Claes Held
email: claes.held@ucr.uu.se

Glen Sumner

Patrick Sheridan

Mathew Mcqueen

Sandra Smith

Gilles Dagenais

Salim Yusuf

Eva Lonn

Correlations between plasma homocysteine and folate concentrations and carotid atherosclerosis in high-risk individuals: baseline data from the Homocysteine and Atherosclerosis Reduction Trial (HART)

Keywords: carotid intima-media thickness, folate, homocysteine, plaque

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Introduction

Homocysteine has been proposed as a risk factor for atherosclerosis. [START_REF] Mccully | Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis[END_REF] Epidemiological studies suggest that mild to moderate elevations in plasma total homocysteine (tHcy) concentrations are associated with an increased risk for atherosclerotic vascular diseases. [START_REF] Eikelboom | Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence[END_REF][START_REF] Wald | Homocysteine and cardiovascular disease: evidence on causality from a metaanalysis[END_REF][START_REF] Klerk | MTHFR 677C→T polymorphism and risk of coronary heart disease[END_REF][START_REF] Boushey | A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes[END_REF] Overall, these observational studies have concluded the relationship to be continuous, graded, and independent of other cardiovascular (CV) risk factors. [START_REF] Boushey | A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes[END_REF] While earlier retrospective epidemiological studies may have overestimated the strength of this association for myocardial infarction, a modest but significant association between tHcy and myocardial infarction is shown in prospective cohort studies and the relationship to stroke remains substantial in these more recent prospective observational evaluations, 6 as well as in mendelian randomization studies. [START_REF] Casas | Homocysteine and stroke: evidence on a causal link from mendelian randomization[END_REF] In experimental studies, hyperhomocysteinemia leads to increased oxidative stress, inhibition of nitric oxide synthase, proliferation of smooth muscle cells, endothelial dysfunction and promotes thrombosis. [START_REF] Harker | Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons[END_REF][START_REF] Welch | Homocysteine and atherothrombosis[END_REF][START_REF] Harker | Homocysteinemia: vascular injury and arterial thrombosis[END_REF] Therapy with folic acid or combined folic acid and vitamins B6 and B12 lowers tHcy levels and was suggested as a treatment to reduce the risk of CV events. To date, four completed trials in high-risk populations have generally failed to demonstrate the clinical benefits. [START_REF] Toole | Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial[END_REF][START_REF] Lonn | Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in high-risk chronic vascular disease[END_REF][START_REF] Bønaa | for the NOR-VIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction[END_REF][START_REF] Albert | A randomized trial of folic acid and B-vitamins in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS); presented at the AHA[END_REF] However, it was suggested that these trials do not necessarily disprove the 'homocysteine theory of atherosclerosis', and that their results may relate to the tHcy-lowering independent effects of the administration of high-dose B vitamins and ensuing complex metabolic consequences. [START_REF] Loscalzo | Homocysteine trialsclear outcomes for complex reasons[END_REF] The Heart Outcomes Prevention Evaluation (HOPE)-2 study, the largest B vitamin intervention trial completed to date, reported no significant reduction in overall major CV events in a high-risk population treated with folic acid and vitamins B 6 and B 12 . [START_REF] Lonn | Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in high-risk chronic vascular disease[END_REF] However, the trial showed a reduction in the risk for stroke. The Homocysteine and Atherosclerosis Reduction Trial (HART) is a substudy of the HOPE-2 trial and aims to evaluate the effects of homocysteine-lowering vitamin therapy on the progression of carotid atherosclerosis, as evaluated by serial B-mode quantitative ultrasound (US) examinations.

Carotid intima-media thickness (IMT) is an accepted surrogate marker for atherosclerosis disease burden. Several case-control and crosssectional studies have evaluated the association between tHcy and carotid IMT in healthy individuals, in individuals with homocysteinuria or specific CV risk factors, the majority being small or moderate in size and with inconsistent findings. [START_REF] Durga | Homocysteine and carotid intima-media thickness: a critical appraisal of the evidence[END_REF] In high-risk populations with vascular disease, the associations have been examined only in a few and rather small studies, generally showing trends towards significant relationships. [START_REF] Durga | Homocysteine and carotid intima-media thickness: a critical appraisal of the evidence[END_REF] Low plasma folate levels may also impact on atherosclerotic disease burden, as suggested by a recent study of healthy middle-age individuals, in which low folate concentrations were independently associated with increased carotid IMT. [START_REF] Durga | Low concentrations of folate, not hyperhomocysteinemia, are associated with carotid intima-media thickness[END_REF] The effect of tHcy-lowering B vitamins on atherosclerosis progression is currently unclear. HART is the largest randomized trial evaluating the effects of B vitamins on carotid IMT. The current report outlines baseline characteristics and examines associations between baseline tHcy, folate and B vitamins and carotid IMT and to a plaque calcification score.

Methods

The design and results of the HOPE-2 study have been described in detail previously. [START_REF] Lonn | Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in high-risk chronic vascular disease[END_REF][START_REF] Lonn | The HOPE-2 Investigators. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial[END_REF] A total of 5522 patients were randomized at 145 centers in 13 countries to daily therapy with combined folic acid 2.5 mg, vitamins B6 50 mg and B12 1 mg or to placebo. Median follow-up was 5 years. The primary study outcome was the composite of CV death, myocardial infarction and stroke. The HART substudy of the HOPE-2 trial is a prospective trial, conducted in 923 patients and aims to assess the effects of the study intervention on atherosclerosis progression.

Patients had yearly carotid ultrasound examinations and the effect of homocysteine-lowering B vitamins on carotid IMT will be assessed. The HART study will be published separately. Both the HOPE-2 and the HART trials were sponsored by the Canadian Institutes of Health Research and coordinated by the Population Health Research Institute, McMaster University. The current report provides the baseline characteristics of the HART study participants and evaluates associations between tHcy, folate and B vitamin concentrations and carotid IMT and plaque calcification at baseline.

Patients

Between January 18 and December 31 2000, 923 patients were recruited from 10 Canadian HOPE-2 study centers. Clinical eligibility criteria for the HART study were identical to those for the main parent HOPE-2 trial. [START_REF] Lonn | Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in high-risk chronic vascular disease[END_REF][START_REF] Lonn | The HOPE-2 Investigators. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial[END_REF] Thus, men and women 55 years or older with stable coronary, cerebral or peripheral artery disease or diabetes and at least one additional CV risk factor (smoking, hypertension, dyslipidemia and/or microalbuminuria) were included, irrespective of their baseline tHcy levels. Exclusion criteria included current use of vitamin supplements containing folic acid > 200 μg/day, known adverse reactions to folic acid and/or vitamins B12 or B6, planned revascularization or other clinically significant CV or non-CV disease, expected to limit any patient's adherence and ability to complete the trial. In addition, HART study patients had to have an adequate carotid IMT examination at baseline, defined as clear imaging of at least four predefined carotid artery segments. The study was conducted in accordance with the Helsinki declaration and was approved by the ethics committee of each participating center. All patients provided written informed consent.

