Michael D. Sosin

Low dose methotrexate and bone marrow suppression

Bone marrow suppression can occur even with low doses of methotrexate Methotrexate is an antimetabolite that, apart from its use in malignant disorders, is taken orally in low doses for the control of conditions such as rheumatoid arthritis and psoriasis. When used in chemotherapy it causes profound suppression of bone marrow. However, even at a low dose it may be associated with bone marrow suppression—particularly in the presence of renal insufficiency or when other drugs are taken concomitantly (box 1). Its unusual weekly dosing regimen can result in dose error by patients or clinicians. We present three cases of bone marrow suppression in patients taking low dose methotrexate who presented at a district general hospital during a period of four years (table). View this table: Details of patients with bone marrow suppression after taking methotrexate ### Case 1 A 78 year old woman with rheumatoid arthritis had been taking a weekly dose of 17.5 mg of methotrexate for two months. Before this the dose had been gradually built up over several years. She was admitted with breathlessness and found to be pancytopenic (haemoglobin concentration 100 g/l, white cell count 3.0 × 109/l, neutrophils 2.5 × 109/l, platelets 13 × 109/l). A month earlier her full blood count had been normal. Methotrexate treatment was discontinued. She was treated with intravenous folinic acid and antibiotics and was given transfusions of blood products. Her blood count showed recovery (haemoglobin concentration 137 g/l, white …

Heart failure—the importance of ethnicity

Heart failure is a major public health problem in the Western world. Aetiological factors involved in its development include hypertension, diabetes, and ischaemic heart disease—all of which differ in prevalence, and possibly mechanism, between patients of differing ethnicity. Unfortunately, epidemiological and therapeutic trials have involved almost exclusively white populations, and evidence from these trials cannot necessarily be assumed to be generalisable to populations that include high proportions of patients from other ethnic origins. This review will discuss the mechanistic and therapeutic differences that exist in heart failure between those of European origin, and patients from the major ethnic minority groups of the UK.

An 8-year follow-up study of acute admissions with heart failure in a multiethnic population

In 1994, we reported a cross‐sectional survey of acute heart failure admissions to a city centre hospital serving a multiethnic population and found ethnic differences in aetiological factors and short‐term (in‐patient) mortality. We analysed long‐term mortality data for this original survey cohort after 8 years’ follow‐up. At 8 years’ follow‐up, the total mortality was 90.5% amongst Europeans and 87.0% amongst non‐Europeans (log rank test, P=0.0705). The non‐European patients had significantly better survival at all time points until 6 years, after which the survival curves start to converge. In univariate analysis, age <75.6 years (that is, the median age of the whole cohort), use of beta‐blockers, use of ACE inhibitors, and absence of atrial fibrillation were significantly associated with increased survival. In addition, patients who had had an echocardiographic examination had significantly prolonged survival when compared to those who did not. Using a Cox multiple regression analysis, age, renal impairment, atrial fibrillation, absence of echocardiography, absence of beta‐blockers or ACE inhibitor use (and not ethnicity) remained significant predictors of mortality at 8 years. While this follow‐up study has suggested that survival following admission for acutely decompensated heart failure is not different between different ethnic groups when corrected for age, it is clear from the younger age of heart failure patients from ethnic minority groups and the relatively high prevalence, that the burden of heart failure is greater in these populations. Future observational and therapeutic trials in heart failure should include sufficient numbers of participants from ethnic minority groups to ensure that the results can be applied to the population at risk.

Elevated angiogenin levels in chronic heart failure

Background. Abnormal indices of angiogenesis have been reported in chronic heart failure (CHF). We tested the hypothesis that circulating angiogenin (a potent inducer of neovascularization in vivo) is higher in CHF patients compared with controls and associated with indices of CHF severity: brain natriuretic peptide (BNP), Simpsons left ventricular ejection fraction (EF), and New York Heart Association (NYHA) class. Methods. Using a cross-sectional approach, we measured serum angiogenin and BNP levels in 109 consecutive patients with CHF (85 males; mean age 60 (standard deviation (SD) 10 yrs) and 112 asymptomatic controls with normal cardiac function and related levels to echocardiographic parameters. Results. Angiogenin was significantly higher in CHF patients compared to controls (P<0.001). On univariate analysis, angiogenin was positively associated with age, plasma glucose, insulin, and BNP (all P<0.001); and negatively correlated with diastolic blood pressure (P=0.04) and EF (P=0.002). Angiogenin levels increased in an ordinal fashion with NYHA class, exaggerated by the presence of diabetes mellitus (pseudo R2=0.15, P<0.001). In multivariate analysis, angiogenin levels were only associated with deteriorating NYHA classification (beta=0.14 (95% confidence interval (CI) 0.09–0.19), P<0.001). Angiogenin was also a modest discriminator for the presence of CHF (area under the curve 0.72; 95% CI 0.62–0.82), P<0.001). Conclusion. Angiogenin is related to worsening heart failure severity (NYHA classification), with the highest levels in NYHA class III. Further research is warranted to determine the validity of angiogenin in a diagnostic and prognostic capacity in CHF.

Hibernating myocardium in heart failure.

Ischemic left ventricular systolic dysfunction may result from myocardial necrosis or from hypocontractile areas of viable myocardium. In some cases, recovery of contractility may occur on revascularization – this reversibly dysfunctional tissue is commonly referred to as hibernating myocardium. Observational data suggest that revascularization of patients with ischemic left ventricular systolic dysfunction and known viable myocardium provides a survival benefit over medical therapy. Identification of viable, dysfunctional myocardium may be especially worthwhile in deciding which patients with ischemic left ventricular systolic dysfunction will benefit from revascularization procedures. Randomized, prospective trials evaluating this are currently ongoing. This review will provide an overview of the complex pathophysiology of viable, dysfunctional myocardium, and will discuss outcomes after revascularization. Of the techniques used to determine the presence of hibernating myocardium, functional methods such as stress echocardiography and cardiac magnetic resonance appear more specific, but less sensitive, than the nuclear modalities, which assess perfusion and metabolic activity. Currently, the availability of all methods is variable.

