic and environmental (particularly dietary) causes. A lead to an understanding of homocysteine’s putative prevalent inherited defect in the enzyme N5,N10 methrole in accelerating atherosclerotic consequences.15 ylenetetrahydrofolate reductase increases serum homoOther plausible mechanisms for homocysteine-medi- cysteine levels, but does not appear to increase the risk of ated atherogenesis include altered methylation of vascular damage.20 Elevated homocysteine levels may DNA and altered regulatory proteins associated with result from altered metabolism at the endothelial surface cell membranes, decreased bioavailability of nitric in response to vascular damage and may simply be a oxide, increased elastolysis and collagen accumula- marker for vascular damage rather than playing a direct tion, overstimulation of N-methyl-D-aspartate recep- role in the pathogenesis of atherosclerosis. Our data tors, and excessive adhesion of monocytes and neu- demonstrate no obvious correlation with fibrinogen, trophils to the endothelium.2 Many of homocysteine’s platelets, lipid fractions, and other risk factors for atheffects have been attributed to its pro-oxidant activity, erosclerosis, suggesting that the relation between homowhich is the mechanism through which it inhibits cysteine and atherosclerosis may be more of a marker for production of endothelium-derived relaxing factor and vascular damage. It may be premature to attempt to activates quiescent vascular smooth muscle cells.16 decrease homocysteine levels by dietary vitamin suppleHowever, the major mechanism for homocysteine’s mentation; this interventional therapy is currently being effect had yet to be determined. The atherosclerotic risk from high homocysteine studied in several trials in which the results are yet levels appears to be similar for the peripheral arteries, pending. coronary arteries, and cerebrovascular disease in 50The present study indicates that serum total hoto 75-year-old patients,17 implying that there is an mocysteine levels in adults are circadian (p ⴝ 0.030), effect on the arterial tree independent of the classic the highest levels occur during the late evening (10:36 risk factors, where hypertension is correlated most with cerebrovascular disease, elevated low-density li- P.M.) and the lowest levels occur during the morning. poprotein cholesterol is correlated with coronary ar- We found a small increase in homocysteine levels in tery disease, and smoking is correlated with peripheral diabetics compared with nondiabetics, but the difference was not statistically significant (12.99 vs 11.83 artery disease. The circadian pattern of homocysteine is distinct ␮mol/L), implying that increased atherosclerotic risk from the classic risk factors for atherosclerotic com- in insulin-resistant diabetics cannot be explained by plications. Serum total cholesterol and low-density differences in homocysteine levels in normal subjects. lipoprotein cholesterol levels peak in the early morn- This corroborates a study in healthy volunteers ing, which is when most myocardial infarctions occur, where plasma homocysteine levels did not correlate whereas platelets peak in the afternoon, which is the with steady plasma glucose levels during an insulin time when the second peak of myocardial infarctions suppression test.21 TABLE 1 Concentration Limits of Serum Homocysteine Levels Measured Every 3 Hours (8/24)



1. Bostom AG, Silbershatz H., Rosenberg IH, Selhub J, D’Agostino RB, Wolf PA, Jacques PF, Wilson PW. Non-fasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Inter Med 1999 159:1077–1080. 2. Domagaia TB, Undas A, Libura M, Szczeklik A. Pathogenesis of vascular disease in hyperhomocysteinemia (review). J Cardiovasc Risk 1998;5:234 –247. 3. Wuillemin WA, Solenthaler M. Hypercysteinemia: a risk factor for arterial and venous thrombosis (review) (in German). Vasa 1999;28:151–155. 4. Gerhard GT, Duell PB. Homocysteine and atherosclerosis (review). Curr Opin Lipidol 1999;10:417– 428. 5. Morrow LE, Grimsley EW. Long term diuretic therapy in hypertensive patients. Effects on serum homocysteine, vitamin B6, vitamin B12, and red blood cell folate concentrations. South Med J 1999;92:866 – 870. 6. Mahmud N, Molloy A, McPartlin J, Corbally R, Whitehead AS, Scott JM, Weir DG. Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications. Gut 1999;45:389 –394. 7. Aarsand AK, Carlsen SM. Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment. J Intern Med 1998;244:169 –174. 8. Nedrebo BG, Ericsson UB, Nygrd O, Refsum H, Ueland PM, Aakvaag A, Aanderud S, Lien EA. Plasma total homocysteine level in hyperthyroid and hypothyroid patients. Metabolism: 1998;4:89 –93. 9. Norlund L, Grubb A, Fex G, Leksell H, Nilsson JE, Schencj H, Hultberg B. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med 1998;36:175–178. 10. Miller JW. Homocysteine and Alzheimer’s disease (review). Nutr Rev 1999; 57:126 –129. 11. Ubbink JB, Fehily AM, Pickering J, Elwood PC, Vermaak WJ. Homocysteine and ischemic heart disease in the Caerphilly cohort. Atherosclerosis 1998;40: 349 –356. 12. Mansoor MA. Comparison of Abbott IMX total homocysteine assay with high pressure liquid chromatography method for the assessment of total homocysteine in plasma and serum from a Norwegian population. Scan J Clin Lab Invest 1999;59:369 –374.