Laboratory measurements

Plasma tHcy, folate and B vitamin concentrations were measured at baseline in all study patients. For tHcy, the Abbott IMX immunofluorescence method (Abbott, Mississauga, Canada) was used, folate using the Roche chemiluminescence method (Roche Diagnostics, Mannheim, Germany), B6 (pyridoxal) was measured by HPLC using the Chromsystems kit (Instruments and Chemicals, GmbH, Munchen, Germany) and B12 by immunoassay using the Immulite 2000 Analyzer (Diagnostic Products Corporation, Los Angeles, USA). The coefficients of variation for these analyses were all within acceptable ranges.

Carotid ultrasonography

All scans were performed by five sonographers (who underwent training and certification) at three laboratories who had specific expertise and used high-resolution imaging systems. A standardized, validated imaging protocol was used, [START_REF] Lonn | for the SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis. The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin (SECURE)[END_REF] aimed at recording the maximum carotid IMT in each of 12 predefined 1-cm long carotid artery segments, including the near and far walls of the internal, the bifurcation and the common left and right carotid arteries. All measurements were performed at the Core US Laboratory in Hamilton, Ontario by one of two specifically trained and experienced readers. A standardized and validated US reading protocol [START_REF] Lonn | for the SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis. The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin (SECURE)[END_REF] and the Image-ProPlus software were used (Media Cybernetics, Silver Spring, MD, USA). A minimum of three readings/segment were performed and the highest reading was selected for each segment. Primary and secondary carotid US measurements were defined a priori as the sum of the maximum IMT for each segment, divided by the number of visualized segments (mean max carotid IMT) and the single segment maximum IMT (single max carotid IMT), respectively. For each carotid segment the presence or absence of plaque calcification, defined as bright echoes with acoustic shadowing, was evaluated and a plaque calcification score was computed for each patient, defined as the percentage of segments with calcification among the total number of segments visualized. Scanning and reading reproducibility were high; within and between the sonographer intraclass correlation coefficient (ICC) for repeat scanning they were > 0.90 and within and between the reader ICC they were 0.95 and 0.96, respectively. There were no temporal drifts in scanning or reading.

Statistical analysis

Continuous variables are expressed as mean ± SD or in quartiles unless otherwise stated. Logarithmic transformation was used for carotid IMT and other variables that were not normally distributed. The transformed IMT values were then back transformed for presentation on the original scale. Univariate associations between risk factors and carotid IMT were explored using Pearson's and Spearman rank correlations for continuous variables and analysis of variance (ANOVA) for categorical variables. Univariate comparisons between the plaque calcification score and categorical variables were conducted using logistic regression. Two-sided p-values ≤ 0.05 were considered to be statistically significant for all analyses. Age and sex-adjusted and multivariable models were used to evaluate the associations between tHcy and folate concentrations and carotid atherosclerosis, using stepwise linear regression for IMT measurements and stepwise logistic regression for the plaque calcification score. All variables with a p-value < 0.1 in univariate analyses were tested in the multivariable models. All statistical analyses were performed using the Statistical Analysis Software, version 8.2 (SAS Institute, 1999; Cary, NC, USA).

Results

Patient characteristics

Patient characteristics are presented in Table 1. Study patients had a mean age of 68.6 years and were at high risk for vascular disease events. Indeed, over 85% had coronary, peripheral or cerebral artery disease. Over half of the patients had a history of hypertension and one third had diabetes. Most patients were treated for vascular disease and secondary prevention with aspirin, beta blockers, angiotensinconverting enzyme inhibitors and statins. Major CV risk factors, including serum lipid profile, and systolic and diastolic blood pressure were generally well controlled and within the targets recommended by clinical practice guidelines. High-sensitivity (hs)-CRP levels were elevated. Mean creatinine levels were within normal limits. tHcy levels were elevated: 12.1 ± 5.4 μmol/l; and plasma folate levels were within the normal range: 30.4 ± 9.9 nmol/l.

In multivariable analyses, age (p < 0.0001), plasma folate levels (p < 0.01), sex (p < 0.001), vitamin B12 levels (p < 0.0001), creatinine (p < 0.0001), triglycerides (p < 0.05) and total cholesterol/HDLcholesterol ratio (p < 0.01) were independent predictors of the tHcy concentration and accounted for approximately 27% of the variability of tHcy.

Most patients had evidence of carotid atherosclerosis, with both high mean and single max carotid IMT. The mean plaque calcification score was 27.8% (range 0-100%), indicative of advanced atherosclerosis (Table 1). The majority of the study patients, 81%, had a plaque calcification recorded in at least one carotid segment.

Compared with women, men had a higher mean max carotid IMT (p < 0.001) and single max carotid IMT (p < 0.001) (Table 2) and higher average plaque calcification scores (Table 3). Patients with a history of hypertension and current smoking had greater mean max carotid IMT than those without (p < 0.01). There was no difference in mean or single max carotid IMT in patients with or without a history of diabetes. The mean plaque calcification score was higher among patients with a history of smoking (p < 0.01) and hypertension (p < 0.01) as compared to those without (Table 3).

Univariate and multivariable correlations between risk factors and carotid IMT

In univariate analysis, age showed the strongest association with mean max carotid IMT (r = 0.28; p < 0.0001). Systolic blood pressure (r = 0.16; p < 0.0001) and serum creatinine (r = 0.10; p < 0.01) were modestly but significantly correlated to carotid IMT. Established risk factors such as LDL-cholesterol, HDL-cholesterol and triglycerides were not significantly associated with carotid IMT in univariate analysis, but 72% of the patients were on lipid-lowering therapy. There was no significant association between hs-CRP and mean max carotid IMT.

In multivariable analysis, traditional risk factors such as age (p < 0.0001), sex (p < 0.0001), history of smoking (p < 0.0001), systolic blood pressure (p < 0.0001), body mass index (p < 0.01) and triglycerides (p < 0.001) were all independently associated with mean max carotid IMT and accounted collectively for approximately 20% of the variability in carotid IMT. Association between homocysteine and carotid IMT Mean tHcy levels were elevated, 12.1 ± 5.4 μmol/l. In univariate analyses, tHcy correlated significantly with both single max (r = 0.12; p < 0.001) and mean max (r = 0.13; p < 0.001) carotid IMT. There was a significant and gradual increase in both mean and single max carotid IMT (p < 0.0001 for both variables) across quartiles of tHcy (Table 4 and Figure 1). However, after age and sex adjustment and in multivariable analysis, the association was no longer significant (Table 4). When evaluating men and women separately, there were significant univariate associations between tHcy and mean max (p < 0.0001) and single max (p < 0.01) carotid IMT in men, but after age adjustment the relationship was no longer significant. In women, no significant associations between tHcy and carotid IMT Values are mean (95% CI).

The p-values denote differences between groups. were found, although the statistical power of this analysis was lower.

Associations between homocysteine and plaque calcification

The plaque calcification score increased gradually across quartiles of tHcy (p < 0.0001 for trend; Figure 2). This association remained significant after adjustment for age and sex (p < 0.01) and in multivariable analysis (p < 0.01).

Association between plasma folate levels and carotid IMT

The mean baseline folate concentration was 30.4 ± 9.9 nmol/l. There was a trend towards a gradual decrease in mean max carotid IMT across quartiles of plasma folate in both univariate and multivariable analyses. The association was observed from the lowest to the third fourth of the folate distribution. There was no clear relationship to carotid mean max IMT in the highest fourth of the folate distribution (Table 4 and Figure 1). No significant association between folate concentration and single max IMT was noted.