Carbimazole-induced lupus

We describe the case of a 50-year-old lady admitted with a 3-week history of dyspnoea and left-sided pleuritic pain associated with pleural effusion. This common clinical picture nevertheless gave rise to a significant diagnostic challenge. The medical history included a diagnosis of thyrotoxicosis made 6 months previously that was being treated with carbimazole by her general practitioner. Key-investigation results were as follows: (1) pleural fluid was sterile and exudative, with no malignant cells, (2) erythrocyte sedimentation rate, C reactive protein and D-dimer were raised, (3) antinuclear antibody, anti-dsDNA and antihistone antibodies were newly positive, (4) imaging revealed a large left ventricular mass consistent with thrombus in the absence of evidence of a myocardial infarction. Based on the above investigations we hypothesised that carbimazole had induced systemic lupus erythematosus, manifesting as serositis resulting in an exudative pleural effusion and a proinflammatory/prothrombotic state. Carbimazole was stopped. The patients pleural effusion completely resolved and she remains asymptomatic.

Markers of thrombosis and hemostasis in acute coronary syndromes: relationship to increased heart rate and reduced heart-rate variability.

Acute coronary syndromes (ACS) are characterized by abnormal heart‐rate variability (HRV) and biomarkers of endothelial damage and thrombosis.

Plasma indices of angiogenesis in rheumatoid disease: relationship to cardiovascular risk factors and cardiac function.

INTRODUCTION Rheumatoid Disease (RD) is associated with increased rates of cardiovascular disease (CVD). Angiogenesis is central to RD, and well-recognized in CVD. We hypothesised that plasma levels of two indices associated with angiogenesis, vascular endothelial growth factor (VEGF) and angiogenin, would be higher among RD patients compared to healthy controls (HC), would relate to CVD risk factors, calculated 10-year coronary heart disease (CHD) and stroke risk scores. METHODS 144 clinic patients with established RD and 63 HC were recruited in a cross-sectional study. RD patients were grouped according to the presence (RD-CVD, n=73 or absence (non-CVD RD; n=71) of CVD risk factors. Angiogenin and VEGF levels were quantified by ELISA. RESULTS There were no significant differences for VEGF or angiogenin, between RD-CVD, non-CVD RD and HC groups (p=NS). Calculated risks for both CHD (p=0.017) and stroke (p=0.016) were higher when RD-CVD was compared to non-CVD RD and HC. Upon multivariate analysis, methotrexate use (p=0.006) and prior mycocardial infarction (MI) (p=0.034) were associated with higher angiogenin levels; body mass index (BMI) (p=0.034) and presence of RD (p=0.029) itself predicted lower levels. For RD patients, serum creatinine (p<0.001) and CRP levels, VEGF levels, and NSAID/COX2 inhibitor use (all p<0.05) were independently associated with CHD risk; plasma VEGF and serum creatinine levels were independently associated with stroke risk (p<0.05). CONCLUSIONS Although levels of angiogenin were not significantly different between HC and RD patients, RD may have some influence on their variation. Methotrexate use and prior MI predicted higher angiogenin levels, whilst levels of VEGF were negatively associated with 10-year CHD and stroke risk.

Plasma indices of endothelial and platelet activation in Rheumatoid Disease: Relationship to cardiovascular co-morbidity

BACKGROUND Rheumatoid Disease (RD) is associated with ischaemic heart disease (IHD). We sought to investigate whether abnormalities of endothelial function and platelet activation in patients with established RD were related to co-morbid cardiovascular risk factors. METHODS In a cross-sectional study, RD patients with no cardiac risk factors and normal cardiac function (RD, n=73), those with cardiovascular disease or risk factors and normal cardiac function (RD-risk, n=59), and those with left ventricular systolic dysfunction (RD-LVSD, n=21) were recruited, and compared to healthy controls (HC, n=76). Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction), soluble E-selectin (sE-sel, a marker of endothelial activation), and soluble P-selectin (sP-sel, an index of platelet activation) were studied. RESULTS Plasma levels of vWF and sP-sel (but not sE-sel) were significantly higher among 153 RD patients compared to controls (p=0.002 and p<0.001, respectively). Levels of vWF progressively rose with increasing cardiovascular risk across the four subgroups (p for trend<0.001). Previous IHD was independently associated with vWF levels, and diabetes mellitus (DM) was similarly associated with all three markers. RD itself and beta-blocker use were associated with sP-sel. CONCLUSION Plasma levels of vWF and sP-sel are higher among RD patients. Levels of vWF were particularly influenced by cardiac risk factor status, and associated with known IHD and DM.

Rheumatoid disease and the heart: from epidemiology to echocardiography.

Rheumatoid disease (RD) is a common chronic inflammatory condition associated with progressive joint destruction. Sufferers of RD experience reduced life expectancy, reflected in the increased standardised mortality rates reported in several studies over the last 50 years. Most studies indicate that the increased mortality affecting this population is mainly due to cardio-vascular disease. Epidemiological data have revealed an increased risk of developing ischaemic heart disease and heart failure in RD. The increased risk of ischaemic heart disease may result from traditional risk factors but data suggest that RD may confer risk independently. Although pericardial involvement, valvopathy and myocarditis are the most well-recognised cardiac manifestations of RD, and constitute a rheumatoid heart disease, these features are relatively benign. The current prevalence of rheumatoid heart disease in the era of early administration of disease-modifying therapy requires evaluation.