13. Ferna´ndez JR, Hermida RC. Inferential statistical method for analysis of nonsinusoidal hybrid time series with unequidistant observations. Chronobiol Int 1998;15:191–204. 14. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J. Scott JM. Homocysteine and ischemic heart disease results of a prospective study with implications regarding prevention. Arch Intern Med 1998;158:862– 867. 15. Hoogeveen EK, Kostense PJ, Beks PJ, Mackay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CL. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998;18:133–138. 16. Brude IR, Finstad HS, Seljeflot I, Drevon CA, Sandstad B, Hjermann I, Amesen H, Nenseter MS. Plasma homocysteine concentration related to diet, endothelial function and mononuclear cell gene expression among male hyperlipidemic smokers. Eur J Clin Invest 1999;29:100 –108. 17. Abbasi F, Facchini F, Humphreys MH, Reaven GM. Plasma homocysteine concentrations in healthy volunteers are not related to differences in insulinmediated glucose disposal. Atherosclerosis 1999;146:175–178. 18. Assman G, Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Munster study. Am J Cardiol 1992; 70:10H–13H. 19. Bremner WF, Sothern RB, Kanabrocki EL, Ryan M, McCormick JB, Dawson S, Connors ES, Rothschild R, Third JLHC, Vahed S, Nemchausky BA, Shirazi P, Olwin JH. Relationship between circadian patterns in levels of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men. Am Heart J 2000;139:164 –173. 20. Folasom AR, Nieto J, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphism and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1998;98:204 –210. 21. Hyanek H, Stribrny J, Sebesta P, Niederle P, Kramar J, Kozich V, Orendac O, Zaykova K, Mandysova E, Baruvka V, et al. Hyperhomocysteinemia. A risk factor for the development of vascular diseases not associated with lipid levels (in Czech). Cas Lek Cesk 1997;136:720 –723.

Frequency, Risk Factors, and Clinical Outcomes of Left Ventricular Assist Device-Associated Ventricular Thrombus Muredach P. Reilly, MB, Susan E. Wiegers, MD, Andrew J. Cucchiara, Mary Lou O’Hara, MSN, Theodore J. Plappert, CVT, Evan Loh, MD, Michael A. Acker, MD, and Martin St. John Sutton, FRCP


static supply of donor organs has necessitated the development of left ventricular (LV) assist deA vices (ADs) to bridge patients to cardiac transplanta-

patients receiving LVAD support at a single center over a 2-year period.

tion.1–5 Thromboembolic complication rates of 20% to 30% were initially a major limitation to the widespread use of LVADs.6 –9 The success of the Heartmate (Thermocardiosystem Inc., Woburn, Massachusetts) device has been partly due to the reduced incidence of thromboembolic events (approximately 4%), obviating the need for long-term anticoagulation.1,2,10 Extracorporeal LVADs, used mainly as short-term support for postcardiotomy cardiogenic shock, continue to be associated with thromboembolic events and require full anticoagulation.8,9 This study examines the predictors of LV thrombus in consecutive

A retrospective cohort study of 51 consecutive patients who required LVAD support between December 1996 and December 1998 at a single university medical center was performed. Patients were included in the study if they had a transesophageal echocardiogram (TEE) during the period of LVAD support. Fifty-one of 53 patients, supported by LVADs during the study period, had at least 1 TEE (total ⫽ 83 studies; mean 1.63/patient; median 2; range 1 to 4) and are included in this report. Devices implanted included Biomedicus (Medtronic Inc., Eden Prairie, Minnesota) and ABIOMED (Cardiovascular Lab, Danvers, Massachusetts), short-term extracorporeal devices used for acute postcardiotomy failure, and Heartmate and Thoratec (Pleasanton, California), used as a long-term bridge to transplantation. LVAD-associated LV thrombus was defined as the presence of an LV intracavitary mass lesion consistent with thrombus diagnosed by TEE by 2 independent

From the Divisions of Cardiology and Cardiovascular Surgery, Departments of Medicine and Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania. Dr. Reilly’s address is: University of Pennsylvania, 816 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19014. E-mail:[email protected] Manuscript received March 16, 2000; revised manuscript received and accepted May 24, 2000.


©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 November 15, 2000


0002-9149/00/$–see front matter PII S0002-9149(00)01182-6