Association between folate and plaque calcification

The plaque calcification score decreased gradually across quartiles of folate (p < 0.05 for trend; Figure 2 and Table 4). This relationship remained statistically significant after age and sex adjustment (p < 0.05 for trend) and in multivariable analysis (p < 0.05 for trend; Table 4).

Associations between vitamin B6 and B12 levels and carotid atherosclerosis

Mean baseline vitamin B6 and B12 concentrations were 65.8 ± 81.2 nmol/l and 310 ± 144 pmol/l, respectively. There were no significant correlations between the concentrations of vitamins B6 and B12 and carotid IMT (mean max carotid IMT or single max carotid IMT) or plaque calcification score (data not shown).

Discussion

We report associations between tHcy, folate and vitamins B6 and B12 concentrations and carotid atherosclerosis in a large cohort of patients at high risk for CV events. We observed a gradual and consistent increase in mean and single max carotid IMT across quartiles of tHcy. However, this relationship was weak and not significant after adjusting for age, sex and other traditional risk factors. There was also a trend towards an inverse relationship between plasma folate concentration to mean max carotid IMT, although this association did not reach statistical significance. In contrast to the associations with IMT, both tHcy and low folate concentrations were independently related to carotid plaque calcification across quartiles, even after accounting for other CV risk factors in multivariable analyses.

Our findings are consistent with other studies in patients with established vascular disease, which in general showed weak associations between tHcy levels and carotid IMT, as recently reviewed, [START_REF] Durga | Homocysteine and carotid intima-media thickness: a critical appraisal of the evidence[END_REF] although these studies were smaller. Observational studies on other high-risk individuals, such as those with uremia, hypercholesterolemia, type 2 diabetes, insulin resistance, immune disorders or neurological abnormalities have generally failed to demonstrate consistent associations between tHcy levels and carotid IMT. In a previous large study on individuals at higher than average coronary heart disease (CHD) risk, which enrolled siblings of CHD patients and other high-risk individuals, a significant increase in carotid IMT across quintiles of tHcy was reported. This association was weak and significant only in those > 55 years. [START_REF] Tsai | Plasma homocysteine and its association with carotid intimal-medial wall thickness and prevalent coronary heart disease: NHLBI Family Heart Study[END_REF] Similarly, in a large cross-sectional study in a general population with mildly elevated tHcy levels, a significant but weak correlation between tHcy and carotid IMT was seen. [START_REF] Mcquillan | Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS)[END_REF] Whether raised homocysteine concentrations may cause ischemic heart disease and stroke is still under debate. [START_REF] Wald | Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence[END_REF] In our study, the association between tHcy and low folate and plaque calcification score was more robust than the association with carotid IMT. Calcification of plaques is a result of increased atherosclerotic disease burden and more advanced disease. However, studies evaluating the clinical importance of plaque calcification as a marker of risk for CV events have been inconsistent and controversial. [START_REF] Nandalur | Carotid artery calcification on CT may independently predict stroke risk[END_REF][START_REF] Grogan | B-mode ultrasonographic characterization of carotid atherosclerotic plaques in symptomatic and asymptomatic patients[END_REF] Figure 2 Carotid artery plaque calcification score (%) across quartiles of plasma total homocysteine (p < 0.01 for trend in multivariable analysis) and plasma folate concentrations (p < 0.05 for trend in multivariable analysis).

We observed trends towards an inverse association to carotid IMT. A previous study [START_REF] Durga | Low concentrations of folate, not hyperhomocysteinemia, are associated with carotid intima-media thickness[END_REF] suggested that this association was only seen at very low serum folate levels. Our study was initiated after the legislated implementation of food supplementation with folic acid in Canada [START_REF] Ray | Declining rate of folate insufficiency among adults following increased folic acid food fortification in Canada[END_REF][START_REF] Robertson | Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products[END_REF] and indeed most patients in our study had normal plasma folate levels. Thus, in folate-replete individuals with vascular disease, as represented by our population, serum folate levels may not be predictive of carotid IMT measurements. However, low folate concentration was more strongly related to plaque calcification, as was also found for tHcy.

There were no significant associations between plasma vitamin B6 and B12 levels and either carotid IMT or plaque calcification in our population. This observation is interesting in the light of recent data, suggesting a modest effect of vitamin B6 and B12 supplementation on carotid IMT levels in vascular disease [START_REF] Till | Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, vitamins B6 and B12[END_REF] and renal transplant patients. [START_REF] Marcucci | Homocysteinelowering therapy and carotid intima-media thickness in renal transplant recipients[END_REF] Our patients had normal baseline vitamin B6 and B12 concentrations. It is possible that vitamin B6 and B12 supplementation affects carotid IMT only in patients who have B vitamin deficiencies.

While recent randomized controlled clinical trials have failed to identify a reduction in major vascular events with tHcy-lowering B vitamins, [START_REF] Toole | Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial[END_REF][START_REF] Lonn | Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in high-risk chronic vascular disease[END_REF][START_REF] Bønaa | for the NOR-VIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction[END_REF][START_REF] Albert | A randomized trial of folic acid and B-vitamins in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS); presented at the AHA[END_REF] homocysteine lowering requires further study, particularly with regards to stroke. There still remains a debate on the interpretation of available epidemiological data and the trial results, [START_REF] Wald | Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence[END_REF] but in a late metaanalysis [START_REF] Bazzano | Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials[END_REF] there was no significant benefit of folic acid supplementation on the risk of CHD. The epidemiological association between tHcy and stroke is stronger than for coronary heart disease. 6,7 Also, a revised analysis of the VISP trial suggested a possible treatment benefit in subsets of people at high risk of stroke with B12 vitamin abnormalities [START_REF] Spence | Vitamin intervention for stroke prevention trial. An efficacy analysis[END_REF][START_REF] Spence | Homocysteine. Call off the funeral[END_REF] and in the HOPE-2 trial tHcy lowering reduced stroke rates. A recent meta-analysis on eight trials 32 concluded an 18% reduction in the risk of stroke. Therefore, the HART trial remains relevant and is expected to provide additional important information on the effects of tHcy lowering on carotid atherosclerosis.

In conclusion, in this population of patients at high CV risk, tHcy concentration was only weakly associated with carotid IMT. In contrast, tHcy was independently associated to plaque calcification, a measure of more advanced atherosclerosis. Although plasma folate and B vitamin levels were predictive of tHcy levels, there was no clear and consistent relationship demonstrated between plasma levels of folate, vitamins B6 and B12 and carotid IMT. However, low levels of folate were independent predictors of plaque calcification. Overall, associations between both Hcy and folate to plaque calcification were stronger than to carotid IMT, which may have clinical importance since this parameter may be a better marker of advanced atherosclerosis in this population.

The HART study will evaluate the effects of tHcy-lowering therapy with combined folic acid 2.5 mg and vitamins B6 50 mg and B12 1 mg administered as a combined pill once daily for an average of 5 years versus matching placebo on the progression of carotid IMT and the plaque calcification score. The associations between tHcy and folate and carotid atherosclerosis and the awaited treatment results of the HART trial are highly relevant, considering the results on stroke in the HOPE-2 trial, which are in contradistinction with the neutral results of the trial on the main primary outcome, and the results of the VISP and NORVIT trials.

Figure 1

 1 Figure 1 Mean maximum carotid IMT and single maximum carotid IMT across quartiles of plasma total homocysteine and plasma folate concentrations.

Table 1

 1 Baseline characteristics of the HART study patients (n = 923)

	Age (years)

Table 3

 3 Percent plaque calcification in males and females and in patients with selected cardiovascular risk factors

		Plaque	p
		calcification (%)
	Males	28.2 (27.3-29.2)	0.088
	Females	26.5 (24.8-28.3)
	Diabetes	28.0 (26.6-29.5)	0.713
	No diabetes	27.7 (26.6-28.8)
	Hypertension	28.9 (27.8-30.0)	0.002
	No hypertension	26.0 (24.6-27.4)
	Current smoker	31.6 (28.7-34.7)	0.008
	Not current smoker	27.4 (26.6-28.4)
	Ever smoked	28.6 (27.6-29.6)	0.002
	Never smoked	25.5 (23.9-27.2)

Table 2

 2 Mean and single maximum carotid IMT in males and females and in patients with selected cardiovascular risk factors

		Mean max carotid IMT (mm)	p	Single max carotid IMT (mm)	p
	Males	1.25 (1.23-1.28)	<0.001	2.35 (2.29-2.41)	<0.0001
	Females	1.13 (1.10-1.17)		2.08 (1.99-2.17)
	Diabetes	1.22 (1.19-1.26)	0.86	2.24 (2.16-2.33)	0.33
	No diabetes	1.23 (1.20-1.25)		2.30 (2.23-2.36)
	Hypertension	1.25 (1.22-1.27)	0.005	2.33 (2.27-2.39)	0.01
	No hypertension	1.19 (1.15-1.22)		2.20 (2.12-2.28)
	Current smoker	1.33 (1.26-1.40)	0.003	2.40 (2.22-2.57)	0.19
	Not current smoker	1.21 (1.19-1.24)		2.27 (2.22-2.32)
	Ever smoked	1.25 (1.23-1.27)	0.0001	2.30 (2.24-2.36)	0.13
	Never smoked	1.16 (1.12-1.20)		2.21 (2.12-2.31)
	All IMT values are mean (95% CI), mm.
	The p-values denote differences between groups.

Table 4

 4 Carotid IMT and percent plaque calcification by quartile of plasma Hcy and folate concentration

	Quartiles of Hcy	Q1	Q2	Q3	Q4	p for trend p age and sex	p multivariable
	(μmol/l)						adjusted
		< 9.4	9.4-11.2	11.2-13.4	> 13.4
	Mean max carotid IMT	1.16	1.21	1.24	1.28	<0.0001	0.17	0.22
	(mm)
	Single max carotid IMT	2.14	2.24	2.31	2.43	<0.0001	0.10	0.11
	(mm)
	Carotid plaque	24.0	27.0	28.8	30.8	<0.0001	<0.01	<0.01
	calcification (%)
	Quartiles of folate	Q1	Q2	Q3	Q4	p for trend p age and sex	p multivariable
	(nmol/l)	< 23.0	23.0-28.5	28.5-39.4	> 39.4		adjusted
	Mean max carotid IMT	1.26	1.22	1.18	1.22	0.08	0.12	0.05
	(mm)
	Single max carotid IMT	2.34	2.24	2.20	2.29	0.43	0.64	0.33
	(mm)
	Carotid plaque	30.2	26.5	26.4	26.9	<0.05	<0.05	<0.05
	calcification (%)

Values are means for each quartile. The p-values denote trend across quartiles. Variables with a p-value <0.1 in univariate analyses were tested in multivariable models.

Vascular Medicine 2008; 13: 245-253

Acknowledgements

The invaluable work of the sonographers Sandra Smith, Rose Djuric, Laura Newkirk, Céline Boutin and Carol Derksen is greatly appreciated. Dr Held was supported by grants from the Janne Elgqvist foundation, the Erik and Edith Fernstrom Foundation and the Swedish Heart and Lung Foundation. Prof Salim Yusuf is supported by a chair from the Heart and Stroke Foundation of Ontario. This study was sponsored by the Canadian Institutes of Health Research grants MT-44159 and MT-15418. HOPE-2 registration: ClinicalTrials.gov. number NCT00106886; Current Controlled Trials number ISRCTN14017017. HART registration: Clinical Trials.gov number NCT00217178; Current Controlled Clinical Trials number ISRCTN43616311.


Michel K Barsoum
email: barsoum.michel@mayo.edu

Raymond Shields

Panel A

published or not. The documents may come

Images in vascular medicine

Ormond's disease: an unusual cause of abdominal pain

Michel K Barsoum and Raymond Shields

A 47-year-old male smoker with hyperlipidemia reported suffering from dull, aching, mid-abdominal pain with right groin pain for 4 months. The pain was associated with nausea, diminished appetite and a weight loss of 10 pounds (4.5 kg). He reported back pain radiating to the buttocks with bilateral calf claudication that was not relieved completely with rest. He also described significant nocturnal sweats and fever of 99-100.5°F (37.2-38.1°C). Pertinent laboratory evaluation revealed an erythrocyte sedimentation rate of 87 mm/hour and a C-reactive protein of 77.4 mg/l. Antineutrophil cytoplasmic antibodies, rheumatoid factor, and antinuclear antibody were negative. Antiphospholipid IgG antibodies were borderline elevated. The urinalysis demonstrated microscopic hematuria.

Computed tomographic angiography of the abdomen revealed periaortic soft tissue thickening and enhance-ment of 4.5-5.0 cm, while the opacified lumen measured 1.6 cm (Panel A, arrow). Severe atheromatous disease involved the distal aorta extending into the iliac vessels. The celiac, superior mesenteric artery (SMA), and renal arteries were patent.

An indium white blood cell scan revealed normal tracer uptake. The clinical findings and laboratory evaluation led to a low suspicion for malignancy or infection. Prednisone was started and 2 months later the groin pain, fever and chills were resolved with improvement of the back and abdominal pain. The inflammatory markers returned to normal.

Computed tomographic angiography of the abdomen after 2 months of treatment revealed a marked reduction in the infrarenal periaortic soft tissue thickening with no aneurysmal disease (Panel B, arrow).

The clinical manifestations of idiopathic retroperitoneal fibrosis or Ormond's disease include inflammatory abdominal aortic aneurysm as well as chronic periaortitis. [START_REF] Ormond | Idiopathic retroperitoneal fibrosis: a discussion of the etiology[END_REF] Periaortic fibrous tissue may encase adjacent structures causing obstructive complications such as deep venous thrombosis and ureteral obstruction. In the case presented, the inflammatory component predominated with rapid response to steroid therapy. Advanced atherosclerotic disease is also associated with retroperitoneal fibrosis, which was apparent in this case. [START_REF] Vaglio | Retroperitoneal fibrosis[END_REF][START_REF] Warnatz | Immunosuppressive treatment of chronic periaortitis: a retrospective study of 20 patients with chronic periaortitis and a review of the literature[END_REF]

Vascular Medicine 2008; 13: 313-314


Gillian Libby
email: g.libby@dundee.ac.uk

S R Mcewan

Jjf Belch

No difference in the association between birth weight and total cholesterol for males and females. A SHARP (Scottish Heart and Arterial Disease Risk Prevention) study

Keywords: birth weight, cholesterol, SHARP, Walker

No difference in the association between birth weight and total cholesterol for males and females. A SHARP (Scottish Heart and Arterial Disease Risk Prevention) study

Introduction

Studies examining the association between birth weight and total cholesterol have generally shown an inverse relationship. It has been noted, however, that in contrast with blood pressure studies, the relationship between birth weight and adult total cholesterol has not been consistent for males and females. A recent meta analysis [START_REF] Lawlor | Sex differences in the association between birth weight and total cholesterol. A meta-analysis[END_REF] found some evidence of a stronger effect in males compared with females, but the results were dominated by one very large study. [START_REF] Davies | Low birth weight is associated with higher adult total cholesterol concentration in men: findings from an occupational cohort of 25843[END_REF] A further large study published since this review, in contrast, found an association in females but not males and when these results were incorporated into the meta analysis the original sex difference was 'abolished'. [START_REF] Cooper | Sex differences in the association between birthweight and lipid levels in middle-age: findings from the 1958 British birth cohort[END_REF] Despite over 30 publications reporting regression coefficients separately for men and women there have been only five large (>1000 individuals) [START_REF] Davies | Low birth weight is associated with higher adult total cholesterol concentration in men: findings from an occupational cohort of 25843[END_REF][START_REF] Cooper | Sex differences in the association between birthweight and lipid levels in middle-age: findings from the 1958 British birth cohort[END_REF][START_REF] Lauren | Relation of early life factors to cardiovascular disease risk, morbidity and mortality[END_REF][START_REF] Miura | Birth weight, childhood growth and cardiovascular disease risk factors in Japanese aged 20 years[END_REF][START_REF] Skidmore | Birth weight and lipids in a national birth cohort study[END_REF] such studies in adults. In addition, some studies have used recalled birth weight or had limited data on potential confounding factors that could impact total cholesterol levels in adult life.

We therefore examined the relationship between birth weight and total cholesterol in a large healthy working population with prospectively collected perinatal data and taking into account a range of confounding factors. We set out to examine this relationship in males and females separately, in addition to all individuals together.

Methods

Detailed information on pregnancy and birth came from the Walker cohort, 7 a database of 48,404 babies out of 64,196 born in Dundee, Scotland between 1952 and 1966, of whom 34,183 have been traced and 21,000 are still resident in the area. Birth weight and gestation (calculated as the time between the date of last menstrual period and the date of birth) were obtained from documented records made at the time of pregnancy and birth. These data were record-linked by a unique patient identifier to extensive information relating to adult environmental, demographic and health factors in the SHARP (Scottish Heart and Arterial disease Risk Prevention) cohort, [START_REF] Mcewan | Vascular risk factor profiles in the first phase of the Scottish Heart and Arterial Risk Prevention (SHARP) Survey[END_REF] which consisted of a working population screened for cardiovascular risk factors. In brief, after extensive publicity about the SHARP screening programme, a specially adapted bus staffed by a regular team of experienced nurses visited over 700 workplaces between 1991 and 1993 at the employers' request and employees were invited to volunteer to have a cardiovascular risk assessment. Variables including height, weight and blood pressure were measured and a blood sample was taken. Individuals were questioned on lifestyle and prescribed medication and a detailed family history of cardiovascular disease was taken. Overall, around 75% of employees took up the offer of screening.

Non-fasting total cholesterol was analysed on finger prick blood samples using a Lipotrend C machine (Boehringer Mannheim, Lewes, UK). Strict quality control was maintained by reference samples tested in the regional biochemistry laboratory and the Wolfson Institute in Birmingham, England.

Data analysis

The contribution of birth weight to adult total cholesterol whilst allowing for the influence of other factors in adulthood was assessed using a series of univariable and multivariable regression models as outlined by Lucas, et al. [START_REF] Lucas | Fetal origins of adult diseasethe hypothesis revisited[END_REF] Early life: unadjusted birth weight as a predictor of total cholesterol.

Early life adjusted: birth weight adjusted for gestation and age at time of cholesterol testing.

Later life: adult BMI adjusted for age as a predictor of total cholesterol.

Early and later life: early and later life models combined and adjusted for cigarette consumption, alcohol intake, adult socioeconomic status and family history of cardiovascular disease.

As part of the regression analysis, a formal interaction test of birth weight and sex on the prediction of total cholesterol was carried out.

Socioeconomic status was represented by social class which was defined from information on occupation reported in the SHARP database using standard occupational classifications 10 (i.e. 1: professional; 2: managerial and technical; 3N: skilled (non-manual); 3M: skilled (manual); 4: partly skilled; 5: unskilled).

Results

There were 34,183 traced individuals from the Walker cohort who had a unique patient identifier which could be used to link to the SHARP cohort of 8254 individuals who were born between 1952 and 1966. There were 1158 individuals in the Walker database who also had information recorded in the SHARP database and these 1158 comprised the study population.

There were few differences in birth characteristics between the study population and the rest of the Walker cohort. Mean birth weight for the study population was slightly higher (3.36 kg (SD 0.49) vs 3.33 kg (SD 0.75)), but is unlikely to be of clinical significance. The study population individuals were less likely to have been breastfed (64.9% vs 70.2%), but there were no differences between the groups for gestation, percentage of males, mother's parity or mothers experiencing pre-eclampsia.

The individuals were aged 24-42 years (median 32 years, SD 4.51) at the time of the cardiovascular risk factor assessment. Their birth weights ranged from 1.52 kg to 5.36 kg, with a median weight of 3.36 g. Fifty-four individuals (4.7%) had a low birth weight of ≤2.50 kg compared to 5.2% in the traced Walker cohort. The demographic characteristics of the study population by males and females are shown in Table 1. There were 7% of females and 7.8% of males with a BMI > 30.

Seven individuals reported receiving thyroxine, which may have had an effect on their cholesterol levels. They were all included in the analysis. There were no individuals receiving statin treatment.

There was no interaction between birth weight and sex in the prediction of total cholesterol (p = 0.57). This was confirmed by the regression analysis (Table 2), which for both males and females showed no relationship between birth weight and total cholesterol either unadjusted or after adjustment for adult BMI and other potential confounders.

For all individuals together, there was no association between birth weight and adult total cholesterol until adjusted for adult BMI, which showed a slight decrease of 0.13 mmol/l (95% CI -0.24 to -0.01) for each 1 kg increase in birth weight.

Further adjustment for confounders showed that increasing age, BMI and cigarette consumption were all associated with increasing total cholesterol. As shown in previous studies, alcohol intake appeared to be inversely associated with total cholesterol.

Discussion

We were unable to show an inverse association between birth weight and adult total cholesterol for either males or females. This is in contrast with a number of other studies. Rather, for both sexes, adult risk factors had a greater impact on cholesterol levels. For all individuals together there was a small decrease in cholesterol with increasing birth weight, but only after adjusting for adult BMI. Some previous studies have found a difference by sex with a stronger association in either males or females. The smaller numbers in our groups may have obscured any association but the whole study population of >1000 individuals also failed to show an association until adjustment for BMI.

As our study was not subject to the limitations of some previous studies, it is plausible that we were able to accurately detect no association between birth weight and total cholesterol. Where associations have been found previously they have been generally weak and may have been the result of chance findings. [START_REF] Huxley | Birth weight and subsequent cholesterol levels[END_REF] Our study had the major advantage of having a relatively large cohort of individuals for whom birth weight was obtained from records collected at birth. We could also adjust for gestation. Though this was provided by calculation (as ultrasound was not available at the time), it is likely that slight under-and over-estimation of gestation would be equally likely, with no bias resulting. We were also able to adjust for a range of consistently collected adult risk factors that could impact cholesterol levels. An additional advantage came from the timing of the risk screening, carried out in the early 1990s before cholesterollowering drugs were regularly prescribed.

Cholesterol was measured in the non-fasting state as screening appointments were scheduled throughout the day. It was measured by fingerstick method, which it has been suggested is not as accurate as that recorded from venous samples, with the fingerstick method producing a higher reading. [START_REF] Greenland | Blood cholesterol concentration: fingersick plasma vs venous serum sampling[END_REF] If this was the case, then it would produce an inflated association between birth weight and cholesterol but our results showed no association. In addition, any discrepancy between fingerstick and venous samples would only bias the results if the measures used differed over the birth weight distribution.

Details of LDL and HDL levels would have enhanced the analysis but were not available. Breastfeeding has been associated with lower levels of total cholesterol in adulthood [START_REF] Owen | Infant feeding and blood cholesterol: a study in adolescents and a systematic review[END_REF] and infant feeding type could have provided an interesting addition to the analysis. Feeding type was recorded but was highly correlated with age, with older individuals in the cohort being far more likely to have been breastfed than younger ones. Feeding type was therefore not included in the analysis.

Individuals in this study were self-selected and may have participated in a health screening, as they were particularly health conscious but equally may have been prompted by a real concern over their health. The opportunity for a cardiovascular screening was taken by around 75% of those eligible.

The study population comprised only a small sample of the Walker cohort. However, it was broadly similar to the remaining Walker cohort, especially regarding birth weight distribution. It was, however, skewed towards social classes 3, 4 and 5 in adulthood, but importantly these groups are often underrepresented in longitudinal studies where individuals are traced in adulthood and invited to participate in research studies.

The results of this study suggest no difference in the relationship between birth weight and total cholesterol for males and females. They also suggest only a minor role for birth weight in directly predicting adult cholesterol levels, though it may have a role in its correlation with adult weight and therefore indirectly with cholesterol. Risk factors in adulthood appear to have a greater impact in determining total cholesterol levels.

Table 1

 1 Demographic details of study population by males and females

	Males (n = 644)	Females (n = 514)	p-value a

IQR, interquartile range; u/w, units per week. a t-test, Wilcoxon or chi-squared test. b Current smokers only.

Table 2

 2 Regression analyses of the effect of birth weight and adult BMI on total cholesterol

		Males (n = 644)	p	Females (n = 514)	p	All (n = 1158)	p
		β (95% CI)		β (95% CI)		β (95% CI)
	Early life model
	Birth weight (+1 kg) a	-0.06 (-0.21, 0.09)	0.3	-0.12 (-0.27, 0.03)	0.1	-0.08 (-0.19, 0.03)	0.1
	Early life adjusted
	Birth weight (+1 kg) b	-0.07 (-0.23, 0.09)	0.3	-0.15 (-0.32, 0.02)	0.07	-0.10 (-0.21, 0.02)	0.08
	Later life model
	BMI (+ 1) c	0.06 (0.04, 0.09)	<0.0001	0.04 (0.02, 0.05)	<0.0001	0.05 (0.04, 0.06)	<0.0001
	Early and later life models combined
	Birth weight (+1 kg) d	-0.11 (-0.03, 0.04)	0.1	-0.15 (-0.31, 0.01)	0.07	-0.13 (-0.24, -0.01)	0.03
	Gestation (+ 1 week)	0.02 (-0.02, 0.06)	0.3	0.02 (-0.02, 0.06)	0.3	0.02 (-0.009, 0.05)	0.2
	Age (+ 1 year)	0.05 (0.03, 0.06)	<0.0001	0.02 (0.00, 0.03)	0.04	0.03 (0.02, 0.05)	<0.0001
	BMI (+ 1)	0.07 (0.05, 0.09)	<0.0001	0.04 (0.02, 0.06)	<0.0001	0.05 (0.04, 0.07)	<0.0001
	Cigarettes (+10 per day)	0.17 (0.08, 0.25)	<0.0001	0.08 (-0.03, 0.18)	0.2	0.12 (0.05, 0.18)	<0.0001
	Total units alcohol	-0.006 (-0.10, -0.002) 0.008	-0.02 (-0.03, -0.003)	0.01	-0.006 (-0.01, -0.002) 0.002
	(+1 unit per week)
	Social class
	3: non-manual vs 1 & 2	0.19 (-0.02, 0.42)	0.08	-0.01 (-0.47, 0.18)	0.8	0.08 (-0.05, 0.22)	0.2
	3: manual vs 1 & 2	0.09 (-0.11, 0.28)	0.3	-0.15 (-0.47, 0.18)	0.3	0.01 (-0.15, 0.17)	0.8
	4 & 5 vs 1 & 2	0.01 (0.20, 0.23)	0.9	-0.04 (-0.33, 0.25)	0.8	-0.02 (-0.19, 0.15)	0.8
	Family history of CVD (yes vs	0.04 (-0.11, 0.18)	0.6	0.67 (-0.18, 0.12)	0.7	0.008 (-0.09, 0.11)	0.8
	no)
	Sex (males vs females)	-		-		0.15 (-0.03, 0.22)	0.1

a Unadjusted. b Adjusted for gestation and age (also adjusted for sex for all individuals). c Adjusted for age (and sex for all individuals). d Birth weight adjusted for all covariates.

Vascular Medicine 2008; 13: 271-274

Acknowledgements

The study was funded by a grant from the SHARP charity which initiated and collected the data for the SHARP cohort.


Olusegun Osinbowale
email: oosinbowale@ochsner.org

John R Bartholomew

Rectus sheath hematoma

Keywords: abdominal compartment syndrome, abdominal pain, anticoagulation, rectus sheath hematoma

Rectus sheath hematoma (RSH) is a known complication of anticoagulation therapy and a source of potential morbidity and mortality. Early diagnosis and appropriate treatment may help to prevent complications including hemodynamic instability, the abdominal compartment syndrome or multiorgan dysfunction. Although the diagnosis can be made clinically, it can be confirmed with computed tomography of the abdomen. Most patients can be managed conservatively; however, it is often necessary to suspend anticoagulation in the acute setting. Rectus sheath hematoma is not a contraindication to resuming anticoagulation once the hematoma has been adequately managed and the patient has returned to a stable clinical baseline.

Introduction

Rectus sheath hematoma is an uncommon complication of anticoagulation that generally presents as sudden onset of abdominal pain. Prompt recognition, diagnosis and treatment are essential to minimize further complications including hemodynamic instability, the abdominal compartment syndrome, multiorgan dysfunction and death. Depending on the severity and presentation, most patients may resume anticoagulation within 1-2 weeks following a full recovery.

Case presentation

A 66-year-old male presented to the emergency department (ED) with progressive dyspnea, lowgrade fever, an intermittent cough and right upper quadrant pain. He had a past medical history of peripheral artery disease (PAD), the antiphospholipid syndrome (APS) and mesenteric ischemia requiring long-term total parenteral nutrition (TPN). He was on lifelong anticoagulation for a previous history of pulmonary embolism and super-ior vena cava thrombosis and APS. His surgical history included a partial bowel resection.

On physical examination, he was afebrile (98.9°F), his blood pressure was 120/60 mmHg, pulse rate was 90 and respirations were 20 per minute. He was alert but chronically ill-appearing. He had a 2/6 systolic murmur with a regular rhythm and a tunneled catheter (for his total parenteral nutrition) was present on his right upper chest wall. His lungs were clear to auscultation; however, his abdomen was tender to palpation in both upper quadrants. Bowel sounds were present and no palpable masses or organomegaly were noted. His legs were unremarkable with normal pulses. Computed axial tomography (CT) of the chest was performed in the ED and reported new thrombosis in his superior vena cava extending into the azygous vein and chronic extensive upper lung peribronchovascular ground-glass opacities consistent with a pneumonitis. An abdominal CT scan revealed diverticulosis in the sigmoid colon without evidence of diverticulitis.

The patient was admitted for intravenous antibiotics for suspected line infection. His coumadin was held due to a supratherapeutic international normalized ratio (INR) (Table 1). Over the next few days he improved slowly but continued to complain of an intermittent cough, present for the last 2 weeks. His tunneled catheter was removed on hospital day 4, but the following day there was sudden worsening and a change in the character of his abdominal pain. Surgical consultation noted a diffusely tender abdomen with a palpable left upper quadrant mass. On repeat physical examination, there was no ecchymosis or erythema but his bowel sounds were now hypoactive. A repeat CT scan of the abdomen demonstrated a 17 × 13 × 17 cm mixed attenuation left upper quadrant collection displacing his spleen and left kidney and a left upper quadrant 5 × 9 × 16 cm rectus sheath hematoma (Figures 123).

Discussion

Rectus sheath hematoma (RSH) was considered the most likely diagnosis for this patient's abdominal pain. His admission CT was negative for RSH (Figures 4 and 5); a repeat CT scan was performed to characterize, confirm and classify the extent of his hematoma and to determine whether any intraabdominal organs were involved. Berna, et al. have published a classification system (Grades I-III) for RSH as determined by CT imaging (Table 2). [START_REF] Berna | Rectus sheath hematoma: diagnostic classification by CT[END_REF][START_REF] Berna | Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy[END_REF] Our patient had a Grade I hematoma. Hematoma grade has several clinical implications. First, knowledge of RSH grade aids practitioners in assessing patient risk and anticipating potential complications. Berna's 2000 paper describes that patients with Grade III hematomas were the most likely to require blood products, either to replace volume or reverse effects of anticoagulation. Notwithstanding improve-ments in blood product screening and handling, risks of infection, transfusion reactions and issues of anxiety prevail. Additionally, anticoagulated patients with Grades II and III RSH are likely to require anticoagulation reversal, which carries a theoretical risk of new venous thromboembolism in patients with thrombophilia, although this risk is not well documented in the medical literature. Hospital stay is longest in patients with Grade III RSH; Berna reports hospital stays of 10-16 days in these patients compared to 1-10 days in Grade II RSH patients. [START_REF] Berna | Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy[END_REF] Finally, various complications from bleeding have been reported. These complications are more apt to occur with higher RSH grades and include muscle necrosis, hypovolemic shock, cardiac arrhythmias, myocardial infarction and abdominal compartment syndrome. They carry increased morbidity and mortality risk in the acute setting, not to mention the additional healthcare costs. Even so, once clinically stabilized, most patients may safely resume therapeutic anticoagulation in a supervised setting within 1-2 weeks of RSH. [START_REF] Berna | Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy[END_REF] Risk factors for RSH include anticoagulation, trauma, repeated Valsalva maneuvers, hypertension, coughing and elderly individuals. [START_REF] Titone | Spontaneous' hematoma of the rectus abdominis muscle: critical review of 50 cases with emphasis on early diagnosis and treatment[END_REF] Associated signs include pain, a low-grade fever, tachycardia, abdominal guarding, and ecchymoses. Laboratory findings may demonstrate a decrease in the hemoglobin level, although this may be misleading early in the course. Leukocytosis, thrombocytosis and prolonged clotting studies in patients on oral anticoagulation may also be present. Although a palpable abdominal wall mass is a very specific finding for RSH, this is not always apparent, particularly with bilateral hematomas. The examiner should also be aware of several physical signs of RSH including Cullen's sign, Grey-Turner's sign, Carnett's sign and Fothergill's sign (Table 3). Carnett's sign, also known as the abdominal wall test, has been shown to be up to 95% specific for an isolated abdominal wall process. [START_REF] Thomson | Abdominal-wall tenderness: a useful sign in the acute abdomen[END_REF] Ultrasound may also be useful in the diagnosis but with less sensitivity, ranging from 70% to 90% in published reviews. Computed axial tomography of the abdomen is useful in excluding other intra-abdominal processes and is the gold standard with virtually 100% sensitivity and specificity for RSH. [START_REF] Berna | Rectus sheath hematoma: diagnostic classification by CT[END_REF][START_REF] Berna | Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy[END_REF][START_REF] Cherry | Rectus sheath hematoma: review of 126 cases at a single institution[END_REF][START_REF] Gallego | Ultrasonography and computed tomography reduce unnecessary surgery in abdominal rectus sheath haematoma[END_REF] Epidemiologically, RSH demonstrates a male: female ratio of 1:2-3 and primarily occurs between the ages of 50 and 60 years. It accounts for 1.5-2% of cases of unexplained abdominal pain and may occur more often in the right lower quadrant for reasons that have not been elucidated in published reviews. This predilection for the lower abdominal quadrants may be due in part to anatomic considerations as most cases of RSH involve the superior and inferior epigastric vessels, which run along the posterior border of the rectus muscle. The superior portions of the rectus muscle are covered completely by a sheath stemming from aponeuroses of the internal and external oblique abdominal wall muscles and the transversalis muscle, but there may be a deficiency of this sheath below the linea semicircularis or arcuate line of Douglas, an area between the umbilicus and the pubic symphysis. This allows a large RSH to extend intraperitoneally by path of least resistance.

A proper and rapid diagnosis is important to outcomes, as mortality risk from RSH is 4% overall, but may be as high as 25% in patients on anticoagulation. Higher mortality rates (up to two to three times that of the average risk patient) have also been documented in pregnant women. [START_REF] Luhmann | Rectus sheath hematoma: a series of unfortunate events[END_REF] Most patients can be managed conservatively with intravenous fluid resuscitation, pain management, withholding anticoagulants and a gradual increase in their activity. [START_REF] Cherry | Rectus sheath hematoma: review of 126 cases at a single institution[END_REF][START_REF] Luhmann | Rectus sheath hematoma: a series of unfortunate events[END_REF][START_REF] O'mara | Abdominal compartment syndrome as a consequence of rectus sheath hematoma[END_REF][START_REF] Costello | Rectus sheath haematoma: 'a diagnostic dilemma?[END_REF] Some cases may require blood Table 2 CT classification of rectus sheath hematoma [START_REF] Berna | Rectus sheath hematoma: diagnostic classification by CT[END_REF][START_REF] Berna | Conservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy[END_REF] Grade I Mild RSH that is intramuscular, unilateral, and does not dissect along fascia adjacent to the rectus muscle Grade II Moderate RSH that is intramuscular, dissects along adjacent fascia and may involve bilateral rectus muscles but without extension into the prevesical space Grade III

Severe RSH that dissects along the fascia and extends into the peritoneum and the prevesical space transfusion products and vitamin K to reverse their anticoagulation and to optimize hemodynamic stability, while the more serious cases require intensive care unit monitoring and may result in tissue necrosis due to hypoperfusion. [START_REF] Dineen | Small bowel infarction complicating rectus sheath haematoma in an anticoagulated patient[END_REF] Patients may also develop abdominal hypertension which may progress to the abdominal compartment syndrome (ACS) and an increased risk of significant morbidity or death. [START_REF] Luhmann | Rectus sheath hematoma: a series of unfortunate events[END_REF][START_REF] Sieh | Intra-abdominal hypertension and abdominal compartment syndrome[END_REF] When a bleeding vessel is identified in a patient suitable for intervention, catheter-based arterial embolization or laparotomy with vessel ligation and evacuation of the hematoma can improve the outcome. [START_REF] Rimola | Percutaneous arterial embolization in the management of rectus sheath hematoma[END_REF] Acute compartment syndrome is characterized by increased intra-abdominal pressure, which is seen most often with abdominal trauma and may lead to end-organ hypoperfusion. It represents a difficult situation due to additional diagnostic and therapeutic challenges. It is critical to maintain vigilance for this complication by recognizing signs of intraabdominal hypertension and to recruit the assistance of experienced specialists in its management. The ability to cause end-organ dysfunction that progresses to multisystem organ failure within several hours to days makes ACS the most dreaded complication of RSH. Thus, the presence of intraabdominal hypertension should prompt a more aggressive approach to management. Normal intra-abdominal pressure is zero, although it may increase slowly (i.e. over several weeks and months) without significant risk of ACS in chronic conditions such as pregnancy or ascites. [START_REF] Sieh | Intra-abdominal hypertension and abdominal compartment syndrome[END_REF] Physiological derangements in ACS include impaired venous return, elevated diaphragm, increased intrathoracic pressure, decreased cardiac preload and increased peripheral vascular resistance mostly occurring over a time frame of several hours. Tissue hypoperfusion is further exacerbated by impaired cardiac output and cardiopulmonary dysfunction. Compen-satory mechanisms of tachycardia and tachypnea may only be briefly sustainable, particularly in a patient with poor reserve or who is acutely anemic from high-grade RSH or other recent blood loss, and the patient's condition may worsen as long as ACS is not recognized and addressed.

Clinical signs of ACS include oliguria, decreased cardiac output, alterations in minute ventilation, intracranial hypertension and altered splanchnic blood flow. The diagnosis can be confirmed using indwelling catheter manometry of the bladder to measure the intra-abdominal pressure. In most published reviews, the causes of death in RSH include multiple organ failure as a result of hemodynamic compromise; acute renal failure related to hypovolemic shock; and worsening of chronic cardiac failure in the setting of hemodynamic instability. [START_REF] Luhmann | Rectus sheath hematoma: a series of unfortunate events[END_REF][START_REF] O'mara | Abdominal compartment syndrome as a consequence of rectus sheath hematoma[END_REF][START_REF] Orlando | The abdominal compartment syndrome[END_REF] Although the incidence of abdominal compartment syndrome in RSH is unknown, ACS may occur in 5.5% to 35% of trauma patients with intraperitoneal injury. Management of ACS varies with grade or severity. Even after surgical decompression, patients remain at risk for complications related to the surgical wound and infection; mortality rates may be as high as 50% in cases of an open abdomen after decompressive laparotomy. [START_REF] Orlando | The abdominal compartment syndrome[END_REF] The surgical literature advocates use of an ACS grading system based on the level of intra-abdominal hypertension and organ dysfunction to determine optimal timing of surgical decompression, with intra-abdominal pressures above 25 mmHg defining Grades III and IV ACS. [START_REF] O'mara | Abdominal compartment syndrome as a consequence of rectus sheath hematoma[END_REF][START_REF] Sieh | Intra-abdominal hypertension and abdominal compartment syndrome[END_REF][START_REF] Meldrum | Prospective characterization and selective management of the abdominal compartment syndrome[END_REF]

Conclusion

Our patient was managed conservatively, although he did require two units of packed red blood cells and reversal of his supratherapeutic INR with oral vitamin K. He likely developed the RSH as a complication of anticoagulation and intermittent coughing. His creatinine normalized with fluid resuscitation and he did not develop any other signs of multisystem organ failure. He was discharged on therapeutic subcutaneous low-molecular weight heparin to continue treatment of his APS, with plans for eventual return to coumadin.

In summary, sudden abdominal pain has a multitude of potential causes, including RSH, acute mesenteric ischemia, acute volvulus, bowel herniation with incarceration or strangulation, hollow viscous perforation, acute appendicitis, ureteral or choledochal lithiasis, referred pain from acute myocardial ischemia, pulmonary infarction, pneumonia and acute esophageal spasm. Early diagnosis and appropriate management of these conditions is critical to optimal patient outcomes. [START_REF] Edlow | Rectus sheath hematoma[END_REF] Table 3 Physical exam signs in rectus sheath hematoma [START_REF] Thomson | Abdominal-wall tenderness: a useful sign in the acute abdomen[END_REF][START_REF] Luhmann | Rectus sheath hematoma: a series of unfortunate events[END_REF][START_REF] Rimola | Percutaneous arterial embolization in the management of rectus sheath hematoma[END_REF] Cullen's sign Cutaneous discoloration in the periumbilical area in cases of hemorrhage in or around the retroperineum or abdominal wall Grey-Turner's sign Cutaneous discoloration in the flank area in cases of abdominal wall or retroperitoneal hemorrhage Fothergill's sign Tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath Carnett's sign Tenderness within the abdominal wall that persists, and does not improve, with head raise

Figure 1

 1 Figure 1 This CT image of the abdomen demonstrates a left-sided RSH (arrow) at the level of the gastric body. Note asymmetry from the contralateral rectus abdominis muscle.

Figure 2

 2 Figure 2 This CT image of the abdomen demonstrates a left-sided RSH (closed arrow) at the level of the kidneys. Note the intramuscular hematocrit signal within the left rectus abdominis muscle body causing a visible asymmetry of the overlying abdominal contour (open arrow).

Figure 3

 3 Figure 3 CT image of the abdomen demonstrating extension of the left-sided RSH (arrow) into the pelvis.

Figure 4

 4 Figure 4 CT image of the same patient on initial presentation demonstrating normal rectus sheaths bilaterally (arrows) and in upper abdomen.

Figure 5

 5 Figure 5 CT image of the same patient on initial presentation demonstrating normal rectus sheaths (arrows) in mid-abdomen.

Table 1

 1 Coagulation results

	Hospital day	INR
	1	4 . 1
	2	5 . 2
	3	6 . 8 a
	4	3 . 3
	5	1 . 9
	INR, international normalized ratio.

a 2.5 mg oral vitamin K given.

Section of Vascular Medicine, Department of Cardiology Ochsner Clinic Foundation, New Orleans, USA;

Department of Hematology & Medical Oncology, Cleveland Clinic Foundation, Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA

Vascular Medicine 2008; 13: 275-279